Relationships Between Ion Channels, Mitochondrial Functions and Inflammation in Human Aging

Aging is often associated with a loss of function. We believe aging to be more an adaptation to the various, and often continuous, stressors encountered during life in order to maintain overall functionality of the systems. The maladaptation of a system during aging may increase the susceptibility to diseases. There are basic cellular functions that may influence and/or are influenced by aging. Mitochondrial function is amongst these. Their presence in almost all cell types makes of these valuable targets for interventions to slow down or even reserve signs of aging. In this review, the role of mitochondria and essential physiological regulators of mitochondria and cellular functions, ion channels, will be discussed in the context of human aging. The origins of inflamm-aging, associated with poor clinical outcomes, will be linked to mitochondria and ion channel biology

Abnormal thymic stromal lymphopoietin expression in the duodenal mucosa of patients with coeliac disease

OBJECTIVE: The short isoform of thymic stromal lymphopoietin (TSLP), a cytokine constitutively expressed by epithelial cells, is crucial in preserving immune tolerance in the gut. TSLP deficiency has been implicated in sustaining intestinal damage in Crohn's disease. We explored mucosal TSLP expression and function in refractory and uncomplicated coeliac disease (CD), a T-cell-mediated enteropathy induced by gluten in genetically susceptible individuals. DESIGN: TSLP isoforms-long and short-and receptors-TSLPR and interleukin (IL)-7Rα-were assessed by immunofluorescence, immunoblotting and qRT-PCR in the duodenum of untreated, treated, potential and refractory patients with CD. The ability of the serine protease furin or CD biopsy supernatants to cleave TSLP was evaluated by immunoblotting. The production of interferon (IFN)-γ and IL-8 by untreated CD biopsies cultured ex vivo with TSLP isoforms was also assessed. RESULTS: Mucosal TSLP, but not TSLPR and IL-7Rα, was reduced in untreated CD and refractory CD in comparison to treated CD, potential CD and controls. Transcripts of both TSLP isoforms were decreased in active CD mucosa. Furin, which was overexpressed in active CD biopsies, was able to cleave TSLP in vitro. Accordingly, refractory and untreated CD supernatants showed higher TSLP-degrading capacity in comparison to treated CD and control supernatants. In our ex vivo model, both TSLP isoforms significantly downregulated IFN-γ and IL-8 production by untreated CD biopsies. CONCLUSIONS: Reduced mucosal TSLP expression may contribute to intestinal damage in refractory and untreated CD. Further studies are needed to verify whether restoring TSLP might be therapeutically useful especially in refractory patients with CD

An examination of the Apo-1/Fas promoter Mva I polymorphism in Japanese patients with multiple sclerosis

BACKGROUND: The Apo-1/Fas (CD95) molecule is an apoptosis-signaling cell surface receptor belonging to the tumor necrosis factor (TNF) receptor family. Both Fas and Fas ligand (FasL) are expressed in activated mature T cells, and prolonged cell activation induces susceptibility to Fas-mediated apoptosis. The Apo-1/Fas gene is located in a chromosomal region that shows linkage in multiple sclerosis (MS) genome screens, and studies indicate that there is aberrant expression of the Apo-1/Fas molecule in MS. METHODS: Mva I polymorphism on the Apo-1/Fas promoter gene was detected by PCR-RFLP from the DNA of 114 Japanese patients with conventional MS and 121 healthy controls. We investigated the association of the Mva I polymorphism in Japanese MS patients using a case-control association study design. RESULTS: We found no evidence that the polymorphism contributes to susceptibility to MS. Furthermore, there was no association between Apo-1/Fas gene polymorphisms and clinical course (relapsing-remitting course or secondary-progressive course). No significant association was observed between Apo-1/Fas gene polymorphisms and the age at disease onset. CONCLUSIONS: Overall, our findings suggest that Apo-1/Fas promoter gene polymorphisms are not conclusively related to susceptibility to MS or the clinical characteristics of Japanese patients with MS

