The Emperor's New Clothes: PDE5 and the Heart

Phosphodiesterase-5 (PDE5) is highly expressed in the pulmonary vasculature, but its expression in the myocardium is controversial. Cyclic guanosine monophosphate (cGMP) activates protein kinase G (PKG), which has been hypothesized to blunt cardiac hypertrophy and negative remodeling in heart failure. Although PDE5 has been suggested to play a significant role in the breakdown of cGMP in cardiomyocytes and hence PKG regulation in the myocardium, the RELAX trial, which tested effect of PDE5 inhibition on exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF) failed to show a beneficial effect. These results highlight the controversy regarding the role and expression of PDE5 in the healthy and failing heart. This study used one- and two-dimensional electrophoresis and Western blotting to examine PDE5 expression in mouse (before and after trans-aortic constriction), dog (control and HFpEF) as well as human (healthy and failing) heart. We were unable to detect PDE5 in any cardiac tissue lysate, whereas PDE5 was present in the murine and bovine lung samples used as positive controls. These results indicate that if PDE5 is expressed in cardiac tissue, it is present in very low quantities, as PDE5 was not detected in either humans or any model of heart failure examined. Therefore in cardiac muscle, it is unlikely that PDE5 is involved the regulation of cGMP-PKG signaling, and hence PDE5 does not represent a suitable drug target for the treatment of cardiac hypertrophy. These results highlight the importance of rigorous investigation prior to clinical trial design.     

Self-Medication Practices in Mekelle,Ethiopia

Background

Self-medication makes consumers more health conscious, reduces treatment burden on healthcare facilities and curtails the cost and time of obtaining access to treatment. However, it increases risks such as drug resistance, adverse drug reactions, incorrect diagnosis, drug interactions and polypharmacy. The purpose of this study was to assess the practices and factors associated with self-medication in Mekelle, Tigray region, Ethiopia.

Methods

A cross-sectional study was undertaken in Mekelle from February to March 2013. A structured and pre-tested questionnaire was used for data collection to assess self-medication practices. Data were analyzed using of Statistical Package for Social Sciences (SPSS) version 20.0.

Results

Among self-medicated study participants, 199(73.7%) were males and 71(26.3%) were females with mean age of 28.65 years. The most frequently reported illnesses or symptoms of illnesses that prompted self-medication of study participants were headache/fever (20.7%), gastrointestinal diseases (17.3%) and respiratory tract infections (15.9%) with the main reasons being mildness of the disease, prior experience and less expensive. The majority of drug consumers made their requests by telling their symptoms, by mentioning specific names of the drugs and by showing old samples. Analgesics/antipyretics, gastrointestinal drugs, respiratory drugs and oral rehydration salt were the most frequently requested categories of drugs. Pharmacists followed by other healthcare providers were the most frequently reported source of drug information for self-medication.

Conclusions

The results of this study demonstrated that self-medication practices were common for a wide range of illnesses. Health professionals, especially community pharmacists need to educate people on the benefits and risks of self-medication to encourage responsible self-medication.     

School Water,Sanitation, and Hygiene,Soil-Transmitted Helminths,and Schistosomes: National Mapping in Ethiopia

BackgroundIt is thought that improving water, sanitation, and hygiene (WASH) might reduce the transmission of schistosomes and soil-transmitted helminths, owing to their life cycles. However, few large-scale studies have yet assessed the real extent of associations between WASH and these parasites.Conclusions/SignificanceImproving school WASH may reduce transmission of these parasites. However, different forms of WASH appear to have different effects on infection with the various parasites, with our analysis finding the strongest associations between water and S. mansoni, sanitation and A. lumbricoides, and hygiene and hookworm.     

Anti-Remodeling Effects of Rapamycin in Experimental Heart Failure: Dose Response and Interaction with Angiotensin Receptor Blockade

While neurohumoral antagonists improve outcomes in heart failure (HF), cardiac remodeling and dysfunction progress and outcomes remain poor. Therapies superior or additive to standard HF therapy are needed. Pharmacologic mTOR inhibition by rapamycin attenuated adverse cardiac remodeling and dysfunction in experimental heart failure (HF). However, these studies used rapamycin doses that produced blood drug levels targeted for primary immunosuppression in human transplantation and therefore the immunosuppressive effects may limit clinical translation. Further, the relative or incremental effect of rapamycin combined with standard HF therapies targeting upstream regulators of cardiac remodeling (neurohumoral antagonists) has not been defined. Our objectives were to determine if anti-remodeling effects of rapamycin were preserved at lower doses and whether rapamycin effects were similar or additive to a standard HF therapy (angiotensin receptor blocker (losartan)). Experimental murine HF was produced by transverse aortic constriction (TAC). At three weeks post-TAC, male mice with established HF were treated with placebo, rapamycin at a dose producing immunosuppressive drug levels (target dose), low dose (50% target dose) rapamycin, losartan or rapamycin + losartan for six weeks. Cardiac structure and function (echocardiography, catheterization, pathology, hypertrophic and fibrotic gene expression profiles) were assessed. Downstream mTOR signaling pathways regulating protein synthesis (S6K1 and S6) and autophagy (LC3B-II) were characterized. TAC-HF mice displayed eccentric hypertrophy, systolic dysfunction and pulmonary congestion. These perturbations were attenuated to a similar degree by oral rapamycin doses achieving target (13.3±2.1 ng/dL) or low (6.7±2.5 ng/dL) blood levels. Rapamycin treatment decreased mTOR mediated regulators of protein synthesis and increased mTOR mediated regulators of autophagy. Losartan monotherapy did not attenuate remodeling, whereas Losartan added to rapamycin provided no incremental benefit over rapamycin alone. These data lend support to investigation of low dose rapamycin as a novel therapy in human HF.