500
2,644.37
5.29
699

Publication History View all

  • [Show abstract] [Hide abstract]
    ABSTRACT: Most patients with type 2 diabetes mellitus (T2DM) are overweight or obese. Both T2DM and overweight/obesity are associated with increased patient risk of cardiovascular events and mortality. Despite being the recognized cornerstone of treatment, weight loss and maintenance of weight loss are difficult for patients with T2DM, particularly as treatments for T2DM may cause weight gain. Sodium glucose cotransporter 2 (SGLT2) inhibitors, a new class of drug for the treatment of patients with T2DM, reduce renal glucose reabsorption, resulting in urinary glucose excretion. Due to the caloric loss associated with decreased glucose in urine, treatment with SGLT2 agents offers the benefit of weight loss to patients, as well as reduction in hyperglycemia. Clinical trials of SGLT2 inhibitors in patients with T2DM, ranging in length from 4 to 90 weeks, have shown patient weight reductions from baseline of up to 4.7 kg. Such weight loss may have beneficial effects on adherence to medication, glycemic control, and cardiovascular risk in patients with T2DM.
    Postgraduate Medicine 09/2013; 125(5):92-100. DOI:10.3810/pgm.2013.09.2698
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There is continuing belief that cardiac parasympathetic postganglionic fibres are sparse or absent from the ventricles. This review of the literature shows that the supposition is a myth. Early studies considered that fine silver stained fibres coursing amongst ventricle myocardial cells were likely cardiac parasympathetic postganglionic fibres. The conclusions were later supported by acetyl cholinesterase staining using a method that appeared not to be associated with noradrenaline nerve fibres. The conclusion is critically examined in the light of several recent histological studies using the acetyl cholinesterase method and also a more definitive technique (CHAT), that suggest a widespread location of parasympathetic ganglia and a relatively dense parasympathetic innervation of ventricular muscle in a range of mammals including man. The many studies demonstrating acetylcholine release in the ventricle on vagal nerve stimulation and a high density of acetylcholine M2 receptors is in accord with this as are tests of ventricular performance from many physiological studies. Selective control of cardiac functions by anatomically segregated parasympathetic ganglia is discussed. It is argued that the influence of vagal stimulation on ventricular myocardial action potential refractory period, duration, force and rhythm is evidence that vagal fibres have close apposition to myocardial fibres. This is supported by clear evidence of accentuated antagonism between sympathetic activity and vagal activity in the ventricle and also by direct effects of vagal activity independent of sympathetic. The idea of differential control of atrial and ventricle physiology by vagal C and vagal B preganglionic fibres is examined as well as differences in chemical phenotypes and their function. The latter is reflected in medullary and supramedullary control. The importance of this knowledge to understanding the normal physiology of cardiac autonomic control and significance to pathology is referred to.
    The Journal of Physiology 07/2013; 591(17). DOI:10.1113/jphysiol.2013.257758
  • [Show abstract] [Hide abstract]
    ABSTRACT: Significant advances have been made in the last 5 years that have finally allowed investigators to start targeting stromal cells such as fibroblasts in inflammatory disease. Rheumatoid arthritis is a prototype inflammatory disease, in which fibroblasts maintain the persistence of inflammation in the joint underpinned by a unique pathological phenotype driven by multiple epigenetic modifications. The step changes that are enabling the development of such therapies are an improved understanding of the mechanisms by which fibroblasts mediate persistence and the discovery of new markers that identify discrete functional subsets of fibroblast cells that have potential as disease-specific therapeutic targets.
