Pancreatic Duct Cells in Human Islet Cell Preparations Are a Source of Angiogenic Cytokines Interleukin-8 and Vascular Endothelial Growth Factor

OBJECTIVE—Engraftment and function of human islet cell implants is considered to be dependent on their rapid and adequate revascularization. Studies with rodent islet grafts have shown that vascular endothelial growth factor (VEGF) expression by β-cells can promote this process. The present work examines whether human islet preparations produce VEGF as well as interleukin (IL)-8, another angiogenic protein, and assesses the role of contaminating duct cells in VEGF and IL-8–mediated angiogenesis

Characterization of the Autocrine/Paracrine Function of Vitamin D in Human Gingival Fibroblasts and Periodontal Ligament Cells

Background: We previously demonstrated that 25-hydroxyvitamin D-3, the precursor of 1 alpha,25-dihydroxyvitamin D-3, is abundant around periodontal soft tissues. Here we investigate whether 25-hydroxyvitamin D-3 is converted to 1 alpha,25-dihydroxyvitamin D-3 in periodontal soft tissue cells and explore the possibility of an autocrine/paracrine function of 1 alpha,25-dihydroxyvitamin D-3 in periodontal soft tissue cells. Methodology/Principal Findings: We established primary cultures of human gingival fibroblasts and human periodontal ligament cells from 5 individual donors. We demonstrated that 1 alpha-hydroxylase was expressed in human gingival fibroblasts and periodontal ligament cells, as was cubilin. After incubation with the 1 alpha-hydroxylase substrate 25-hydroxyvitamin D-3, human gingival fibroblasts and periodontal ligament cells generated detectable 1 alpha,25-dihydroxyvitamin D-3 that resulted in an up-regulation of CYP24A1 and RANKL mRNA. A specific knockdown of 1 alpha-hydroxylase in human gingival fibroblasts and periodontal ligament cells using siRNA resulted in a significant reduction in both 1 alpha, 25-dihydroxyvitamin D-3 production and mRNA expression of CYP24A1 and RANKL. The classical renal regulators of 1 alpha-hydroxylase (parathyroid hormone, calcium and 1 alpha,25-dihydroxyvitamin D-3) and Porphyromonas gingivalis lipopolysaccharide did not influence 1 alpha-hydroxylase expression significantly, however, interleukin-1 beta and sodium butyrate strongly induced 1 alpha-hydroxylase expression in human gingival fibroblasts and periodontal ligament cells. Conclusions/Significance: In this study, the expression, activity and functionality of 1 alpha-hydroxylase were detected in human gingival fibroblasts and periodontal ligament cells, raising the possibility that vitamin D acts in an autocrine/paracrine manner in these cells.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000305781700070&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Multidisciplinary SciencesSCI(E)PubMed13ARTICLE6e39878

Understanding non-governmental organizations in world politics: the promise and pitfalls of the early ‘science of internationalism’

The years immediately preceding the First World War witnessed the development of a significant body of literature claiming to establish a ‘science of internationalism’. This article draws attention to the importance of this literature, especially in relation to understanding the roles of non-governmental organizations in world politics. It elaborates the ways in which this literature sheds light on issues that have become central to twenty-first century debates, including the characteristics, influence, and legitimacy of non-governmental organizations in international relations. Amongst the principal authors discussed in the article are Paul Otlet, Henri La Fontaine and Alfred Fried, whose role in the development of international theory has previously received insufficient attention. The article concludes with evaluation of potential lessons to be drawn from the experience of the early twentieth century ‘science of internationalism’

Differential Cytokine Gene Expression According to Outcome in a Hamster Model of Leptospirosis

Leptospirosis is a widespread bacterial infection that is transmitted by soil or water contaminated by the urine of infected animals, or directly from these animals. It has highly diverse clinical presentations, making its differential diagnosis difficult. Though most cases are minor and self-resolving, there are also severe forms that include a sepsis pattern and multiple organ failure, and have possible fatal outcomes. Predictors of disease evolution and outcome are scarce, yet they would be very valuable to clinicians as well as to better decipher disease pathogenesis. In this study, we used a hamster model of leptospirosis to evaluate if immune genes were differentially expressed between individuals and if their expression levels could help forecast the outcome of the disease. We found that hamsters that later died from leptospirosis had significantly higher expression levels of both pro- and anti-inflammatory mediators compared to survivors. These results suggest that expression levels of these immune effectors might be helpful predictors of outcome in leptospirosis and that septic shock contributes to fatal leptospirosis

