The unexpected science of estrogen receptor-β selective agonists: a new class of anti-inflammatory agents?

In the nine years since the unexpected discovery of a second form of the estrogen receptor (ER), ERβ has been mentioned in about 2,800 literature citations. Such prolific research is testimony to interest in explaining its role in estrogen physiology as well as investigating its potential as a drug target. Our current understanding is that ERα, not ERβ is responsible for mediating the effects of estrogens in “classic” model systems such as the reproductive tract and skeleton. The role of ERβ is still being defined, but profiling of ERβ selective agonists in several animal models of human disease indicates these compounds may have utility as novel anti-inflammatory agents. The challenge for the future is to elucidate their mechanism of action and determine the clinical relevance of the impressive preclinical observations

Prion protein lacks robust cytoprotective activity in cultured cells

<p>Abstract</p> <p>Background</p> <p>The physiological function of the cellular prion protein (PrP^C) remains unknown. However, PrP^Chas been reported to possess a cytoprotective activity that prevents death of neurons and other cells after a toxic stimulus. To explore this effect further, we attempted to reproduce several of the assays in which a protective activity of PrP had been previously demonstrated in mammalian cells.</p> <p>Results</p> <p>In the first set of experiments, we found that PrP over-expression had a minimal effect on the death of MCF-7 breast carcinoma cells treated with TNF-α and <it>Prn-p</it>^{<it>0/0 </it>}immortalized hippocampal neurons (HpL3-4 cells) subjected to serum deprivation. In the second set of assays, we observed only a small difference in viability between cerebellar granule neurons cultured from PrP-null and control mice in response to activation of endogenous or exogenous Bax.</p> <p>Conclusion</p> <p>Taken together, our results suggest either that cytoprotection is not a physiologically relevant activity of PrP^C, or that PrP^C-dependent protective pathways operative <it>in vivo </it>are not adequately modeled by these cell culture systems. We suggest that cell systems capable of mimicking the neurotoxic effects produced in transgenic mice by N-terminally deleted forms of PrP or Doppel may represent more useful tools for analyzing the cytoprotective function of PrP^C.</p

Effect of a Fruit and Vegetable Prescription Program on Children's Fruit and Vegetable Consumption.

IntroductionMost children in families with low income do not meet dietary guidance on fruit and vegetable consumption. Fruit and vegetable prescription programs improve access to and affordability of health-supporting foods for adults, but their effect on dietary behavior among children is not known. The objective of this study was to describe the extent to which exposure to a fruit and vegetable prescription program was associated with changes in consumption among participants aged 2 to 18.MethodsWe used data from a modified National Cancer Institute screener to calculate fruit and vegetable intake among 883 children who were overweight or had obesity and participated in a 4- to 6-month fruit and vegetable prescription program at federally qualified health centers during 4 years (2012-2015). Secondary analyses in 2017 included paired t tests to compare change in fruit and vegetable consumption (cups/day) between first and last visits and multivariable linear regressions, including propensity dose-adjusted models, to model this change as a function of sociodemographic and program-specific covariates, such as number of clinical visits and value of prescription redemption.ResultsWe found a dose propensity-adjusted increase of 0.32 cups (95% confidence interval, 0.19-0.45 cups) for each additional visit while holding constant the predicted number of visits and site. An equal portion of the change-score increase was attributed to vegetable consumption and fruit consumption (β = 0.16 for each).ConclusionFruit and vegetable prescription programs in clinical settings may increase fruit and vegetable consumption among children in low-income households. Future research should use a comparison group and consider including qualitative analysis of site-specific barriers and facilitators to success

A single-blind, pilot randomised trial of a weight management intervention for adults with intellectual disabilities and obesity: study protocol

Background: The prevalence of obesity in adults with intellectual disabilities has consistently been reported to be higher than the general population. Despite the negative impact of obesity on health, there is little evidence of the effectiveness of weight management interventions for adults with intellectual disabilities and obesity. Preliminary results from a single-stranded feasibility study of a multi-component weight management intervention specifically designed for adults with intellectual disabilities and obesity (TAKE 5) and that satisfied clinical recommendations reported that it was acceptable to adults with intellectual disabilities and their carers. This study aims to determine the feasibility of a full-scale clinical trial of TAKE 5.&lt;p&gt;&lt;/p&gt; Methods: This study will follow a pilot randomised trial design. Sixty-six obese participants (body mass index (BMI) ≥30 kg/m2) will be randomly allocated to the TAKE 5 multi-component weight management intervention or a health education ‘active’ control intervention (Waist Winners Too (WWToo)). Both interventions will be delivered over a 12-month period. Participants’ anthropometric measures (body weight, BMI, waist circumference, percentage body fat); indicators of activity (levels of physical activity and sedentary behaviour) and well-being will be measured at three time points: baseline, 6 and 12 months. The researcher collecting outcome measures will be blind to study group allocation.&lt;p&gt;&lt;/p&gt; Conclusions: The data from this study will generate pilot data on the acceptability of randomisation, attrition rates and the estimates of patient-centred outcomes of TAKE 5, which will help inform future research and the development of a full-scale randomised clinical trial

Prion protein repeat expansion results in increased aggregation and reveals phenotypic variability

