Perthes' disease of the hip: socioeconomic inequalities and the urban environment.

INTRODUCTION: Perthes' disease is a puzzling childhood hip disorder for which the aetiology is unknown. It is known to be associated with socioeconomic deprivation. Urban environments have also been implicated as a risk factor, however socioeconomic deprivation often occurs within urban environments and it is unclear if this association is the result of confounding. The objective of the current work was to gain a greater understanding of the influence of the urban/rural environment in Perthes' disease. METHODS: This was a descriptive observational study using the Scottish Morbidity Record, based in Scotland, UK using data from 2000-2010. A total of 443 patients with a discharge diagnosis of Perthes' disease were included. Socioeconomic deprivation was determined using the Scottish Index of Multiple Deprivation, and exposure to the 'urban environment' was recorded based on the Scottish Urban-Rural Classification. RESULTS: There was a strong association with socioeconomic deprivation, with rates among the most deprived quintile more than twice those of the most affluent (RR 2.1 (95% CI 1.5 to 2.9)). Urban areas had a greater rate of Perthes' disease discharges (RR 1.8 (95% CI 1.1 to 3.2)), though this was a reflection of greater deprivation in urban areas. Stratification for socioeconomic deprivation revealed similar discharge rates in urban and rural environments, suggesting that the aetiological determinants were not independently associated with urban environments. CONCLUSIONS: The occurrence of Perthes' disease within urban environments is high, yet this appears to be a reflection of higher socioeconomic deprivation exposure. Disease rates appear equivalent in similarly deprived urban and non-urban areas, suggesting that the determinant is not a consequence of the urban environment

Cerberus : a human powered vehicle

A recumbent trike was designed and built for the ASME Human Powered Vehicle Challenge held at San Jose State University in April of 2013. The vehicle was designed to be low cost for use by commuters and as primary transportation in developing countries. The vehicle placed 11th overall in the competition out of 29 teams, and scored 8th in the innovation event, which was its best ranking out of the 5 individual events

Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction

Diabetes, obesity and Alzheimer’s disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), APP and β-amyloid (Aβ) are linked with vascular disease development and raised BACE1 and Aβ accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, raised Aβ and vascular dysfunction is unclear. We report that diet-induced obesity (DIO) in mice raised plasma and vascular Aβ42 that correlated with decreased NO bioavailability, endothelial dysfunction and raised blood pressure. Genetic or pharmacological reduction of BACE1 activity and Aβ42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or Aβ42 infusion into control diet-fed mice to mimic obese levels impaired NO production, vascular relaxation and raised blood pressure. In humans, raised plasma Aβ42 correlated with diabetes and endothelial dysfunction. Mechanistically, higher Aβ42 reduced endothelial NO synthase (eNOS), cyclic GMP and protein kinase G (PKG) activity independently of diet whereas endothelin-1 was increased by diet and Aβ42. Lowering Aβ42 reversed the DIO deficit in the eNOS-cGMP-PKG pathway and decreased endothelin-1. Our findings suggest that BACE1 inhibitors may have therapeutic value in the treatment of vascular disease associated with diabetes

Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice.

Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age-related disease. The molecular mechanisms by which ExT induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that ExT might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery. Here, we show that aged (24-30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, ExT in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion. Interestingly, RNAseq of explanted hearts showed that ExT did not significantly modulate biological pathways targeted by conventional HF medications. However, it reversed multiple age-related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how ExT potentially reverses cardiac aging phenotypes in HFpEF

From cheek swabs to consensus sequences : an A to Z protocol for high-throughput DNA sequencing of complete human mitochondrial genomes

Background: Next-generation DNA sequencing (NGS) technologies have made huge impacts in many fields of biological research, but especially in evolutionary biology. One area where NGS has shown potential is for high-throughput sequencing of complete mtDNA genomes (of humans and other animals). Despite the increasing use of NGS technologies and a better appreciation of their importance in answering biological questions, there remain significant obstacles to the successful implementation of NGS-based projects, especially for new users. Results: Here we present an ‘A to Z’ protocol for obtaining complete human mitochondrial (mtDNA) genomes – from DNA extraction to consensus sequence. Although designed for use on humans, this protocol could also be used to sequence small, organellar genomes from other species, and also nuclear loci. This protocol includes DNA extraction, PCR amplification, fragmentation of PCR products, barcoding of fragments, sequencing using the 454 GS FLX platform, and a complete bioinformatics pipeline (primer removal, reference-based mapping, output of coverage plots and SNP calling). Conclusions: All steps in this protocol are designed to be straightforward to implement, especially for researchers who are undertaking next-generation sequencing for the first time. The molecular steps are scalable to large numbers (hundreds) of individuals and all steps post-DNA extraction can be carried out in 96-well plate format. Also, the protocol has been assembled so that individual ‘modules’ can be swapped out to suit available resources