Dietary Vitamin D3 Supplements Reduce Demyelination in the Cuprizone Model

Vitamin D is emerging as a probably important environmental risk factor in multiple sclerosis, affecting both susceptibility and disease progression. It is not known to what extent this effect is due to a modulation of peripheral lymphocyte function, or to intrathecal effects of vitamin D. We investigated the effect of dietary vitamin D3 content on de/remyelination in the cuprizone model, which is a well established toxic model of demyelination, with no associated lymphocyte infiltration. The mice received diets either deficient of (<50 IU/kg), or supplemented with low (500 IU/kg), high (6200 IU/kg) or very high (12500 IU/kg) amounts of vit D3. Cuprizone (0.2%) was added to the diet for six weeks, starting two weeks after onset of the experimental diets. Mouse brain tissue was histopathologically evaluated for myelin and oligodendrocyte loss, microglia/macrophage activation, and lymphocyte infiltration after six weeks of cuprizone exposure, and two weeks after discontinuation of cuprizone exposure. High and very high doses of vitamin D3 significantly reduced the extent of white matter demyelination (p = 0.004) and attenuated microglia activation (p = 0.001). No differences in the density of oligodendrocytes were observed between the diet groups. Two weeks after discontinuation of cuprizone exposure, remyelination was only detectable in the white matter of mice receiving diets deficient of or with low vitamin D3 content. In conclusion, high dietary doses of vitamin D3 reduce the extent of demyelination, and attenuate microglia activation and macrophage infiltration in a toxic model of demyelination, independent of lymphocyte infiltration

Vitamin D and HIV Progression among Tanzanian Adults Initiating Antiretroviral Therapy

Background: There is growing evidence of an association between low vitamin D and HIV disease progression; however, no prospective studies have been conducted among adults receiving antiretroviral therapy (ART) in sub-Saharan Africa. Methods Serum 25-hydroxyvitamin D (25(OH)D) levels were assessed at ART initiation for a randomly selected cohort of HIV-infected adults enrolled in a trial of multivitamins (not including vitamin D) in Tanzania during 2006–2010. Participants were prospectively followed at monthly clinic visits for a median of 20.6 months. CD4 T-cell measurements were obtained every 4 months. Proportional hazard models were utilized for mortality analyses while generalized estimating equations were used for CD4 T-cell counts. Results: Serum 25(OH)D was measured in 1103 adults 9.2% were classified as vitamin D deficient (30 ng/mL). After multivariate adjustment, vitamin D deficiency was significantly associated with increased mortality as compared to vitamin D sufficiency (HR: 2.00; 95% CI: 1.19–3.37; p = 0.009), whereas no significant association was found for vitamin D insufficiency (HR: 1.24; 95% CI: 0.87–1.78; p = 0.24). No effect modification by ART regimen or change in the associations over time was detected. Vitamin D status was not associated with change in CD4 T-cell count after ART initiation. Conclusions: Deficient vitamin D levels may lead to increased mortality in individuals receiving ART and this relationship does not appear to be due to impaired CD4 T-cell reconstitution. Randomized controlled trials are needed to determine the safety and efficacy of vitamin D supplementation for individuals receiving ART

Protection from ultraviolet damage and photocarcinogenesis by vitamin d compounds

© Springer Nature Switzerland AG 2020. Exposure of skin cells to UV radiation results in DNA damage, which if inadequately repaired, may cause mutations. UV-induced DNA damage and reactive oxygen and nitrogen species also cause local and systemic suppression of the adaptive immune system. Together, these changes underpin the development of skin tumours. The hormone derived from vitamin D, calcitriol (1,25-dihydroxyvitamin D3) and other related compounds, working via the vitamin D receptor and at least in part through endoplasmic reticulum protein 57 (ERp57), reduce cyclobutane pyrimidine dimers and oxidative DNA damage in keratinocytes and other skin cell types after UV. Calcitriol and related compounds enhance DNA repair in keratinocytes, in part through decreased reactive oxygen species, increased p53 expression and/or activation, increased repair proteins and increased energy availability in the cell when calcitriol is present after UV exposure. There is mitochondrial damage in keratinocytes after UV. In the presence of calcitriol, but not vehicle, glycolysis is increased after UV, along with increased energy-conserving autophagy and changes consistent with enhanced mitophagy. Reduced DNA damage and reduced ROS/RNS should help reduce UV-induced immune suppression. Reduced UV immune suppression is observed after topical treatment with calcitriol and related compounds in hairless mice. These protective effects of calcitriol and related compounds presumably contribute to the observed reduction in skin tumour formation in mice after chronic exposure to UV followed by topical post-irradiation treatment with calcitriol and some, though not all, related compounds

INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes

Background The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials. Methods In this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. Discussion The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers