Inhibition of SLPI ameliorates disease activity in experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>The secretory leukocyte protease inhibitor (SLPI) exerts wide ranging effects on inflammatory pathways and is upregulated in EAE but the biological role of SLPI in EAE, an animal model of multiple sclerosis is unknown</p> <p>Methods</p> <p>To investigate the pathophysiological effects of SLPI within EAE, we induced SLPI-neutralizing antibodies in mice and rats to determine the clinical severity of the disease. In addition we studied the effects of SLPI on the anti-inflammatory cytokine TGF-β.</p> <p>Results</p> <p>The induction of SLPI neutralizing antibodies resulted in a milder disease course in mouse and rat EAE. SLPI neutralization was associated with increased serum levels of TGF-β and increased numbers of FoxP3+ CD4+ T cells in lymph nodes. <it>In vitro</it>, the addition of SLPI significantly decreased the number of functional FoxP3+ CD25^hiCD4+ regulatory T cells in cultures of naive human CD4+ T cells. Adding recombinant TGF-β to SLPI-treated human T cell cultures neutralized SLPI's inhibitory effect on regulatory T cell differentiation.</p> <p>Conclusion</p> <p>In EAE, SLPI exerts potent pro-inflammatory actions by modulation of T-cell activity and its neutralization may be beneficial for the disease.</p

Analysis of reported error in Monte Carlo rendered images

Evaluating image quality in Monte Carlo rendered images is an important aspect of the rendering process as we often need to determine the relative quality between images computed using different algorithms and with varying amounts of computation. The use of a gold-standard, reference image, or ground truth (GT) is a common method to provide a baseline with which to compare experimental results. We show that if not chosen carefully the reference image can skew results leading to significant misreporting of error. We present an analysis of error in Monte Carlo rendered images and discuss practices to avoid or be aware of when designing an experiment

JTT-130, a microsomal triglyceride transfer protein (MTP) inhibitor lowers plasma triglycerides and LDL cholesterol concentrations without increasing hepatic triglycerides in guinea pigs

BACKGROUND: Microsomal transfer protein inhibitors (MTPi) have the potential to be used as a drug to lower plasma lipids, mainly plasma triglycerides (TG). However, studies with animal models have indicated that MTPi treatment results in the accumulation of hepatic TG. The purpose of this study was to evaluate whether JTT-130, a unique MTPi, targeted to the intestine, would effectively reduce plasma lipids without inducing a fatty liver. METHODS: Male guinea pigs (n = 10 per group) were used for this experiment. Initially all guinea pigs were fed a hypercholesterolemic diet containing 0.08 g/100 g dietary cholesterol for 3 wk. After this period, animals were randomly assigned to diets containing 0 (control), 0.0005 or 0.0015 g/100 g of MTPi for 4 wk. A diet containing 0.05 g/100 g of atorvastatin, an HMG-CoA reductase inhibitor was used as the positive control. At the end of the 7(th )week, guinea pigs were sacrificed to assess drug effects on plasma and hepatic lipids, composition of LDL and VLDL, hepatic cholesterol and lipoprotein metabolism. RESULTS: Plasma LDL cholesterol and TG were 25 and 30% lower in guinea pigs treated with MTPi compared to controls (P < 0.05). Atorvastatin had the most pronounced hypolipidemic effects with a 35% reduction in LDL cholesterol and 40% reduction in TG. JTT-130 did not induce hepatic lipid accumulation compared to controls. Cholesteryl ester transfer protein (CETP) activity was reduced in a dose dependent manner by increasing doses of MTPi and guinea pigs treated with atorvastatin had the lowest CETP activity (P < 0.01). In addition the number of molecules of cholesteryl ester in LDL and LDL diameter were lower in guinea pigs treated with atorvastatin. In contrast, hepatic enzymes involved in maintaining cholesterol homeostasis were not affected by drug treatment. CONCLUSION: These results suggest that JTT-130 could have potential clinical applications due to its plasma lipid lowering effects with no alterations in hepatic lipid concentrations

Guidelines and mindlines: why do clinical staff over-diagnose malaria in Tanzania? A qualitative study

