Rag GTPases are cardioprotective by regulating lysosomal function.

The Rag family proteins are Ras-like small GTPases that have a critical role in amino-acid-stimulated mTORC1 activation by recruiting mTORC1 to lysosome. Despite progress in the mechanistic understanding of Rag GTPases in mTORC1 activation, little is known about the physiological function of Rag GTPases in vivo. Here we show that loss of RagA and RagB (RagA/B) in cardiomyocytes results in hypertrophic cardiomyopathy and phenocopies lysosomal storage diseases, although mTORC1 activity is not substantially impaired in vivo. We demonstrate that despite upregulation of lysosomal protein expression by constitutive activation of the transcription factor EB (TFEB) in RagA/B knockout mouse embryonic fibroblasts, lysosomal acidification is compromised owing to decreased v-ATPase level in the lysosome fraction. Our study uncovers RagA/B GTPases as key regulators of lysosomal function and cardiac protection

Children's experiences of care on walking and cycling journeys between home and school in Healthy New Towns: Reframing active school travel

The Healthy New Town programme in England set out to ‘put health into place’ by supporting the design and construction of healthy places to live, including by creating safe environments for active travel. To explore the impact of this approach, this study examined how children and their families experienced school journeys in two contrasting Healthy New Towns in England, one an affluent new town in the early stages of construction and the other more economically deprived and established. We undertook photo-elicitation and go-along interviews with 24 children aged 7-12 years and semi-structured interviews with 17 caregivers. We found that experiences of care were important for children's school travel. In the ‘deprived’ town, opportunities for children to care and to be cared for were enjoyed, facilitated by routes with limited traffic, pockets of ‘nature’, and possibilities to encounter meaningful others. For families living in a town under construction, the need to negotiate unfinished travel infrastructure, and a sense of being ‘in limbo’, was experienced as an absence of care by planners and developers. Interventions to promote children's active travel should consider the role of care-full planning in facilitating walking and cycling journeys

Standardising Costs or Standardising Care? Qualitative Evaluation of the Implementation and Impact of a Hospital Funding Reform in Ontario, Canada

Background  Since 2011, the Government of Ontario, Canada, has phased in hospital funding reforms hoping to encourage standardised, evidence-based clinical care processes to both improve patient outcomes and reduce system costs. One aspect of the reform – quality-based procedures (QBPs) – replaced some of each hospital’s global budget with a pre-set price per episode of care for patients with specific diagnoses or procedures. The QBP initiative included publication and dissemination of a handbook for each of these diagnoses or procedures, developed by an expert technical group. Each handbook was intended to guide hospitals in reducing inappropriate variation in patient care and cost by specifying an evidence-based episode of care pathway. We explored whether, how and why hospitals implemented these episode of care pathways in response to this initiative. Methods  We interviewed key informants at three levels in the healthcare system, namely individuals who conceived and designed the QBP policy, individuals and organisations supporting QBP adoption, and leaders in five case-study hospitals responsible for QBP implementation. Analysis involved an inductive approach, incorporating framework analysis to generate descriptive and explanatory themes from data. Results  The 46 key informants described variable implementation of best practice episode of care pathways across QBPs and across hospitals. Handbooks outlining evidence-based clinical pathways did not address specific barriers to change for different QBPs nor differences in hospitals’ capacity to manage change. Hospitals sometimes found it easier to focus on containing and standardising costs of care than on implementing standardised care processes that adhered to best clinical practices. Conclusion  Implementation of QBPs in Ontario’s hospitals depended on the interplay between three factors, namely complexity of changes required, internal capacity for organisational change, and availability and appropriateness of targeted external facilitators and supports to manage change. Variation in these factors across QBPs and hospitals suggests the need for more tailored and flexible implementation supports designed to fit all elements of the policy, rather than one-size-fits-all handbooks alone. Without such supports, hospitals may enact quick fixes aimed mainly at preserving budgets, rather than pursue evidence- and value-based changes in care management. Overestimating hospitals’ change management capacity increases the risk of implementation failure

Source-specific pollution exposure and associations with pulmonary response in the Atlanta Commuters Exposure Studies

Concentrations of traffic-related air pollutants are frequently higher within commuting vehicles than in ambient air. Pollutants found within vehicles may include those generated by tailpipe exhaust, brake wear, and road dust sources, as well as pollutants from in-cabin sources. Sourcespecific pollution, compared to total pollution, may represent regulation targets that can better protect human health. We estimated source-specific pollution exposures and corresponding pulmonary response in a panel study of commuters. We used constrained positive matrix factorization to estimate source-specific pollution factors and, subsequently, mixed effects models to estimate associations between source-specific pollution and pulmonary response. We identified four pollution factors that we named: crustal, primary tailpipe traffic, non-tailpipe traffic, and secondary. Among asthmatic subjects (N=48), interquartile range increases in crustal and secondary pollution were associated with changes in lung function of −1.33% (95% confidence interval (CI): −2.45, −0.22) and −2.19% (95% CI: −3.46, −0.92) relative to baseline, respectively. Among non-asthmatic subjects (N=51), non-tailpipe pollution was associated with pulmonary response only at 2.5 hours post-commute. We found no significant associations between pulmonary response and primary tailpipe pollution. Health effects associated with traffic-related pollution may vary by source, and therefore some traffic pollution sources may require targeted interventions to protect healt

Human malaria diagnosis using a single-step direct-PCR based on the Plasmodium cytochrome oxidase III gene