    Current Opinion in Pharmacology 04/2013; 13(3). DOI:10.1016/j.coph.2013.02.006
  • BMJ (online) 05/2012; 344:e3175. DOI:10.1136/bmj.e3175
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Lixisenatide is a once-daily glucagon-like peptide 1 (GLP-1) receptor agonist mimicking several favorable actions of endogenous GLP-1 that result in improved glycemic control with little or no hypoglycemia and weight loss. Phase II trials have shown that lixisenatide 20 μg once daily restores first-phase insulin release in patients with type 2 diabetes and improves the second-phase insulin response. Administered once or twice daily for 4 weeks, it significantly reduced postprandial and fasting blood glucose levels, and glycosylated hemoglobin (HbA(1c)). The efficacy and safety of lixisenatide once daily is being assessed in the GETGOAL Phase III clinical trial program. Results have shown beneficial effects on HbA(1c) compared with placebo in combination with commonly used antidiabetes agents, with no increased risk of hypoglycemia and with beneficial weight reduction. Adverse effects were similar to those observed for available GLP-1 receptor agonists, the most frequent being gastrointestinal. Both GLP-1 receptor agonists and long-acting insulin analogs have demonstrated protective effects on beta cells in preclinical studies. This, along with the pronounced effect of lixisenatide on postprandial plasma glucose, provides a rationale for combining it with long-acting basal insulin analogs, in the hope that the additive effects on glycemic control combined with a potential benefit on islet cells may lead to a new treatment approach to control blood glucose better and prevent long-term complications in patients with type 2 diabetes.
    Core Evidence 09/2011; 6:67-79. DOI:10.2147/CE.S15525
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This paper is dedicated to young researchers in diabetes. One such person was Frederick Banting who, with his colleagues, isolated insulin in 1921, saving the lives of literally millions of people. What factors allowed Banting and other scientists to produce work that has immensely benefited the human race? I propose that it is the combination of good scientific background (the 'prepared mind'), commonly some serendipity taken with a good dose of common sense and supplemented by enthusiasm, tenacity and good mentoring, which drives the 'power of observation' and the ability to take forward the good idea. I give examples from history to support this and then discuss some of the 'truths, perspectives and controversies' within the diabetes arena when I first started in diabetes research in the late 1970s. I describe how my appetite was initially 'whetted' for research by moving to an excellent clinical research environment with encouragement to test ideas and controversies initially in a clinical research programme, followed by more scientific/basic research. The work that I performed as a young doctor and research fellow led to a lifelong professional interest in three major areas-causes and interventions for diabetes vascular disease, studies of the molecular genetics of Type 1 and Type 2 diabetes and work on diabetes in different ethnic groups. I provide a summation of my own and other people's work to demonstrate how research can be progressed and lead to patient benefit as well as providing an incredibly rewarding career. I believe that we need to encourage and put more resources into development of young doctors and scientists wishing to undertake research in our discipline. Areas ripe for much-needed clinical research programmes, for example, include work on best practice/provision of health care, application of the evidence base from clinical trials to achieve public health gains, attention to adherence issues and better-tolerated therapies. Most importantly, a greater emphasis on prevention through public health measures and 'buy in' from the whole population is urgently required.
    Diabetic Medicine 08/2011; 28(11):1289-99. DOI:10.1111/j.1464-5491.2011.03396.x
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alpha-1-antitrypsin (A1AT) deficiency is a common genetic condition that predisposes individuals to the development of chronic obstructive pulmonary disease (COPD) as a direct result of damage caused to the lung by proteolytic enzymes released by migrating neutrophils. The lack of A1AT fails to control these enzymes and in the most common genetic deficiency (Pi Z) is due to accumulation of A1AT in the liver as a result of polymer formation. There is no specific treatment for COPD but understanding the pathophysiology of the disease in A1AT deficiency has led to strategies being used or developed to prevent the lung and liver disease. These strategies may have benefits beyond A1AT deficiency. The review covers the history of discovery of the nature and role of A1AT deficiency with particular emphasis on the pathophysiology of the lung disease. Evidence for the role of current therapies is provided together with data of preliminary or experimental strategies that are under development. The reader will gain insight into the role of proteinases in the pathophysiology of COPD with particular reference to A1AT deficiency, which is the only human model of the disease. Current evidence of the efficacy of augmentation is provided together with new ways of readdressing the balance between neutrophil proteinases and natural or synthetic inhibitors or repairing lung damage. A1AT deficiency is a good model to investigate the role of inflammation and proteolytic enzymes in the pathophysiology of COPD. Augmentation therapy is expensive but restores the deficiency to normal and current evidence suggests this ameliorates progression of the disease. Understanding the mechanisms involved has led to the development of newer strategies to protect the lung and liver from the development of disease but efficacy and safety concerns require careful introduction of these strategies. Although the condition is relatively common in the Northern hemisphere, the ability to deliver conventional Phase III clinical trials with lung physiology as the primary outcome will be limited by the sensitivity of the tests and number of patients required.
