Does treatment of subsyndromal depression improve depression and diabetes related outcomes: protocol for a randomised controlled comparison of psycho-education, physical exercise and treatment as usual

<p>Abstract</p> <p>Background</p> <p>The prevalence of mood difficulties in persons with diabetes is approximately twice that in the general population, affecting the health outcomes and patients' quality of life in an undesirable way. Although subsyndromal depression is an important predictor of a more serious clinical depression, it is often overlooked. This study aims to compare the effects of two non-pharmacological interventions for subsyndromal depression, psychoeducation and physical exercise, with diabetes treatment as usual on mood- and diabetes-related outcomes.</p> <p>Methods and Design</p> <p>Type 2 diabetic patients aged 18-65 yrs. who report mood difficulties and the related need for help in a mail survey will be potential participants. After giving informed consent, they will be randomly assigned to one of the three groups (psychoeducation, physical activity, treatment as usual). Depressive symptoms, diabetes distress, health-related quality of life and diabetes self-care activities will be assessed at baseline, at 6 weeks, 6 months and 12 months. A structured clinical interview for DSM-IV Axis I Disorders (SCID-I) will be performed at baseline and at one-year follow-up in order to determine the clinical significance of the patients' depressive symptoms. Disease-related data will be collected from patients' files and from additional physical examinations and laboratory tests.</p> <p>The two interventions will be comparable in terms of format (small group work), duration (six sessions) and approach (interactive learning; supporting the participants' active roles). The group treated as usual will be informed about their screening results and about the importance of treating depression. They will be provided with brief re-education on diabetes and written self-help instructions to cope with mood difficulties.</p> <p>Primary outcomes will be depressive symptoms. Secondary outcomes will be glycaemic control, diabetes-related distress, self-management of diabetes and health-related quality of life. Tertiary outcomes will be biochemical markers reflecting common pathophysiological processes of insulin resistance, inflammation and oxidative damage that are assumed to be intertwined in both diabetes and depression. The mixed-effect linear model will be used to compare the outcome variables.</p> <p>Power analysis has indicated that the two intervention groups and the control group should comprise 59 patients to enable detection of clinically meaningful differences in depressive symptoms with a power of 80% and alpha = 0.05. Outcomes will be analysed on an intention-to-treat basis.</p> <p>Trial Registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN05673017">ISRCTN05673017</a></p

Host-Detrimental Role of Esx-1-Mediated Inflammasome Activation in Mycobacterial Infection

The Esx-1 (type VII) secretion system is a major virulence determinant of pathogenic mycobacteria, including Mycobacterium marinum. However, the molecular events and host-pathogen interactions underlying Esx-1-mediated virulence in vivo remain unclear. Here we address this problem in a non-lethal mouse model of M. marinum infection that allows detailed quantitative analysis of disease progression. M. marinum established local infection in mouse tails, with Esx-1-dependent formation of caseating granulomas similar to those formed in human tuberculosis, and bone deterioration reminiscent of skeletal tuberculosis. Analysis of tails infected with wild type or Esx-1-deficient bacteria showed that Esx-1 enhanced generation of proinflammatory cytokines, including the secreted form of IL-1β, suggesting that Esx-1 promotes inflammasome activation in vivo. In vitro experiments indicated that Esx-1-dependent inflammasome activation required the host NLRP3 and ASC proteins. Infection of wild type and ASC-deficient mice demonstrated that Esx-1-dependent inflammasome activation exacerbated disease without restricting bacterial growth, indicating a host-detrimental role of this inflammatory pathway in mycobacterial infection. These findings define an immunoregulatory role for Esx-1 in a specific host-pathogen interaction in vivo, and indicate that the Esx-1 secretion system promotes disease and inflammation through its ability to activate the inflammasome

GM-CSF Production Allows the Identification of Immunoprevalent Antigens Recognized by Human CD4+ T Cells Following Smallpox Vaccination

The threat of bioterrorism with smallpox and the broad use of vaccinia vectors for other vaccines have led to the resurgence in the study of vaccinia immunological memory. The importance of the role of CD4+ T cells in the control of vaccinia infection is well known. However, more CD8+ than CD4+ T cell epitopes recognized by human subjects immunized with vaccinia virus have been reported. This could be, in part, due to the fact that most of the studies that have identified human CD4+ specific protein-derived fragments or peptides have used IFN-γ production to evaluate vaccinia specific T cell responses. Based on these findings, we reasoned that analyzing a large panel of cytokines would permit us to generate a more complete analysis of the CD4 T cell responses. The results presented provide clear evidence that TNF-α is an excellent readout of vaccinia specificity and that other cytokines such as GM-CSF can be used to evaluate the reactivity of CD4+ T cells in response to vaccinia antigens. Furthermore, using these cytokines as readout of vaccinia specificity, we present the identification of novel peptides from immunoprevalent vaccinia proteins recognized by CD4+ T cells derived from smallpox vaccinated human subjects. In conclusion, we describe a “T cell–driven” methodology that can be implemented to determine the specificity of the T cell response upon vaccination or infection. Together, the single pathogen in vitro stimulation, the selection of CD4+ T cells specific to the pathogen by limiting dilution, the evaluation of pathogen specificity by detecting multiple cytokines, and the screening of the clones with synthetic combinatorial libraries, constitutes a novel and valuable approach for the elucidation of human CD4+ T cell specificity in response to large pathogens