Artificial Shear Stress Effects on Leukocytes at a Biomaterial Interface

Medical devices, such as ventricular assist devices (VADs), introduce both foreign materials and artificial shear stress to the circulatory system. The effects these have on leukocytes and the immune response are not well understood. Understanding how these two elements combine to affect leukocytes may reveal why some patients are susceptible to recurrent device-related infections and provide insight into the development of pump thrombosis. Biomaterials - DLC: diamond-like carbon coated stainless steel; Sap: single-crystal sapphire; and Ti: titanium alloy (Ti6Al4V) were attached to the parallel plates of a rheometer. Whole human blood was left between the two discs for 5 min at +37°C with or without the application of shear stress (0s-1 or 1000s-1). Blood was removed and used for: complete blood cell counts; flow cytometry (leukocyte activation; cell death; microparticle generation; phagocytic ability; and reactive oxygen species (ROS) production); and the production of pro-inflammatory cytokines. L-selectin expression on monocytes was decreased when blood was exposed to the biomaterials both with and without shear. Applying shear stress to blood on a Sap and Ti surface led to activation of neutrophils shown as decreased L-selectin expression. Sap and Ti blunted the LPS-stimulated macrophage migration inhibitory factor (MIF) production, most notably when sheared on Ti.The biomaterials used here have been shown to activate leukocytes in a static environment. The introduction of shear appears to exacerbate this activation. Interestingly, a widely accepted biocompatible material (Ti) utilised in many different types of devices, has the capacity for immune cell activation and inhibition of MIF secretion when combined with shear stress. These findings contribute to our understanding of the contribution of biomaterials and shear stress to recurrent infections and vulnerability to sepsis in some VAD patients as well as pump thrombosis

Molecular characteristics of long-term epilepsy-associated tumours (LEATs) and mechanisms for tumour-related epilepsy (TRE)

Brain tumours are the second most common cause of seizures identified in epilepsy surgical series. While any tumour involving the brain has the potential to cause seizures, specific subtypes are more frequently associated with epilepsy. Tumour-related epilepsy has a profound impact on patients with brain tumours and these seizures are often refractory to anti-epileptic treatments, resulting in long-term disability and patient morbidity. Despite the drastic impact epilepsy-associated tumours have on patients, they have not traditionally enjoyed as much attention as more malignant neoplasms. However, recently a number of developments have been achieved towards furthering our understanding of the molecular and developmental backgrounds of specific epilepsy associated tumours. In addition, the past decade has seen an expansion in the literature on the pathophysiology of tumour-related epilepsy. In this review, we aim to summarise the mechanisms by which tumours may cause seizures and detail recent data regarding the pathogenesis of specific developmental epilepsy-associated tumours. This article is protected by copyright. All rights reserved

Network analysis of host-virus communities in bats and rodents reveals determinants of cross-species transmission.

Bats are natural reservoirs of several important emerging viruses. Cross-species transmission appears to be quite common among bats, which may contribute to their unique reservoir potential. Therefore, understanding the importance of bats as reservoirs requires examining them in a community context rather than concentrating on individual species. Here, we use a network approach to identify ecological and biological correlates of cross-species virus transmission in bats and rodents, another important host group. We show that given our current knowledge the bat viral sharing network is more connected than the rodent network, suggesting viruses may pass more easily between bat species. We identify host traits associated with important reservoir species: gregarious bats are more likely to share more viruses and bats which migrate regionally are important for spreading viruses through the network. We identify multiple communities of viral sharing within bats and rodents and highlight potential species traits that can help guide studies of novel pathogen emergence.This work was supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate (US Department of Homeland Security) and the Fogarty International Center (National Institutes of Health). D.T.S.H. acknowledges funding from a David H. Smith post-doctoral fellowship. A.A.C. is partially funded by a Royal Society Wolfson Research Merit award, and J.L.N.W. is supported by the Alborada Trust. Thanks to Paul Cryan and Michael O'Donnell of the USGS Fort Collins Science Center for help with species distribution analyses.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/ele.1249

Support for viral persistence in bats from age-specific serology and models of maternal immunity.

Spatiotemporally-localised prediction of virus emergence from wildlife requires focused studies on the ecology and immunology of reservoir hosts in their native habitat. Reliable predictions from mathematical models remain difficult in most systems due to a dearth of appropriate empirical data. Our goal was to study the circulation and immune dynamics of zoonotic viruses in bat populations and investigate the effects of maternally-derived and acquired immunity on viral persistence. Using rare age-specific serological data from wild-caught Eidolon helvum fruit bats as a case study, we estimated viral transmission parameters for a stochastic infection model. We estimated mean durations of around 6 months for maternally-derived immunity to Lagos bat virus and African henipavirus, whereas acquired immunity was long-lasting (Lagos bat virus: mean 12 years, henipavirus: mean 4 years). In the presence of a seasonal birth pulse, the effect of maternally-derived immunity on virus persistence within modelled bat populations was highly dependent on transmission characteristics. To explain previous reports of viral persistence within small natural and captive E. helvum populations, we hypothesise that some bats must experience prolonged infectious periods or within-host latency. By further elucidating plausible mechanisms of virus persistence in bat populations, we contribute to guidance of future field studies

Raltitrexed (Tomudex) administration in patients with relapsed metastatic colorectal cancer after weekly irinotecan/5-Fluorouracil/Leucovorin chemotherapy