Background: Nested PCRs based on the Plasmodium 18s-rRNA gene have been extensively used for human malaria diagnosis. However, they are not practical when large quantities of samples need to be processed, further there have been challenges in the performance and when interpreting results, especially when submicroscopic infections are analysed. Here the use of "direct PCR" was investigated with the aim of improving diagnosis in the malaria elimination era.\ud \ud Methods: The performance of the Plasmodium cytochrome oxidase III gene (COX-III) based novel malaria detection strategies (direct nested PCR and direct single PCR) were compared using a 18s-rRNA direct nested PCR as a reference tool. Evaluations were based on sensitivity, specificity and the ability to detect mixed infections using control blood spot samples and field collected blood samples with final species diagnosis confirmation by sequencing.\ud \ud Results: The COX-III direct PCR (limit of detection: 0.6–2 parasites/μL) was more sensitive than the 18s-rRNA direct nested PCR (limit of detection: 2–10 parasites/μL). The COX-III direct PCR identified all 21 positive controls (no mixed infections detected) while the 18s-rRNA direct nested PCR identified 18/21 (including four mixed infections). Different concentrations of simulated mixed infections (Plasmodium vivax and Plasmodium falciparum) suggest that the COX-III direct PCR detects only the predominant species. When the 18s-rRNA direct nested PCR was used to detect Plasmodium in field collected bloods spots (n = 3833), there was discrepancy in the results from the genus PCR (16 % positive) and the species-specific PCR (5 % positive). Further, a large portion of a subset of these positive samples (93 % for genus and 60 % for P. vivax), did not align with Plasmodium sequences. In contrast, the COX-III direct PCR clearly identified (single bands confirmed with sequencing) 2 % positive Plasmodium samples including P. vivax, P. falciparum, Plasmodium malariae and Plasmodium ovale wallikeri.\ud \ud Conclusions: The COX-III single direct PCR is an alternative method for accurate detection of Plasmodium microscopic and submicroscopic infections in humans, especially when a large number of samples require screening. This PCR does not require DNA isolation, is sensitive, quick, produces confident/clear results, identifies all the Plasmodium species infecting humans, and is cost-effective.\u

Book Reviews

Reviews of the following books: Mainers in the Civil War by Harry Gratwick; The 22nd Maine Volunteer Infantry in the Civil War: A History and Roster by Ned Smith; Write Quick: War and a Woman\u27s Life in Letters 1835-1867 Edited by Ann Fox Chandonnet and Robert Gibson Pevear; Civil War Senator: William Pitt Fessenden and the Fight to Save the American Republic by Robert J. Cook; Lincoln\u27s Friend: Leonard Swett by Robert S. Eckley; We Are in His Hands Whether We Live or Die: The Letters of Brevet Brigadier General Charles Henry Howard edited by David K. Thomson; Fanny & Joshua: The Enigmatic Lives of Frances Caroline Adams and Joshua Lawrence Chamberlain by Diane Monroe Smith; This Birth Place of Souls:The Civil War Nursing Diary of Harriet Eaton edited with an Introduction by Jane E. Schultz; Army at Home: Women and the Civil War on the Northern Home Front by Judith Giesberg; A Visitation of God: Northern Civilians Interpret the Civil War by Sean A. Scott; Freedom National: The Destruction of Slavery in the United States, 1861-1865 by James Oakes; War Upon the Land: Military Strategy and the Transformation of Southern Landscapes during the American Civil War by Lisa M. Brady; Remembering the Civil War: Reunion and the Limits of Reconciliation by Caroline E. Janne

Mineralocorticoid receptor antagonism attenuates vascular apoptosis and injury via rescuing protein kinase B activation

This article may also be found at the publisher's website at http://hyper.ahajournals.org/cgi/content/abstract/53/2/158?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=habibi&searchid=1&FIRSTINDEX=0&resourcetype=HWCITEmerging evidence indicates that mineralocorticoid receptor (MR) blockade reduces the risk of cardiovascular events beyond those predicted by its blood pressure-lowering actions; however, the underlying mechanisms remain unclear. To investigate whether protection elicited by MR blockade is through attenuation of vascular apoptosis and injury, independently of blood pressure lowering, we administered a low dose of the MR antagonist spironolactone or vehicle for 21 days to hypertensive transgenic Ren2 rats with elevated plasma aldosterone levels. Although Ren2 rats developed higher systolic blood pressures compared with Sprague-Dawley littermates, low-dose spironolactone treatment did not reduce systolic blood pressure compared with untreated Ren2 rats. Ren2 rats exhibited vascular injury as evidenced by increased apoptosis, hemidesmosome-like structure loss, mitochondrial abnormalities, and lipid accumulation compared with Sprague-Dawley rats, and these abnormalities were attenuated by MR antagonism. Protein kinase B activation is critical to vascular homeostasis via regulation of cell survival and expression of apoptotic genes. Protein kinase B serine473 phosphorylation was impaired in Ren2 aortas and restored with MR antagonism. In vivo MR antagonist treatment promoted antiapoptotic effects by increasing phosphorylation of BAD serine136 and expression of Bcl-2 and Bcl-xL, decreasing cytochrome c release and BAD expression, and suppressing caspase-3 activation. Furthermore, MR antagonism substantially reduced the elevated NADPH oxidase activity and lipid peroxidation, expression of angiotensin II, angiotensin type 1 receptor, and MR in Ren2 vasculature. These results demonstrate that MR antagonism protects the vasculature from aldosterone-induced vascular apoptosis and structural injury via rescuing protein kinase B activation, independent of blood pressure effects