Thioredoxin reductase and glutathione peroxidase in the prevention of oxidative damage to vascular endothelium and the skin

Reactive oxygen species (ROS) contribute to the pathogenesis of a number of common and important diseases which include atherosclerosis and skin cancer. Selenium (Se) supplementation can protect skin and the endothelium from oxidative damage possibly by increasing the synthesis of antioxidant selenoproteins such as the family of glutathione peroxidases (GPX) and thioredoxin reductase (TR). The relative importance of TR and GPX in protecting endothelial cells (EC) and skin cells from oxidative damage was studied using the EAhy926 and HaCaT cell lines as models of human endothelial cells and keratinocytes, respectively. [⁷⁵Se]-labelled human umbilical vein EC (HUVEC) had a similar selenoprotein profile to EAhy926 cells. In HUVEC, human coronary artery EC (HCAEC), bovine aortic EC (BAEC) and EAhy926 cells, the expression of TR, cytoplasmic GPX (cyGPX) and phospholipid hydroperoxide GPX (PHGPX) was increased by incubating cells with increasing sodium selenite concentrations for 48 hr. Basal and Se- induced levels of these selenoproteins were similar in EAhy926 to HUVEC. BAEC differed considerably from HUVEC and EAhy926 cells in their selenoprotein expression. Therefore, EAhy926 cells appear to be a better model than BAEC for studies of selenoprotein function in humans. In EAhy926 cells TR, cyGPX and PHGPX activities were induced 1.9-fold, 5.3 -fold, and 2.6- fold respectively by sodium selenite supplementation (40 nM for 48 hr). Se-deficient EAhy926 cells were susceptible to oxidative damage by tertiary butyl hydroperoxide (tBuOOH) and oxidised low density lipoprotein (oxLDL), as assessed using percentage retention of LDH. Cytotoxicity was attenuated (p < 0.001) by pre-incubation with 40 nM sodium selenite, a concentration which maximally induced TR and cyGPX. Treatment of Se-deficient EAhy926 cells with gold thioglucose (GTG) (1 μM) significantly inhibited TR activity (74.8 % activity retained) (p < 0.01) but not cyGPX or PHGPX. Treated cells were more susceptible to oxidative damage by t-BuOOH (p < 0.05) or oxLDL (p < 0.05), suggesting that TR may provide antioxidant protection. Cells treated with 10 pM GTG showed inhibition of both TR and the GPXs (14.02 % TR activity (p < 0.001), 40.2 % cyGPX activity (p < 0.001), and 77.5 % PHGPX activity (p < 0.01) retained). Such cells were more susceptible to t-BuOOH toxicity than cells treated with 1 μM GTG (p < 0.05). Hence, both TR and the GPXs may be involved in the prevention of oxidative damage to human EC. In HaCaT cells, expression of TR and cyGPX was optimally induced by incubation with sodium selenite concentrations of 10 nM and 100 nM (increased activities of 2.8-fold and3.8 -fold, respectively). Sodium selenite-treated HaCaT cells were significantly protected from oxidative damage mediated by UVB (p < 0.001) or menadione (p < 0.01). Using UVB as the oxidative agent, loss of protection occurred at sodium selenite concentrations greater than 100 nM. At 1000 nM no protective effect of selenite was observed. There was an accompanying loss of cyGPX activity (p < 0.05), but not of TR or PHGPX expression. No loss of protection was demonstrated at the higher sodium selenite concentrations using menadione as oxidative stressor. The concentration of Se used for protection against UVB thus appears crucial. Se-deficient HaCaT cells incubated with a GTG concentration (10 pM) that significantly inhibited TR activity (18.1 % activity retained) (p < 0.001) but not the GPXs were more susceptible to damage by menadione (p < 0.05), but showed no increase in susceptibility to UVB- mediated damage. Treatment with a GTG concentration (100 pM) which significantly inhibited both TR (3.18 % activity retained) (p < 0.001) and cyGPX activity (33.3 % activity retained) (p < 0.001) increased the susceptibility of HaCaT cells to UVB damage when compared to controls (p < 0.01). The data suggest that menadione, a model agent for UVB oxidative stress, may produce misleading results. TR appears to be important in protecting cells against damage mediated by menadione, but cyGPX to be more important in preventing damage caused by UVB. The two different oxidative stress agents may thus differ in their mechanism of toxicity. TR expression regulated by Se supply and the redox state of the cell may affect cell growth. Changes in TR and cyGPX activity were investigated in human foetal (16-20 weeks gestation) and neonatal (1 day-15 weeks postnatal) liver cytosols. TR activity and concentration, and cyGPX activity in human foetal liver were approximately 3-fold greater than in neonatal liver. These human findings contrast markedly with results in the rat where TR and cyGPX activities increase throughout the foetal, newborn and adult stages. These results cast doubt on the rat as a model for studying cyGPX and TR in human development. In conclusion, the data presented in this thesis suggest that both cyGPX and TR are important contributors to the antioxidant defence mechanisms of EAhy926 and HaCaT cells, and may therefore help to protect against atherogenesis and skin cancer formation respectively

