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Mittal S.,Oxford Biomedical Research Center | Gough S.C.L.,Oxford Biomedical Research Center
Diabetic Medicine | Year: 2014

Since the first pancreas transplants in the early 1960s, whole-organ pancreas transplantation, either alone or combined with kidney transplantation, has become commonplace in many countries around the world. Whole-organ pancreas transplantation is available in the UK, with ~200 transplants currently carried out per year. Patient survival and pancreas graft outcome rates are now similar to other solid organ transplant programmes, with high rates of long-term insulin independence. In the present review, we will discuss whole-pancreas transplantation as a treatment for diabetes, focusing on indications for transplantation, the nature of the procedure performed, graft survival rates and the consequences of pancreas transplantation on metabolic variables and the progression of diabetes-related complications. © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.

Byrd J.C.,Ohio State University | Brown J.R.,Dana-Farber Cancer Institute | O'Brien S.,University of Texas M. D. Anderson Cancer Center | Kay N.E.,Mayo Medical School | And 30 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome. METHODS: In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points. RESULTS: At a median follow-up of 9.4 months, ibrutinib significantly improved progressionfree survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P = 0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group. CONCLUSIONS: Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. Copyright © 2014 Massachusetts Medical Society. All rights reserved.

Berney T.,University of Geneva | Johnson P.R.V.,University of Geneva | Johnson P.R.V.,John Radcliffe Hospital | Johnson P.R.V.,Oxford Biomedical Research Center
Transplantation | Year: 2010

As islet transplantation increasingly enters the clinical arena, its coexistence with vascularized pancreas transplantation makes it necessary to reassess the questions of donor selection and allocation. In answering these questions, one must put in the balance the short-term morbidity of pancreas transplantation with the long-term attrition of islet grafts. The preferential allocation of pancreases from obese and older donors for islet isolation has been based on their association with worse pancreas transplant outcomes and better islet isolation results in islet yields. In this overview, we show that transplanted islet mass does not necessarily correlate with graft function and make the case that donor selection criteria for islet transplantation, and hence allocation rules, may need to be redefined. © 2010 by World Health Organization.

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.

Ajjan R.A.,University of Leeds | Owen K.R.,University of Oxford | Owen K.R.,Oxford Biomedical Research Center
Current Diabetes Reports | Year: 2014

Treatment goals in diabetes concentrate on reducing the risk of vascular complications, largely through setting targets for glycated haemoglobin (HbA1c). These targets are based on epidemiological studies of complication development, but so far have not adequately addressed the adverse effects associated with lowering HbA1c towards the normal range. Glucokinase (GCK) mutations cause a monogenic form of hyperglycaemia (GCK-MODY) characterised by fasting hyperglycaemia with low postprandial glucose excursions and a marginally elevated HbA1c. Minimal levels of vascular complications (comparable with nondiabetic individuals) are observed in GCK-MODY, leading to the hypothesis that GCK-MODY may represent a useful paradigm for assessing treatment goals in all forms of diabetes. In this review, we discuss the evidence behind this concept, suggest ways of translating this hypothesis into clinical practice and address some of the caveats of such an approach. © 2014, Springer Science+Business Media New York.

Pal A.,Oxford Center for Diabetes | Mccarthy M.I.,Oxford Center for Diabetes | Mccarthy M.I.,University of Oxford | Mccarthy M.I.,Oxford Biomedical Research Center
Clinical Genetics | Year: 2013

The increasing worldwide prevalence of type 2 diabetes (T2D) motivates efforts to use genetics to define key pathways involved in disease predisposition, and thereby to improve management of the disease. Research over the past 5years has taken the total number of genetic loci implicated in T2D susceptibility beyond 60, and the emphasis is now shifting to the translation of these genetic insights into clinical value. Clinical translation may flow from the identification of novel therapeutic targets, but opportunities also exist with respect to individual prediction, diagnostic biomarkers and therapeutic optimization. To date, the main clinical impact has been seen for relatively rare, monogenic forms of diabetes rather than common T2D. However, the advent of high throughput sequencing approaches may herald discovery of rare and low frequency variants that offer greater translational potential. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

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.

