347 research outputs found

    Measles virus causes immunogenic cell death in human melanoma

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    Oncolytic viruses (OV) are promising treatments for cancer, with several currently undergoing testing in randomised clinical trials. Measles virus (MV) has not yet been tested in models of human melanoma. This study demonstrates the efficacy of MV against human melanoma. It is increasingly recognised that an essential component of therapy with OV is the recruitment of host anti-tumour immune responses, both innate and adaptive. MV-mediated melanoma cell death is an inflammatory process, causing the release of inflammatory cytokines including type-1 interferons and the potent danger signal HMGB1. Here, using human in vitro models, we demonstrate that MV enhances innate antitumour activity, and that MV-mediated melanoma cell death is capable of stimulating a melanoma-specific adaptive immune response

    Deppining of a Superfluid Vortex Inside a Circular Defect

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    In this work we study the process of depinning of a quantum of circulation trapped inside a disk by an applied two dimensional superflow. We use the Gross-Pitaevskii model to describe the neutral superfluid. The collective coordinate dynamics is derived directly from the condensate equation of motion, the nonlinear Schroedinger equation, and it is used to obtain an expression for the critical velocity as a function of the defect radius. This expression is compared with a numerical result obtained from the time independent nonlinear Schroedinger equation. Below the critical velocity, we obtain the dependence of the semiclassical nucleation rate with the flow velocity at infinity. Above the critical velocity, the classical vortex depinning is illustrated with a numerical simulation of the time dependent nonlinear Schroedinger equation.Comment: 8 pages, 5 figures, uses revtex and epsf.st

    Risk of infection in type 1 and type 2 diabetes compared with the general population: a matched cohort study

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    OBJECTIVE We describe in detail the burden of infections in adults with diabetes within a large national population cohort. We also compare infection rates between patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM). RESEARCH DESIGN AND METHODS A retrospective cohort study compared 102,493 English primary care patients aged 40–89 years with a diabetes diagnosis by 2008 (n = 5,863 T1DM and n = 96,630 T2DM) with 203,518 age-sex-practice–matched control subjects without diabetes. Infection rates during 2008–2015, compiled from primary care and linked hospital and mortality records, were compared across 19 individual infection categories. These were further summarized as any requiring a prescription or hospitalization or as cause of death. Poisson regression was used to estimate incidence rate ratios (IRRs) between 1) people with diabetes and control subjects and 2) T1DM and T2DM adjusted for age, sex, smoking, BMI, and deprivation. RESULTS Compared with control subjects without diabetes, patients with diabetes had higher rates for all infections, with the highest IRRs seen for bone and joint infections, sepsis, and cellulitis. IRRs for infection-related hospitalizations were 3.71 (95% CI 3.27–4.21) for T1DM and 1.88 (95% CI 1.83–1.92) for T2DM. A direct comparison of types confirmed higher adjusted risks for T1DM versus T2DM (death from infection IRR 2.19 [95% CI 1.75–2.74]). We estimate that 6% of infection-related hospitalizations and 12% of infection-related deaths were attributable to diabetes. CONCLUSIONS People with diabetes, particularly T1DM, are at increased risk of serious infection, representing an important population burden. Strategies that reduce the risk of developing severe infections and poor treatment outcomes are under-researched and should be explored

    The correlation between reading and mathematics ability at age twelve has a substantial genetic component

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    Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children’s ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child’s cognitive abilities at age twelve

    Understanding the epidemiology of avoidable significant harm in primary care:Protocol for a retrospective cross-sectional study

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    Introduction: Most patient safety research has focused on specialist-care settings where there is an appreciation of the frequency and causes of medical errors, and the resulting burden of adverse events. There have, however, been few large-scale robust studies that have investigated the extent and severity of avoidable harm in primary care. To address this, we will conduct a 12-month retrospective cross-sectional study involving case note review of primary care patients. Methods and Analysis: We will conduct electronic searches of general practice (GP) clinical computer systems to identify patients with avoidable significant harm. Up to sixteen general practices from three areas of England (East Midlands, London and the North West) will be recruited based on practice size, to obtain a sample of around 100,000 patients. Our investigations will include an ‘enhanced sample’ of patients with the highest risk of avoidable significant harm. We will estimate the incidence of avoidable significant harm and express this as ‘per 100,000 patients per year’. Univariate and multivariate analysis will be conducted to identify the factors associated with avoidable significant harm. Ethics/Dissemination: The decision regarding participation by general practices in the study is entirely voluntary; the consent to participate may be withdrawn at any time. We will not seek individual patient consent for the retrospective case note review, but if patients respond to publicity about the project and say they do not wish their records to be included we will follow these instructions. We will produce a report for the Department of Health’s Policy Research Programme and several high-quality peer-reviewed publications in scientific journals. The study has been granted a favourable opinion by the East Midlands Nottingham 2 Research Ethics Committee (reference 15/EM/0411) and Confidentiality Advisory Group approval for access to medical records without consent under section 251 of the NHS Act 2006 (reference 15/CAG/0182)

    Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes

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    <p>Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.</p> <p>Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.</p> <p>Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.</p&gt

    People of the British Isles: preliminary analysis of genotypes and surnames in a UK control population

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    There is a great deal of interest in fine scale population structure in the UK, both as a signature of historical immigration events and because of the effect population structure may have on disease association studies. Although population structure appears to have a minor impact on the current generation of genome-wide association studies, it is likely to play a significant part in the next generation of studies designed to search for rare variants. A powerful way of detecting such structure is to control and document carefully the provenance of the samples involved. Here we describe the collection of a cohort of rural UK samples (The People of the British Isles), aimed at providing a well-characterised UK control population that can be used as a resource by the research community as well as providing fine scale genetic information on the British population. So far, some 4,000 samples have been collected, the majority of which fit the criteria of coming from a rural area and having all four grandparents from approximately the same area. Analysis of the first 3,865 samples that have been geocoded indicates that 75% have a mean distance between grandparental places of birth of 37.3km, and that about 70% of grandparental places of birth can be classed as rural. Preliminary genotyping of 1,057 samples demonstrates the value of these samples for investigating fine scale population structure within the UK, and shows how this can be enhanced by the use of surnames

    Book reviews

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    Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45784/1/11153_2004_Article_BF00140614.pd
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