Designing bus transit services for routine crowd situations at large event venues

National Research Foundation (NRF) Singapore under International Research Centres in Singapore Funding Initiativ

Variation in The Vitamin D Receptor Gene is Associated With Multiple Sclerosis in an Australian Population

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) resulting in accumulating neurological disability. The disorder is more prevalent at higher latitudes. To investigate VDR gene variation using three intragenic restriction fragment length polymorphisms (Apa I, Taq I and Fok I) in an Australian MS case-control population, one hundred and four Australian MS patients were studied with patients classified clinically as Relapsing Remitting MS (RR-MS), Secondary Progressive MS (SP-MS) or Primary Progressive MS (PP-MS). Also, 104 age-, sex-, and ethnicity-matched controls were investigated as a comparative group. Our results show a significant difference of genotype distribution frequency between the case and control groups for the functional exon 9 VDR marker Taq I (p_Gen = 0.016) and interestingly, a stronger difference for the allelic frequency (p_All = 0.0072). The Apa I alleles were also found to be associated with MS (p_All = 0.04) but genotype frequencies were not significantly different from controls (p_Gen = 0.1). The Taq and Apa variants are in very strong and significant linkage disequilibrium (D' = 0.96, P < 0.0001). The genotypic associations are strongest for the progressive forms of MS (SP-MS and PP-MS). Our results support a role for the VDR gene increasing

Experiences of the implementation of a tool for lifestyle intervention in primary health care: a qualitative study among managers and professional groups

<p>Abstract</p> <p>Background</p> <p>In recent years there has been increasing interest in transferring new knowledge into health care practices, a process often referred to as implementation. The various subcultures that exist among health care workers may be an obstacle in this process. The aim of this study was to explore how professional groups and managers experienced the implementation of a new tool for lifestyle intervention in primary health care (PHC). The computer-based tool was introduced with the intention of facilitating the delivery of preventive services.</p> <p>Methods</p> <p>Focus group interviews with staff and individual interviews with managers at six PHC units in the southeast of Sweden were performed 9 months after the introduction of the new working tool. Staff interviews were conducted in groups according to profession, and were analysed using manifest content analysis. Experiences and opinions from the different staff groups and from managers were analysed.</p> <p>Results</p> <p>Implementation preconditions, opinions about the lifestyle test, and opinions about usage were the main areas identified. In each of the groups, managers and professionals, factors related to the existing subcultures seemed to influence their experiences of the implementation. Managers were visionary, GPs were reluctant, nurses were open, and nurse assistants were indifferent.</p> <p>Conclusion</p> <p>This study indicates that the existing subcultures in PHC influence how the implementation of an innovation is perceived by managers and the different professionals. In PHC, an organization with several subcultures and an established hierarchical structure, an implementation strategy aimed at all groups did not seem to result in a successful uptake of the new method.</p

Gammaherpesvirus Latency Accentuates EAE Pathogenesis: Relevance to Epstein-Barr Virus and Multiple Sclerosis

Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS), yet EBV's role in MS remains elusive. We utilized murine gamma herpesvirus 68 (γHV-68), the murine homolog to EBV, to examine how infection by a virus like EBV could enhance CNS autoimmunity. Mice latently infected with γHV-68 developed more severe EAE including heightened paralysis and mortality. Similar to MS, γHV-68EAE mice developed lesions composed of CD4 and CD8 T cells, macrophages and loss of myelin in the brain and spinal cord. Further, T cells from the CNS of γHV-68 EAE mice were primarily Th1, producing heightened levels of IFN-γ and T-bet accompanied by IL-17 suppression, whereas a Th17 response was observed in uninfected EAE mice. Clearly, γHV-68 latency polarizes the adaptive immune response, directs a heightened CNS pathology following EAE induction reminiscent of human MS and portrays a novel mechanism by which EBV likely influences MS and other autoimmune diseases