Nesiritide: Harmful or Harmless?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90328/1/phco.26.10.1465.pd

Moisture transport by Atlantic tropical cyclones onto the North American continent

Tropical Cyclones (TCs) are an important source of freshwater for the North American continent. Many studies have tried to estimate this contribution by identifying TC-induced precipitation events, but few have explicitly diagnosed the moisture fluxes across continental boundaries. We design a set of attribution schemes to isolate the column-integrated moisture fluxes that are directly associated with TCs and to quantify the flux onto the North American Continent due to TCs. Averaged over the 2004–2012 hurricane seasons and integrated over the western, southern and eastern coasts of North America, the seven schemes attribute 7 to 18 % (mean 14 %) of total net onshore flux to Atlantic TCs. A reduced contribution of 10 % (range 9 to 11 %) was found for the 1980–2003 period, though only two schemes could be applied to this earlier period. Over the whole 1980–2012 period, a further 8 % (range 6 to 9 % from two schemes) was attributed to East Pacific TCs, resulting in a total TC contribution of 19 % (range 17 to 22 %) to the ocean-to-land moisture transport onto the North American continent between May and November. Analysis of the attribution uncertainties suggests that incorporating details of individual TC size and shape adds limited value to a fixed radius approach and TC positional errors in the ERA-Interim reanalysis do not affect the results significantly, but biases in peak wind speeds and TC sizes may lead to underestimates of moisture transport. The interannual variability does not appear to be strongly related to the El Nino-Southern Oscillation phenomenon

Upregulated sirtuin 1 by miRNA-34a is required for smooth muscle cell differentiation from pluripotent stem cells

© 2015 Macmillan Publishers Limited. All rights reserved. microRNA-34a (miR-34a) and sirtuin 1 (SirT1) have been extensively studied in tumour biology and longevityaging, but little is known about their functional roles in smooth muscle cell (SMC) differentiation from pluripotent stem cells. Using well-established SMC differentiation models, we have demonstrated that miR-34a has an important role in SMC differentiation from murine and human embryonic stem cells. Surprisingly, deacetylase sirtuin 1 (SirT1), one of the top predicted targets, was positively regulated by miR-34a during SMC differentiation. Mechanistically, we demonstrated that miR-34a promoted differentiating stem cells' arrest at G0G1 phase and observed a significantly decreased incorporation of miR-34a and SirT1 RNA into Ago2-RISC complex upon SMC differentiation. Importantly, we have identified SirT1 as a transcriptional activator in the regulation of SMC gene programme. Finally, our data showed that SirT1 modulated the enrichment of H3K9 tri-methylation around the SMC gene-promoter regions. Taken together, our data reveal a specific regulatory pathway that miR-34a positively regulates its target gene SirT1 in a cellular context-dependent and sequence-specific manner and suggest a functional role for this pathway in SMC differentiation from stem cells in vitro and in vivo

Maternal Obesity during Gestation Impairs Fatty Acid Oxidation and Mitochondrial SIRT3 Expression in Rat Offspring at Weaning

In utero exposure to maternal obesity increases the offspring's risk of obesity in later life. We have also previously reported that offspring of obese rat dams develop hepatic steatosis, mild hyperinsulinemia, and a lipogenic gene signature in the liver at postnatal day (PND)21. In the current study, we examined systemic and hepatic adaptations in male Sprague-Dawley offspring from lean and obese dams at PND21. Indirect calorimetry revealed decreases in energy expenditure (p<0.001) and increases in RER values (p<0.001), which were further exacerbated by high fat diet (45% kcals from fat) consumption indicating an impaired ability to utilize fatty acids in offspring of obese dams as analyzed by PRCF. Mitochondrial function is known to be associated with fatty acid oxidation (FAO) in the liver. Several markers of hepatic mitochondrial function were reduced in offspring of obese dams. These included SIRT3 mRNA (p = 0.012) and mitochondrial protein content (p = 0.002), electron transport chain complexes (II, III, and ATPase), and fasting PGC-1α mRNA expression (p<0.001). Moreover, hepatic LCAD, a SIRT3 target, was not only reduced 2-fold (p<0.001) but was also hyperacetylated in offspring of obese dams (p<0.005) suggesting decreased hepatic FAO. In conclusion, exposure to maternal obesity contributes to early perturbations in whole body and liver energy metabolism. Mitochondrial dysfunction may be an underlying event that reduces hepatic fatty acid oxidation and precedes the development of detrimental obesity associated co-morbidities such as insulin resistance and NAFLD

Pharmacological screening using an FXN-EGFP cellular genomic reporter assay for the therapy of Friedreich ataxia