BACKGROUND: Malaria over-diagnosis in Africa is widespread and costly both financially and in terms of morbidity and mortality from missed diagnoses. An understanding of the reasons behind malaria over-diagnosis is urgently needed to inform strategies for better targeting of antimalarials. METHODS: In an ethnographic study of clinical practice in two hospitals in Tanzania, 2,082 patient consultations with 34 clinicians were observed over a period of three months at each hospital. All clinicians were also interviewed individually as well as being observed during routine working activities with colleagues. Interviews with five tutors and 10 clinical officer students at a nearby clinical officer training college were subsequently conducted. RESULTS: Four, primarily social, spheres of influence on malaria over-diagnosis were identified. Firstly, the influence of initial training within a context where the importance of malaria is strongly promoted. Secondly, the influence of peers, conforming to perceived expectations from colleagues. Thirdly, pressure to conform with perceived patient preferences. Lastly, quality of diagnostic support, involving resource management, motivation and supervision. Rather than following national guidelines for the diagnosis of febrile illness, clinician behaviour appeared to follow 'mindlines': shared rationales constructed from these different spheres of influence. Three mindlines were identified in this setting: malaria is easier to diagnose than alternative diseases; malaria is a more acceptable diagnosis; and missing malaria is indefensible. These mindlines were apparent during the training stages as well as throughout clinical careers. CONCLUSION: Clinicians were found to follow mindlines as well as or rather than guidelines, which incorporated multiple social influences operating in the immediate and the wider context of decision making. Interventions to move mindlines closer to guidelines need to take the variety of social influences into account

Entrepreneurs’ achieved success: developing a multi-faceted measure

Firm performance is typically measured via objective financial indicators. However, researchers increasingly acknowledge that entrepreneurs do not measure their success solely in financial terms but that a range of often subjective indicators matter to them. This article contributes to the debate on entrepreneurial performance by studying how entrepreneurs assess their achieved success. ‘Entrepreneurs’ achieved success’ was conceptualized as a multi-faceted construct that includes entrepreneurs’ self-reported achievement of firm performance, workplace relationships, personal fulfilment, community impact, and personal financial rewards. It was measured via the Subjective Entrepreneurial Success–Achievement Scale (SES-AS). Over the course of three studies (N = 390) the factorial structure of ‘entrepreneurs’ achieved success’ was established and largely replicated in two cultures. Based on a nomological network, we documented relationships among ‘entrepreneurs’ achieved success’, quasi-objective indicators of firm performance, and entrepreneurs’ financial satisfaction, creativity, and health. Based on our research, we propose a new conceptual framework to study performance in the context of entrepreneurship. This framework acknowledges both the success criteria that entrepreneurs wish to achieve and those that they actually achieve, and extends our understanding of firm performance

Historical Research Approaches to the Analysis of Internationalisation

Historical research methods and approaches can improve understanding of the most appropriate techniques to confront data and test theories in internationalisation research. A critical analysis of all “texts” (sources), time series analyses, comparative methods across time periods and space, counterfactual analysis and the examination of outliers are shown to have the potential to improve research practices. Examples and applications are shown in these key areas of research with special reference to internationalisation processes. Examination of these methods allows us to see internationalisation processes as a sequenced set of decisions in time and space, path dependent to some extent but subject to managerial discretion. Internationalisation process research can benefit from the use of historical research methods in analysis of sources, production of time-lines, using comparative evidence across time and space and in the examination of feasible alternative choices

Genomic Analysis of Three Metastatic Prostate Cancer Patients with Exceptional Responses to Carboplatin Indicating Different Types of DNA Repair Deficiency.

Platinum-based regimens have not been proved to increase survival from advanced prostate cancer (PCa). Incontrovertible evidence that a proportion of prostate cancers have homologous recombination DNA (HRD) repair defects, and that such genomic aberrations are synthetically lethal with both poly(ADP)-ribose polymerase inhibition and platinum, has increased interest in the utilisation of these drugs against a subset of these diseases. Here in we report three patients with advanced castration-resistant PCa with HRD defects having exceptional responses to carboplatin