479
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    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.
  • BMJ (online) 01/2012; 344:e3175.
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    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 01/2011; 6:67-79.
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    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.
  • Thorax 10/2010; 65(10):855-6.
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    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.
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    ABSTRACT: The Olympic biathlon is a very demanding physical event that requires high oxygen delivery, good cross-country skiing skills and skilful use of a rifle. Like all high-performance endurance athletes, high cardiac vagal tone is a characteristic and extends the range over which cardiac output can increase. In the biathlete, however, the enhanced vagal control of the heart also allows a strategy for better control of stability needed for accurately firing a rifle at the end of each lap of the race. The role of endurance training, central command, reflexes from muscle, and of the carotid-cardiac baroreceptor reflex in changing vagal tone during intense exercise and recovery is discussed.
    Experimental physiology 10/2009; 95(3):431-40.
  • Diabetic Medicine 06/2009; 26(8):831 - 833.
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    ABSTRACT: Differential expression of human leucocyte antigen (HLA) class II genes has been postulated to influence the risk of developing autoimmune disease. In this study, we investigated the relationship between the level of mRNA expression of DQA1 and DQB1 alleles in peripheral blood mononuclear cells and the influence of the alleles on susceptibility to type 1 diabetes (T1D). Transcripts from pairs of DQA1 and DQB1 alleles were quantified in 59 DQ-heterozygous individuals (29 patients with T1D and 30 healthy control subjects). Luciferase reporter gene assays were used to investigate the relative promoter activities of the alleles associated with high and low risk of disease. DQA1*0301 and the DQB1*06 group of alleles (*0601, *0602, *0603 and *0604) were generally overexpressed in comparison to other alleles. In contrast, mRNA for DQB1*0201/*0202 was generally less abundant than other DQB1 transcripts. These data correlated well with the relative promoter activities observed for the diabetes-associated alleles; the strongest promoters were those derived from DQA1*0301 and DQB1*0602, while a 700-bp fragment derived from the DQB1*0201 promoter showed the lowest activity of the DQB1 constructs. There was no simple correlation between the level of expression of specific DQ alleles and their influence on the risk of diabetes. The functional relevance of our findings and their implications for the pathogenesis of autoimmunity remain to be determined.
    International Journal of Immunogenetics 03/2009; 36(1):47-57.
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    ABSTRACT: Alpha-1-antitrypsin deficiency is associated with variable development of airflow obstruction and emphysema. Index patients have greater airflow obstruction than subjects detected by screening, but it is unclear if this reflects smoking differences and/or ascertainment bias, or is due to additional genetic factors. In this study 72 sibling pairs with alpha-1-antitrypsin deficiency were compared using lung function measurements and HRCT chest. Tag single nucleotide polymorphisms to cover all common variation in four genes involved in relevant inflammatory pathways (Tumour necrosis factor alpha, Transforming growth Factor beta, Surfactant protein B and Vitamin D binding protein) were genotyped using TaqMan technology and compared between pairs for their frequency and relationship to lung function. 63.5% of non-index siblings had airflow obstruction and 59.5% an FEV(1) < 80% predicted. Index siblings had lower FEV(1) and FEV(1)/FVC ratio, a higher incidence of emphysema (all P <or= 0.001) and lower gas transfer (P = 0.02). There was no correlation of FEV(1) between siblings but KCO was significantly correlated (r = 0.42, P = 0.002). Quantitative analyses against lung function showed that a polymorphism in Surfactant protein B was associated with FEV(1) (P = 0.002). This result was replicated in a non-sibling group (P = 0.01). Our results show that clinical differences in families with alpha-1-antitrypsin deficiency are not solely explained by smoking or ascertainment bias and may be due to variation within genes involved in inflammatory pathways.
    COPD Journal of Chronic Obstructive Pulmonary Disease 12/2008; 5(6):353-9.
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