Mammalian prion diseases are fatal neurodegenerative disorders dependent on the prion protein PrP. Expansion of the oligopeptide repeats (ORE) found in PrP is associated with inherited prion diseases. Patients with ORE frequently harbor PrP aggregates, but other factors may contribute to pathology, as they often present with unexplained phenotypic variability. We created chimeric yeast-mammalian prion proteins to examine the influence of the PrP ORE on prion properties in yeast. Remarkably, all chimeric proteins maintained prion characteristics. The largest repeat expansion chimera displayed a higher propensity to maintain a self-propagating aggregated state. Strikingly, the repeat expansion conferred increased conformational flexibility, as observed by enhanced phenotypic variation. Furthermore, the repeat expansion chimera displayed an increased rate of prion conversion, but only in the presence of another aggregate, the [RNQ(+)] prion. We suggest that the PrP ORE increases the conformational flexibility of the prion protein, thereby enhancing the formation of multiple distinct aggregate structures and allowing more frequent prion conversion. Both of these characteristics may contribute to the phenotypic variability associated with PrP repeat expansion diseases

Acute Ingestion Of L-Arginine Alpha-Ketoglutarate Fails To Improve Muscular Strength And Endurance In ROTC Cadets

International Journal of Exercise Science 6(2) : 91-97, 2013. L-Arginine Alpha-Ketoglutarate (AAKG) is purported to stimulate the release of nitric oxide, and is suggested to facilitate muscular performance by increasing blood flow and increase oxygen and nutrient delivery to the working muscle. However, the ergogenic benefit of AAKG during resistance exercise has not been established. Therefore the purpose of this study was to investigate the effects of acute AAKG ingestion in active ROTC Cadets on measures of one-repetition maximal strength (1RM) and muscular endurance. Nineteen apparently healthy males ingested either AAKG (3 g) or a placebo 45 minutes prior to resistance testing in a randomized, double-blind crossover design. Initially, blood lactate (BLA) was obtained followed by 1RM testing on the barbell bench press and leg press. Upon determination of 1RM, participants completed repetitions to failure at 60% of 1RM. Blood lactate measures were immediately taken following the final repetition. Analysis revealed no significant differences between the conditions for bench press 1RM. Additionally, there were no differences between conditions for 1RM leg press, or for number of repetitions performed for the bench press or leg press. Blood lactate values did increase significantly from baseline to post-bench press in both the AAKG (t33 = 7.56, p \u3c 0.01) and placebo conditions (t33 = 8.45, p \u3c 0.01). Further, BLA lactate levels were also significantly greater post leg-press in the AAKG (t33 = 9.23, p \u3c 0.01) and placebo (t33 = 8.10, p \u3c 0.01). The results indicate that acute AAKG supplementation provides no ergogenic benefit in this study

Hair Follicle Dermal Cells Support Expansion of Murine and Human Embryonic and Induced Pluripotent Stem Cells and Promote Haematopoiesis in Mouse Cultures

In the hair follicle, the dermal papilla (DP) and dermal sheath (DS) support and maintain proliferation and differentiation of the epithelial stem cells that produce the hair fibre. In view of their regulatory properties, in this study, we investigated the interaction between hair follicle dermal cells (DP and DS) and embryonic stem cells (ESCs); induced pluripotent stem cells (iPSCs); and haematopoietic stem cells. We found that coculture of follicular dermal cells with ESCs or iPSCs supported their prolonged maintenance in an apparently undifferentiated state as established by differentiation assays, immunocytochemistry, and RT-PCR for markers of undifferentiated ESCs. We further showed that cytokines that are involved in ESC support are also expressed by cultured follicle dermal cells, providing a possible explanation for maintenance of ES cell stemness in cocultures. The same cytokines were expressed within follicles in situ in a pattern more consistent with a role in follicle growth activities than stem cell maintenance. Finally, we show that cultured mouse follicle dermal cells provide good stromal support for haematopoiesis in an established coculture model. Human follicular dermal cells represent an accessible and readily propagated source of feeder cells for pluripotent and haematopoietic cells and have potential for use in clinical applications

Clinical Features, Treatment, and Outcome of HIV-Associated Immune Thrombocytopenia in the HAART Era

The characteristics of HIV-associated ITP were documented prior to the HAART era, and the optimal treatment beyond HAART is unknown. We performed a review of patients with HIV-associated ITP and at least one platelet count <20 × 109/L since January 1996. Of 5290 patients in the BC Centre for Excellence in HIV/AIDS database, 31 (0.6%) had an ITP diagnosis and platelet count <20 × 109/L. Initial ITP treatment included IVIG, n = 12; steroids, n = 10; anti-RhD, n = 8; HAART, n = 3. Sixteen patients achieved response and nine patients achieved complete response according to the International Working Group criteria. Median time to response was 14 days. Platelet response was not significantly associated with treatment received, but complete response was lower in patients with a history of injection drug use. Complications of ITP treatment occurred in two patients and there were four unrelated deaths. At a median followup of 48 months, 22 patients (71%) required secondary ITP treatment. This is to our knowledge the largest series of severe HIV-associated ITP reported in the HAART era. Although most patients achieved a safe platelet count with primary ITP treatment, nearly all required retreatment for ITP recurrence. New approaches to the treatment of severe ITP in this population are needed