PURPOSE: The present study aimed at evaluating the efficacy of Raltitrexed, a specific thymidilate synthase inhibitor, in patients with advanced colorectal cancer (ACC) in relapse (>8 weeks) after a prior response or disease stabilization to first-line chemotherapy combination with lrinotecan+5-Fluorouracil (5-FU)+Leucovorin (LV). METHODS: Twenty-five patients with metastatic ACC entered; 17 males/8 females, median age 61 (range: 47–70), median Karnovsky PS: 80 (70–90), and sites of metastases; liver: 21, lung: 4, lymph nodes: 7, peritoneal: 5 and a life expectancy of at least 3 months, were entered in the present pilot study. All patients had progressed after prior chemotherapy with lrinotecan+5-FU+LV. Raltitrexed was administered at a dose of 3 mg/m(2) i.v. every 21 days. RESULTS: Three patients (12%) achieved a partial response (PR), 8 (32%) had stable disease (SD), and the remaining 14 (56%) developed progressive disease (PD). Median time-to-progression (TTP) was 5.5 months (range, 2–8.5), and median overall survival (OS) 8 months (range, 4.0–12.5). Toxicity was generally mild; it consisted mainly of myelosuppression; neutropenia grade 1–2: 52%-grade 3: 28%, and anemia grade 1–2 only: 36%. Mild mucositis grade 1–2 occured in 13.5% of patients and was the principal non-hematologic toxicity. CONCLUSION: Response to treatment with Raltitrexed is limited in patients with ACC failing after an initial response or non-progression to the weekly lrinotecan+5-FU+LV combination. However, it appears that a limited number of patients with PR/SD may derive clinical benefit, but final proof would require a randomized study

An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays

Bat trait, genetic and pathogen data from large-scale investigations of African fruit bats, Eidolon helvum.

Bats, including African straw-coloured fruit bats (Eidolon helvum), have been highlighted as reservoirs of many recently emerged zoonotic viruses. This common, widespread and ecologically important species was the focus of longitudinal and continent-wide studies of the epidemiological and ecology of Lagos bat virus, henipaviruses and Achimota viruses. Here we present a spatial, morphological, demographic, genetic and serological dataset encompassing 2827 bats from nine countries over an 8-year period. Genetic data comprises cytochrome b mitochondrial sequences (n=608) and microsatellite genotypes from 18 loci (n=544). Tooth-cementum analyses (n=316) allowed derivation of rare age-specific serologic data for a lyssavirus, a henipavirus and two rubulaviruses. This dataset contributes a substantial volume of data on the ecology of E. helvum and its viruses and will be valuable for a wide range of studies, including viral transmission dynamic modelling in age-structured populations, investigation of seasonal reproductive asynchrony in wide-ranging species, ecological niche modelling, inference of island colonisation history, exploration of relationships between island and body size, and various spatial analyses of demographic, morphometric or serological data.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/sdata.2016.4

Computer-Based Interventions for Problematic Alcohol Use:a Review of Systematic Reviews

PURPOSE: The aim of this review is to provide an overview of knowledge and knowledge gaps in the field of computer-based alcohol interventions by (1) collating evidence on the effectiveness of computer-based alcohol interventions in different populations and (2) exploring the impact of four specified moderators of effectiveness: therapeutic orientation, length of intervention, guidance and trial engagement.  METHODS: A review of systematic reviews of randomized trials reporting on effectiveness of computer-based alcohol interventions published between 2005 and 2015.  RESULTS: Fourteen reviews met the inclusion criteria. Across the included reviews, it was generally reported that computer-based alcohol interventions were effective in reducing alcohol consumption, with mostly small effect sizes. There were indications that longer, multisession interventions are more effective than shorter or single session interventions. Evidence on the association between therapeutic orientation of an intervention, guidance or trial engagement and reductions in alcohol consumption is limited, as the number of reviews addressing these themes is low. None of the included reviews addressed the association between therapeutic orientation, length of intervention or guidance and trial engagement.  CONCLUSIONS: This review of systematic reviews highlights the mostly positive evidence supporting computer-based alcohol interventions as well as reveals a number of knowledge gaps that could guide future research in this field

Protocol for faecal microbiota transplantation in ulcerative colitis (FMTUC): a randomised feasibility study

Background The interaction of the gut microbiota with the human host is implicated in the pathogenesis of inflammatory and immunological diseases including ulcerative colitis (UC). Faecal microbiota transplantation (FMT) as a method of restoring gut microbial diversity is of increasing interest as a therapeutic approach in the management of UC. The current literature lacks consensus about the dose of FMT, route of administration and duration of response. Methods and analysis This single-blinded randomised trial will explore the feasibility of FMT in 30 treatment-naïve patients with histologically confirmed distal UC limited to the recto-sigmoid region (up to 40 cm from the anal verge). This study aims to estimate the magnitude of treatment response to FMT under controlled conditions. The intervention (FMT) will be administered by rectal retention enema. It will test the feasibility of randomising patients to: (i) single FMT dose, (ii) five daily FMT doses or (iii) control (no FMT dose). All groups will receive standard antibiotic gut decontamination and bowel preparation before FMT. Recruitment will take place over a 24-month period with a 12-week patient follow-up. Trial objectives include evaluation of the magnitude of treatment response to FMT, investigation of the clinical value of metabolic phenotyping for predicting the clinical response to FMT and testing the recruitment rate of donors and patients for a study in FMT. This feasibility trial will enable an estimate of number of patients needed, help determine optimal study conditions and inform the choice of endpoints for a future definitive phase III study. Ethics and dissemination The trial is approved by the regional ethics committee and is sponsored by Abertawe Bro Morgannwg University’s Health Board. Written informed consent from all patients will be obtained. Serious adverse events will be reported to the sponsor. Trial results will be disseminated via peer review publication and shared with trial participants. Trial registration number ISRCTN58082603; Pre-results