Hilton C.,University of Oxford | Neville M.J.,University of Oxford | Karpe F.,University of Oxford | Karpe F.,Oxford Biomedical Research Center
International Journal of Obesity | Year: 2013

MicroRNAs (miRNAs) are endogenous small RNAs that posttranscriptionally regulate gene expression and that have been shown to have important roles in numerous disease processes. There is growing evidence for an important role of miRNAs in regulating the pathways in adipose tissue that control a range of processes including adipogenesis, insulin resistance and inflammation. Several high-throughput studies have identified differentially expressed miRNAs in adipose tissue pathology and during adipogenesis and a number of these have now been characterised functionally in terms of their actions and targets. This review will summarise the current literature on miRNAs in adipose tissue, as well as discussing the methodologies used in this area of research and the potential application of miRNAs as biomarkers and as therapeutic targets.

Martin N.G.,University of Oxford | Martin N.G.,Oxford Biomedical Research Center | Sadarangani M.,University of Oxford | Sadarangani M.,Oxford Biomedical Research Center | And 3 more authors.
The Lancet Infectious Diseases | Year: 2014

Background: Infection with Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae causes substantial mortality and long-term morbidity in children. We know of no study to assess the long-term trends in hospital admission rates for meningitis and septicaemia caused by these pathogens in children in England. We aimed to do such a study using routinely reported data in England. Methods: In this population-based observational study, we used datasets that include routinely collected administrative statistics for hospital care: the Hospital In-Patient Enquiry (data for England from 1968 to 1985), the Hospital Episode Statistics dataset (data for England from 1989 onwards), and the Oxford record linkage study (data for Oxfordshire and surrounding areas from 1963 to 2011). We analysed annual age-specific and age-standardised admission rates in children younger than 15 years with H influenzae, meningococcal and pneumococcal meningitis, and septicaemia. Findings: We saw a reduction in hospital admission rates for childhood invasive bacterial disease after the introduction of conjugate vaccines against H influenzae, N meningitidis, and S pneumoniae in England. Annual incidence of H influenzae meningitis per 100 000 children decreased from 6·72 admissions (95% CI 6·18-7·26) in 1992 to 0·39 admissions (0·26-0·52) in 1994, after the introduction of routine H influenzae type b vaccination. We saw a small rise in admissions in the early 2000s, peaking at 1·24 admissions per 100 000 children (0·99-1·48) in 2003, which decreased to 0·28 per 100 000 children (0·17-0·39) by 2008 after the introduction of catch-up (2003) and routine (2006) booster programmes for young children. Meningococcal disease increased during the 1990s, reaching a peak in 1999, with 34·54 admissions (33·30-35·78) per 100 000 children. Hospital admissions decreased after the meningococcal serogroup C vaccine was introduced in 1999 and was 12·40 admissions (11·68-13·12) per 100 000 in 2011. Admissions for invasive pneumococcal disease increased from the 1990s reaching a peak in 2006 at 4·45 admissions for meningitis (95% CI 4·0-4·9) per 100 000 children and 2·81 admissions for septicaemia (2·45-3·17) per 100 000 children. A reduction in admissions occurred after the introduction of the pneumococcal conjugate vaccine in 2006: hospital admission rates in 2011 were 2·03 per 100 000 children for meningitis and 1·12 per 100 000 children for septicaemia. Interpretation: Vaccine-preventable invasive bacterial disease in children has decreased substantially in England in the past five decades, most notably with the advent of effective conjugate vaccines since the 1990s. Ongoing disease surveillance and continued development and implementation of vaccines against additional pneumococcal serotypes and serogroup B meningococcal disease are important. Funding: None. © 2014 Elsevier Ltd.

Mentzer A.J.,University of Oxford | O'Connor D.,University of Oxford | O'Connor D.,Oxford Biomedical Research Center | Pollard A.J.,University of Oxford | And 3 more authors.
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2015

Vaccines have revolutionized modern public health. The effectiveness of some vaccines is limited by the variation in response observed between individuals and across populations. There is compelling evidence that a significant proportion of this variability can be attributed to human genetic variation, especially for those vaccines administered in early life. Identifying and understanding the determinants of this variation could have a far-reaching influence upon future methods of vaccine design and deployment. In this review, we summarize the genetic studies that have been undertaken attempting to identify the genetic determinants of response heterogeneity for the vaccines against hepatitis B, measles and rubella. We offer a critical appraisal of these studies and make a series of suggestions about how modern genetic techniques, including genome-wide association studies, could be used to characterize the genetic architecture of vaccine response heterogeneity. We conclude by suggesting how the findings from such studies could be translated to improve vaccine effectiveness and target vaccination in a more cost-effective manner. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

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