Copyright @ 2013 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in the inhibition of gene expression and an insufficiency of the mitochondrial protein frataxin. There is a correlation between expansion length, the amount of residual frataxin and the severity of disease. As the coding sequence is unaltered, pharmacological up-regulation of FXN expression may restore frataxin to therapeutic levels. To facilitate screening of compounds that modulate FXN expression in a physiologically relevant manner, we established a cellular genomic reporter assay consisting of a stable human cell line containing an FXN-EGFP fusion construct, in which the EGFP gene is fused in-frame with the entire normal human FXN gene present on a BAC clone. The cell line was used to establish a fluorometric cellular assay for use in high throughput screening (HTS) procedures. A small chemical library containing FDA-approved compounds and natural extracts was screened and analyzed. Compound hits identified by HTS were further evaluated by flow cytometry in the cellular genomic reporter assay. The effects on FXN mRNA and frataxin protein levels were measured in lymphoblast and fibroblast cell lines derived from individuals with FRDA and in a humanized GAA repeat expansion mouse model of FRDA. Compounds that were established to increase FXN gene expression and frataxin levels included several anti-cancer agents, the iron-chelator deferiprone and the phytoalexin resveratrol.Muscular Dystrophy Association (USA), the National Health and Medical Research Council (Australia), the Friedreich’s Ataxia Research Alliance (USA), the Brockhoff Foundation (Australia), the Friedreich Ataxia Research Association (Australasia), Seek A Miracle (USA) and the Victorian Government’s Operational Infrastructure Support Program

Using Routinely Collected Administrative Data in Public Health Research: Geocoding Alcohol Outlet Data

We describe our process of geocoding alcohol outlets to create a national longitudinal exposure dataset for Wales, United Kingdom from 2006 to 2011. We investigated variation in the availability of data items and the quality of alcohol outlet addresses held within unitary authorities. We used a standard geocoding method augmented with a manual matching procedure to achieve a fully spatially referenced dataset. We found higher quality addresses are held for outlets based in urban areas, resulting in the automatic geocoding of 68 % of urban outlets, compared to 48 % in rural areas. Missing postcodes and a lack of address structure contributed to a lower geocoding proportion. An urban rural bias was removed with the development of a manual matching procedure. Only one-half of the unitary authorities provided data on on/off sales and opening times, which are important availability factors. The resulting outlet dataset is suitable for contributing to the evidence-base of alcohol availability and alcohol-related harm. Local government should be encouraged to use standardised data fields, including addresses, to enable accurate geocoding of alcohol outlets and facilitate research that aims to prevent alcohol-related harm. Standardising data collection would enable efficient secondary data reuse using record linkage techniques, allowing the retrospective creation and evaluation of population-based natural experiments to provide evidence for policy and practice

Steep HIV prevalence declines among young people in selected Zambian communities: population-based observations (1995–2003)

BACKGROUND: Understanding the epidemiological HIV context is critical in building effective setting-specific preventive strategies. We examined HIV prevalence patterns in selected communities of men and women aged 15–59 years in Zambia. METHODS: Population-based HIV surveys in 1995 (n = 3158), 1999 (n = 3731) and 2003 (n = 4751) were conducted in selected communities using probability proportional to size stratified random-cluster sampling. Multivariate logistic regression and trend analyses were stratified by residence, sex and age group. Absence, <30% in men and <15% in women in all rounds, was the most important cause of non-response. Saliva was used for HIV testing, and refusal was <10%. RESULTS: Among rural groups aged 15–24 years, prevalence declined by 59.2% (15.7% to 6.4%, P < 0.001) in females and by 44.6% (5.6% to 3.1%, P < 0.001) in males. In age-group 15–49 years, declines were less than 25%. In the urban groups aged 15–24, prevalence declined by 47% (23.4% to 12.4%, P < 0.001) among females and 57.3% (7.5% to 3.2%, P = 0.001) among males but were 32% and 27% in men and women aged 15–49, respectively. Higher educated young people in 2003 had lower odds of infection than in 1995 in both urban [men: AOR 0.29(95%CI 0.14–0.60); women: AOR 0.38(95%CI 0.19–0.79)] and rural groups [men: AOR 0.16(95%CI 0.11–0.25), women: AOR 0.10(95%CI 0.01–7.34)]. Although higher mobility was associated with increased likelihood of infection in men overall, AOR, 1.71(95%CI 1.34–2.19), prevalence declined in mobile groups also (OR 0.52 95%CI 0.31–0.88). In parallel, urban young people with ≥11 school years were more likely to use condoms during the last casual sex (OR 2.96 95%CI 1.93–4.52) and report less number of casual sexual partners (AOR 0.33 95%CI 0.19–0.56) in the last twelve months than lower educated groups. CONCLUSION: Steep HIV prevalence declines in young people, suggesting continuing declining incidence, were masked by modest overall declines. The concentration of declines in higher educated groups suggests a plausible association with behavioural change