At the Center of Things: How an Academic Library Built a Bridge between Art and Science on Campus

The University of Houston Libraries sponsored an interdisciplinary event for students, faculty, and the public, titled the Artists’ Health and Wellness Colloquium and Resource Fair. Aspiring and working artists were instructed in how to maintain good health and to avoid overstressing their bodies as they practice their art. Scholars presented both historical and trending perspectives on the intersection of art and health science. The event was held in order to facilitate learning in two key research areas and to demonstrate the library\u27s ability to bridge disparate disciplines and forge new partnerships with multiple academic units simultaneously. This article presents planning strategies for librarians who seek to partner with dissimilar campus entities as part of event planning

Strengthening public health in South Africa: building a stronger evidence base for improving the health of the nation

An assessment of the relative burden attributable to selected risk factors provides an important evidence base for prioritising risk factors that should be targeted for public health interventions. Selecting interventions should be based on a robust and transparent process of scientific evaluations of their effectiveness, as well as assessment of their cost effectiveness, local applicability and appropriateness, and likely effects on health inequalities. Establishing such an evidence base is an ongoing process that is still at an early stage in South Africa. A recent review of disease control priorities for developing countries (DCPP) examined the global evidence regarding the effectiveness of interventions for major health burdens. Despite acknowledging the lack of intervention trials in developing countries, this DCPP review provides a unique resource for identifying interventions that might be useful in South Africa

Rituximab versus azathioprine as therapy for maintenance of remission for anti-neutrophil cytoplasm antibody-associated vasculitis (RITAZAREM): study protocol for a randomized controlled trial.

BACKGROUND: Rituximab is effective as therapy for induction of remission in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the effect of rituximab is not sustained, and subsequent relapse rates are high, especially in patients with a history of relapse. There is a need to identify whether maintenance therapy with rituximab is superior to the current standard of azathioprine or methotrexate for prevention of relapse following induction with rituximab. METHODS/DESIGN: RITAZAREM is an international, multicenter, open-label, randomized controlled trial designed to demonstrate the superiority of repeated doses of intravenous rituximab compared to daily orally administered azathioprine as a relapse prevention strategy in patients with AAV with relapsing disease who undergo induction of remission with rituximab. Patients with AAV will be recruited at the time of relapse and will receive rituximab and glucocorticoid induction therapy. If the disease is controlled by 4 months, patients will be randomized in a 1:1 ratio to receive rituximab (1000 mg every 4 months for five doses) or azathioprine (2 mg/kg/day) as maintenance therapy. Patients will be followed for a minimum of 36 months. The primary outcome is the time to disease relapse. It is estimated that 190 patients will need to be recruited to ensure that at least 160 are randomized. DISCUSSION: The RITAZAREM trial will provide the largest trial dataset for the use of rituximab as remission-induction therapy for patients with AAV comparing two remission-maintenance strategies following induction with rituximab, and explore whether prolonged B-cell depletion leads to sustained treatment-free remissions after discontinuation of immunosuppressive therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01697267 . Registered on 31 August 2012

Positive Youth Development: Processes, Programs, and Problematics

Using the tripartite conception of positive youth development (PYD) suggested by Hamilton (1999) – as a developmental process, a philosophy or approach to youth programming, and as instances of youth programs and organizations focused on fostering the healthy or positive development of youth – we review different theoretical models of the developmental process involved in PYD. In addition, we review the ideas for and the features of youth development programs aimed at promoting PYD. We discuss the need for research interrelating different, theoretically-predicated measures of PYD and, as well, the importance of clear links between models of the PYD developmental process and of the youth development programs seeking to enhance PYD among diverse youth. We discuss several conceptual and practical problematics that must be addressed in order to integrate the three facets of PYD scholarship