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Oxford, United Kingdom

Clostridium difficile is a major cause of nosocomial diarrhea, with 30-day mortality reaching 30%. The cell surface comprises a paracrystalline proteinaceous S-layer encoded by the slpA gene within the cell wall protein (cwp) gene cluster. Our purpose was to understand the diversity and evolution of slpA and nearby genes also encoding immunodominant cell surface antigens. Whole-genome sequences were determined for 57 C. difficile isolates representative of the population structure and different clinical phenotypes. Phylogenetic analyses were performed on their genomic region (>63 kb) spanning the cwp cluster. Genetic diversity across the cwp cluster peaked within slpA, cwp66 (adhesin), and secA2 (secretory translocase). These genes formed a 10-kb cassette, of which 12 divergent variants were found. Homologous recombination involving this cassette caused it to associate randomly with genotype. One cassette contained a novel insertion (length, approximately 24 kb) that resembled S-layer glycosylation gene clusters. Genetic exchange of S-layer cassettes parallels polysaccharide capsular switching in other species. Both cause major antigenic shifts, while the remainder of the genome is unchanged. C. difficile genotype is therefore not predictive of antigenic type. S-layer switching and immune escape could help explain temporal and geographic variation in C. difficile epidemiology and may inform genotyping and vaccination strategies. Source


Nielsen S.,Aarhus University Hospital | Karpe F.,University of Oxford | Karpe F.,Oxford Biomedical Research Center
Current Opinion in Lipidology | Year: 2012

Purpose of Review: Plasma free fatty acids (FFA) are major substrates for hepatic VLDL-triglycerides (VLDL-TG) production. In addition, it is a common belief that VLDL-TG production is a substrate driven process primarily determined by systemic FFA delivery. This review summarizes recent research of our understanding of the regulation of VLDL-TG production. Recent Findings: Recent studies have shown that increasing FFA flux is not inevitably associated with increased VLDL-TG production. Exercise induced increase in FFA flux resulting in unchanged VLDL-TG production in lean patients as well as in obese patients with increased hepatic fat despite exercise reduced hepatic fat content. With respect to the other inseparable conditions of insulin resistance and hyperinsulinemia, recent studies demonstrate that increased hepatic VLDL-TG production precedes the insulin resistance-associated impairment of the regulation of hepatic glucose production, whereas isolated chronic hyperinsulinemia (insulinoma) was not associated with increased VLDL-TG production. Insulin has been shown to have acute potent temporary suppressing effect on VLDL-TG production and new data demonstrates that increased glucagon reduces VLDL-TG production. Finally, recent studies indicate that sex hormones, oestrogen and testosterone, have no or very modest impact on VLDL-TG production. Summary: Regulation of hepatic VLDL-TG production involves interplay between systemic FFA delivery, hormonal, and nutritional factors that act in concert with hepatic fatty acid handling to regulate short-term and long-term VLDL-TG production. The results of recent studies underscore that our current understanding of these relationships is complex and needs further research. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Watts G.F.,University of Western Australia | Karpe F.,University of Oxford | Karpe F.,Oxford Biomedical Research Center
Heart | Year: 2011

Although statins significantly decrease the incidence of cardiovascular disease (CVD), residual CVD risk remains high. This may partly be due to uncorrected atherogenic dyslipidaemia. The driving force behind atherogenic dyslipidaemia is hypertriglyceridaemia, which results from hepatic oversecretion and/or hypocatabolism of triglyceride-rich lipoproteins, and is typical of type 2 diabetes and metabolic syndrome. Persistent atherogenic dyslipidaemia in patients treated with a statin according to low-density lipoprotein-cholesterol goals may be corrected with niacin, fibrates or n-3 fatty acids. Clinical trial evidence to inform best practice is limited, but new data support adding fenofibrate to a statin. A consistent feature of fibrate clinical trials is the specific benefit of these agents in dyslipidaemic patients and the improvement in diabetic retinopathy with fenofibrate. Ongoing clinical trials may provide good evidence for adding niacin to a statin. Low-dose n-3 fatty acids could be used routinely after a myocardial infarction, but the value of higher doses of n-3 fatty acids in reducing CVD risk remains to be demonstrated. Source


Andrews S.M.,University of Oxford | Pollard A.J.,University of Oxford | Pollard A.J.,Oxford Biomedical Research Center
The Lancet Infectious Diseases | Year: 2014

Neisseria meningitidis is an important cause of invasive bacterial infection in children worldwide. Although serogroup C meningococcal disease has all but disappeared in the past decade as a direct result of immunisation programmes in Europe, Canada, and Australia, meningitis and septicaemia caused by serogroup B meningococci remain uncontrolled. A vaccine (4CMenB) has now been licensed for use in the European Union, comprising three immunogenic antigens (identified with use of reverse vaccinology) combined with bacterial outer-membrane vesicles. The vaccine has the potential to reduce mortality and morbidity associated with serogroup B meningococci infections, but uncertainty remains about the breadth of protection the vaccine might induce against the diverse serogroup B meningococci strains that cause disease. We discuss drawbacks in the techniques used to estimate coverage and potential efficacy of the vaccine, and their effects on estimates of cost-effectiveness, both with and without herd immunity. For parents, and clinicians treating individual patients, the predicted benefits of vaccination outweigh existing uncertainties if any cases can be prevented, but future use of the vaccine must be followed by rigorous post-implementation surveillance to reassess its value to health systems with directly recorded epidemiological data. © 2014 Elsevier Ltd. Source


McCarthy M.I.,University of Oxford | McCarthy M.I.,Oxford Biomedical Research Center | McCarthy M.I.,University of Geneva
Diabetologia | Year: 2015

Individual predisposition to type 2 diabetes is influenced by the combined effect of a constellation of genetic variants and a multitude of environmental exposures. Identification of the specific genetic variants involved, and the mechanisms through which they operate, provides a powerful approach for delivering biological insights that can drive translational benefit, one that is already widely exploited in the personalised management of monogenic and syndromic forms of diabetes. This commentary develops the argument that equivalent translational advances for more common forms of diabetes are unlikely to result solely from the ability to define more complete individual inventories of genetic risk and environmental exposure. They will also require identification of complex molecular signatures able to provide integrative, empirical, longitudinal readouts of disease progression. These signatures will track causal mechanisms and capture an individual’s position within a complex spectrum of pathophysiological processes, thereby supporting personalised approaches to intervention and treatment. This is one of a series of commentaries under the banner ‘50 years forward’, giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965–2015). © 2015, Springer-Verlag Berlin Heidelberg. Source

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