    Expert Opinion on Emerging Drugs 12/2010; 15(4):685-94. DOI:10.1517/14728214.2010.512287
  • Thorax 10/2010; 65(10):855-6. DOI:10.1136/thx.2010.149294
  • [Show abstract] [Hide abstract]
    ABSTRACT: To examine the literature on competing interests for individuals and organizations involved in healthcare and to determine the nature and extent of the problem, and the most effective methods of management. A Medline search from 1950 to August 2009 identified 6803 publications (605 in languages other than English) on the subject of conflict of interest or competing interests. Of these, 1073 were letters, 785 editorials, 434 reviews and 212 referred to competing interests in the context of clinical guidelines. Conflicts of interest (competing interests) and bias are ubiquitous. In medicine, they may have the potential to cause harm to patients or obstruct research and new treatments. Competing interests may arise from financial, academic or personal factors. Most interventions relate to managing competing financial interests derived from relationships with the pharmaceutical industry. Transparency is a necessary, but not a sufficient component in managing bias. Organizations should develop integrated systems for declaring, monitoring and managing financial interests; insight into other forms of bias could be improved through educational programmes. Marketing masquerading as education should be prohibited for undergraduates and trainees, and by professional organizations. Universities and journals should separate their conflicted roles as regulators and beneficiaries in commercial relationships.
    Current opinion in critical care 12/2009; 15(6):583-90. DOI:10.1097/MCC.0b013e328332f53a
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to uniquely describe CT scan appearance, densitometry, and health status in subjects with protease inhibitor SZ phenotype (PiSZ) alpha(1)-antitrypsin deficiency (AATD) compared with matched subjects with protease inhibitor ZZ phenotype (PiZZ). The presence and type of emphysema seen on CT scan, upper and lower zone densitometry, health status, physiology, and symptoms were compared for 126 subjects (63 with PiSZ, 63 with PiZZ) from the UK AATD registry, matched for age, gender, and smoking status. Similar analyses were performed for lung index and nonindex subgroups. A lower proportion of PiSZ index (46%) and non-PiSZ index (15%) subgroup case patients showed visible emphysema on CT scans compared with matched PiZZ index (91%; p < 0.001) and non-PiZZ index (61%; p = 0.011) case patients. Sixty-five percent of subjects with PiSZ and 74% with PiZZ had panacinar emphysema (p = 0.54); however, a greater proportion (p = 0.005) of the PiSZ group (39%) had upper zone-predominant emphysema compared with the PiZZ group (12%). Densitometric analysis revealed less extensive emphysema in the lower zones, but not the upper zones, of subjects with PiSZ than those with PiZZ. When subjects were matched for ascertainment method, health status was similar between the two phenotypes, despite the differences in CT scan and densitometry findings, and more abnormal respiratory physiology test results in subjects with PiZZ. Subjects with PiSZ showed less emphysema on CT scans, more apical predominance, less abnormal respiratory physiology test results, but similar health status impairment compared with matched subjects with PiZZ.
    Chest 11/2009; 136(5):1284-90. DOI:10.1378/chest.09-0057
Information provided on this web page is aggregated encyclopedic and bibliographical information relating to the named institution. Information provided is not approved by the institution itself. The institution’s logo (and/or other graphical identification, such as a coat of arms) is used only to identify the institution in a nominal way. Under certain jurisdictions it may be property of the institution.