Effectiveness of a self-management intervention with personalised genetic and lifestyle-related risk information on coronary heart disease and diabetes-related risk in type 2 diabetes (CoRDia): study protocol for a randomised controlled trial

Background Many patients with type 2 diabetes fail to achieve good glycaemic control. Poor control is associated with complications including coronary heart disease (CHD). Effective self-management and engagement in health behaviours can reduce risks of complications. However, patients often struggle to adopt and maintain these behaviours. Self-management interventions have been found to be effective in improving glycaemic control. Recent developments in the field of genetics mean that patients can be given personalised information about genetic- and lifestyle-associated risk of developing CHD. Such information may increase patients’ motivation to engage in self-management. The Coronary Risk in Diabetes (CoRDia) trial will compare the effectiveness of a self-management intervention, with and without provision of personalised genetic- and lifestyle-associated risk information, with usual care, on clinical and behavioural outcomes, the cognitive predictors of behaviour, and psychological wellbeing. Methods/Design Participants will be adults aged 25–74 years registered with general practices in the East of England, diagnosed with type 2 diabetes, with no history of heart disease, and with a glycated haemoglobin level of ≥6.45 % (47 mmol/mol). Consenting participants will be randomised to one of three arms: usual care control, group self-management only, group self-management plus personalised genetic- and lifestyle-associated risk information. The self-management groups will receive four weekly 2-hour group sessions, focusing on knowledge and information sharing, problem solving, goal setting and action planning to promote medication adherence, healthy eating, and physical activity. Primary outcomes are glycaemic control and CHD risk. Clinical data will be collected from GP records, including HbA1c, weight, body mass index, blood pressure, and HDL and total cholesterol. Self-reported health behaviours, including medication adherence, healthy eating and physical activity, and cognitive outcomes will be assessed by questionnaire. Measures will be taken at baseline, 3 months (questionnaire only), 6 months and 12 months post-baseline. Discussion This study will determine whether the addition of personalised genetic- and lifestyle-associated CHD risk information to a group self-management intervention improves diabetes control and CHD risk compared with group self-management and usual care. Effectiveness of the combined intervention on health behaviours cognitions theorised to predict them, and psychological outcomes will also be investigated. Trial registration This study has been registered at ClinicalTrials.gov; registration identifier NCT01891786, registered 28 June 2013

Bordetella Adenylate Cyclase Toxin Mobilizes Its β2 Integrin Receptor into Lipid Rafts to Accomplish Translocation across Target Cell Membrane in Two Steps

Bordetella adenylate cyclase toxin (CyaA) binds the αMβ2 integrin (CD11b/CD18, Mac-1, or CR3) of myeloid phagocytes and delivers into their cytosol an adenylate cyclase (AC) enzyme that converts ATP into the key signaling molecule cAMP. We show that penetration of the AC domain across cell membrane proceeds in two steps. It starts by membrane insertion of a toxin ‘translocation intermediate’, which can be ‘locked’ in the membrane by the 3D1 antibody blocking AC domain translocation. Insertion of the ‘intermediate’ permeabilizes cells for influx of extracellular calcium ions and thus activates calpain-mediated cleavage of the talin tether. Recruitment of the integrin-CyaA complex into lipid rafts follows and the cholesterol-rich lipid environment promotes translocation of the AC domain across cell membrane. AC translocation into cells was inhibited upon raft disruption by cholesterol depletion, or when CyaA mobilization into rafts was blocked by inhibition of talin processing. Furthermore, CyaA mutants unable to mobilize calcium into cells failed to relocate into lipid rafts, and failed to translocate the AC domain across cell membrane, unless rescued by Ca2+ influx promoted in trans by ionomycin or another CyaA protein. Hence, by mobilizing calcium ions into phagocytes, the ‘translocation intermediate’ promotes toxin piggybacking on integrin into lipid rafts and enables AC enzyme delivery into host cytosol

Multidrug efflux pumps:structure, function and regulation

Infections arising from multidrug-resistant pathogenic bacteria are spreading rapidly throughout the world and threaten to become untreatable. The origins of resistance are numerous and complex, but one underlying factor is the capacity of bacteria to rapidly export drugs through the intrinsic activity of efflux pumps. In this Review, we describe recent advances that have increased our understanding of the structures and molecular mechanisms of multidrug efflux pumps in bacteria. Clinical and laboratory data indicate that efflux pumps function not only in the drug extrusion process but also in virulence and the adaptive responses that contribute to antimicrobial resistance during infection. The emerging picture of the structure, function and regulation of efflux pumps suggests opportunities for countering their activities