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  • br Methods The study covered vaccinations and survival

    2018-10-25


    Methods The study covered vaccinations and survival of all children born within the Matlab HDSS between 1986 and 1999 and with follow-up to December 31, 2001. The previous study analysed the role of vaccination for child survival between 6weeks and 9months of age when MV is supposed to be given and between 9 and 60months of age (Breiman et al., 2004). The present reanalysis focuses on BCG and DTP and is therefore limited to the 6weeks to 9months age group.
    Results
    Discussion
    Ethical Approval See Breiman et al., 2004.
    Role of the Funding Source
    Data Sharing
    Introduction Diabetic retinopathy (DR) is the number one cause of blindness among working age adults. Despite recent advances using pharmacotherapy, a cure for DR has yet to be realized. The recent evidence from large clinical trials demonstrating a strong association between lipid abnormalities and DR progression provides a unique opportunity to uncover innovative pathogenic mechanisms in DR (Ferris et al., 1996; Lyons et al., 2004; Keech et al., 2005). Specifically, recent studies demonstrate that intensive control of cholesterol levels can significantly slow down DR progression in type 2 diabetic individuals (Keech et al., 2005; Klein et al., 1999; Du et al., 2013). Unlike macrovascular complications, the Diabetes Control and Complications Trial (DCCT), Epidemiology of Diabetes Interventions and Complications (EDIC) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) eye trials, as well as Blue Mountain Eye Study and the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) studies did not find a direct correlation between the development of DR and circulating lipid levels, suggesting that retinal-specific mechanisms may be at play. We have previously demonstrated that diabetic dyslipidemia promotes retinal vascular degeneration at several levels. First, changes in retinal-specific lipid metabolism can contribute to low-grade chronic inflammation resulting in endothelial cell injury (Opreanu et al., 2011). Second, there is inadequate repair of the injured retinal toll like receptor by bone marrow-derived (BMD) circulating angiogenic cells (CACs) (Chakravarthy et al., 2016). These cells are exquisitely sensitive to the damaging diabetic milieu and are adversely impacted by dyslipidemia. Finally, activated myeloid cells promote a pro-inflammatory environment in the retina (Chakravarthy et al., 2016; Hazra et al., 2013). Thus, retinal endothelial cell injury, activated myeloid cells and failed attempts by CACs to repair injured retinal capillaries collectively result in progression to the vaso-degenerative stage of the disease. The role of diabetes-induced cholesterol metabolic abnormalities at each of these levels is addressed in this study. Cholesterol metabolism of retina and brain is unique among peripheral organs due to the tight barrier separating them from systemic circulation (Dietschy and Turley, 2001; Fliesler and Bretillon, 2010). In the brain, cholesterol is exclusively supplied by local synthesis. Retina also synthesizes cholesterol, but unlike brain, retina has mechanisms for cholesterol delivery from the systemic circulation (Fliesler et al., 1993; Pikuleva and Curcio, 2014; Tserentsoodol et al., 2006). In healthy retina, most of the blood-borne cholesterol is delivered via the outer blood retinal barrier (BRB) located at the RPE layer (Fliesler and Bretillon, 2010). In the diabetic retina, an abnormal increase in cholesterol uptake is observed in the inner BRB (retinal microvasculature) in addition to the outer BRB (Fliesler et al., 1993; Zheng et al., 2012). Retinal vasculature and RPE play an important role in cholesterol elimination. Unlike most peripheral tissues where HDL-mediated reverse cholesterol transport (RCT) represents the major pathway of cholesterol elimination, both RCT and metabolism of cholesterol to more soluble oxysterols, are active in the retina (Mast et al., 2011; Pikuleva and Curcio, 2014; Tserentsoodol et al., 2006). The first step of RCT, cellular efflux of cholesterol, is controlled by ATP binding cassette transporters ABCA1 and ABCG1, scavenger receptor class B type I (SR-BI), cluster of differentiation 36 (CD36), and caveolin-1, all expressed in the retina (Duncan et al., 2009; Tserentsoodol et al., 2006). The second elimination pathway, metabolism of cholesterol to more soluble oxysterols, is realized via cytochrome P450 enzymes (CYPs). The oxysterol profile of the retina suggests that all known pathways of cholesterol metabolism in extraocular organs are operative in the retina.