The Leeds Winter Warmth Campaign: Stakeholder Evaluation

The winter of 2012/13 was longer and colder than usual; whilst temperatures were average in December, it was colder than usual from January through to May. March was the coldest it has been for 50 years (Met Office, 2013). This evaluation focuses on the organisations funded by the Winter Warmth campaign to deliver services to Leeds residents. The overriding aim of the evaluation was to inform the operation of possible future schemes, with good practices and any issues identified. The views of organisations on the need for the funds and how the campaign was organised were ascertained. How they delivered the services, reached clients and worked with other stakeholders is explored and their suggestions for improvements described. This report should be read alongside the overall campaign report, by Leeds City Council, and the beneficiary report

Reduced microrna-150 is associated with poor survival in pulmonary arterial hypertension

Rationale: MicroRNAs (miRNAs or miRs) are implicated in the pathogenesis of various cardiovascular diseases, including pulmonary arterial hypertension (PAH). Objectives: We sought to measure changes in plasma levels of miRNAs in patients with PAH and relate them to the severity of the disease. Methods: A microarray screen was performed on total plasma RNA from eight patients with PAH and eight healthy control subjects. Quantitative polymerase chain reaction confirmed reduced miR-150 concentrations and was then used to measure miR-150 levels in (1) two separate cohorts of patients with PAH, from London (n = 145) and Sheffield (n = 30), respectively; (2) circulating microvesicles and blood cells; and (3) lungs from a monocrotaline rat model. Measurements and Main Results: Fifty-eight miRNAs showed differences in plasma concentration and miR-150 the largest downregulation in PAH. Receiver-operator-characteristic analysis showed both raw and normalized plasma miR-150 levels correlated with 2-year survival (P,0.01) in patientswith PAH. Cox regression analysis confirmed miR-150 levels as a significant predictor of survival. Age, baseline cardiac index, World Health Organization functional class, 6-minute walk distance, disease duration, and red cell distribution width also predicted survival. Entering these covariates in a multivariable model verified plasma miR-150 levels as an independent predictor of survival in PAH (hazard ratio, 0.533; P = 0.010). miR-150 levels alsopredictedsurvival ina second, independent PAH cohort. miR-150 levels were significantly reduced in circulating microvesicles from patients with PAH and the lungs of the monocrotaline rat. Conclusions: Reduced circulating miR-150 levels are associated with poor survival in PAH

Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1

JmjC domain-containing proteins play a crucial role in the control of gene expression by acting as protein hydroxylases or demethylases, thereby controlling histone methylation or splicing. Here, we demonstrate that silencing of Jumonji domain-containing protein 6 (Jmjd6) impairs angiogenic functions of endothelial cells by changing the gene expression and modulating the splicing of the VEGF-receptor 1 (Flt1). Reduction of Jmjd6 expression altered splicing of Flt1 and increased the levels of the soluble form of Flt1, which binds to VEGF and placental growth factor (PlGF) and thereby inhibits angiogenesis. Saturating VEGF or PlGF or neutralizing antibodies directed against soluble Flt1 rescued the angiogenic defects induced by Jmjd6 silencing. Jmjd6 interacts with the splicing factors U2AF65 that binds to Flt1 mRNA. In conclusion, Jmjd6 regulates the splicing of Flt1, thereby controlling angiogenic sprouting