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The molecular mechanisms of sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometric data were collected from research kidney biopsies donated by young persons with type 2 diabetes (T2D), aged 12 to 21 years, and healthy controls (HCs). Participants with T2D were obese and had higher estimated glomerular filtration rates and mesangial and glomerular volumes than HCs. Ten T2D participants had been prescribed SGLT2i (T2Di[+]) and 6 not (T2Di[-]). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster with highest expression in T2Di(-) patients. However, transcriptional alterations with SGLT2i treatment were seen across nephron segments, particularly in the distal nephron. SGLT2i treatment was associated with suppression of transcripts in the glycolysis, gluconeogenesis, and tricarboxylic acid cycle pathways in PT, but had the opposite effect in thick ascending limb. Transcripts in the energy-sensitive mTORC1-signaling pathway returned toward HC levels in all tubular segments in T2Di(+), consistent with a diabetes mouse model treated with SGLT2i. Decreased levels of phosphorylated S6 protein in proximal and distal tubules in T2Di(+) patients confirmed changes in mTORC1 pathway activity. We propose that SGLT2i treatment benefits the kidneys by mitigating diabetes-induced metabolic perturbations via suppression of mTORC1 signaling in kidney tubules., Introduction The incedence of youth-onset type 2 diabetes (T2D) is rapidly rising among children and adolescents globally (1). It is associated with a more severe clinical course than youth-onset type [...]

With an aging population, kidney health becomes an important medical and socioeconomic factor. Kidney aging mechanisms are not well understood. We previously showed that podocytes isolated from aged mice exhibit increased expression of programmed cell death protein 1 (PD-1) surface receptor and its 2 ligands (PD-L1 and PD-L2). PDCD1 transcript increased with age in microdissected human glomeruli, which correlated with lower estimated glomerular filtration rate and higher segmental glomerulosclerosis and vascular arterial intima-to-lumen ratio. In vitro studies in podocytes demonstrated a critical role for PD-1 signaling in cell survival and in the induction of a senescence- associated secretory phenotype. To prove PD-1 signaling was critical to podocyte aging, aged mice were injected with anti-PD- 1 antibody. Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life span of podocytes, but not that of parietal epithelial, mesangial, or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrated that anti-PD-1 antibody treatment improved the health span of podocytes. Administering the same anti-PD-1 antibody to young mice with experimental focal segmental glomerulosclerosis (FSGS) lowered proteinuria and improved podocyte number. These results suggest a critical contribution of increased PD-1 signaling toward both kidney and liver aging and in FSGS., Introduction The US population is aging, and the number of Americans aged 65 and older will more than double over the next 40 years (US Census Bureau); Eurostat forecasts that [...]

This study introduces a large fire containment strategy that builds upon recent advances in spatial fire planning, notably the concept of potential wildland fire operation delineations (PODs). Multiple PODs can be clustered together to form a 'box' that is referred as the 'response POD' (or rPOD). Fire lines would be built along the boundary of an rPOD to contain a large fire. Assets such as communities and infrastructure within an rPOD could be protected through 'point zone protection.' We develop a mixed integer program model to optimally aggregate PODs into an rPOD with an objective of coordinating containment and point protection to maximize net value change under different fire weather scenarios and resource availability constraints. This optimization framework leverages emerging fire risk assessment and response planning methods by considering factors that drive selection of the optimal rPOD including fire-related benefits and losses, the fire line construction effort required to contain fire, and the point protection requirement within the rPOD to reduce asset losses. The model could be used to support prefire assessment and planning, training, and incident response decisions. We use a portion of the Lolo National Forest in western Montana, U.S.A., as a study site for demonstration. Key words: decision support, mixed integer program, planning, risk assessment, wildland fire management. Cette etude introduit une vaste strategie de confinement qui s'appuie sur les recents progres en planification spatiale du feu, notamment le concept de delimitations des operations potentielles (POD) de maitrise des feux de vegetation. Plusieurs POD peuvent etre regroupes pour former une <> appelee <> (ou rPOD). Les coupe-feu seraient amenages le long de la limite d'un rPOD pour confiner un feu de grande dimension. Les actifs, tels que les communautes et les infrastructures, situes a l'interieur d'un rPOD pourraient etre proteges via la protection d'endroits specifiques. Nous avons elabore un modele de programmation partiellement en nombres entiers pour regrouper de facon optimale les POD dans un rPOD. L'objectif de ce regroupement est de coordonner le confinement et la protection d'endroits specifiques pour maximiser le changement net de valeur selon different scenarios de conditions meteorologiques propices aux incendies forestiers et de contraintes de disponibilite des ressources. Ce cadre d'optimisation met a profit revaluation emergeante du risque d'incendie et les methodes de planification des interventions en tenant compte des facteurs qui determinent le choix du rPOD optimal, incluant les pertes et les benefices lies au feu, l'effort requis pour amenager des coupe-feu visant a contenir le feu et la necessite de proteger des endroits specifiques a l'interieur du rPOD pour reduire les pertes d'actifs. Le modele pourrait etre utilise avant un feu en appui a revaluation et a la planification, ainsi qu'a l'entrainement et aux decisions d'intervention lors d'incidents. Nous utilisons une partie de la foret nationale de Lolo situee dans l'ouest du Montana, aux Etats-Unis, comme site d'etude a des fins de demonstration. [Traduit par la Redaction] Mots-cles: aide a la decision, programmation partiellement en nombres entiers, planification, evaluation du risque, gestion des feux de vegetation., Introduction Management of wildland fires presents a complex decision environment characterized by changing fire conditions, partial control, and uncertainty (Thompson 2013). In the United States (US), although nearly all ignitions [...]

Podocytes are key to the glomerular filtration barrier by forming a slit diaphragm between interdigitating foot processes; however, the molecular details and functional importance of protein folding and degradation in the ER remain unknown. Here, we show that the SEL1L-HRD1 protein complex of ER-associated degradation (ERAD) is required for slit diaphragm formation and glomerular filtration function. SEL1L-HRD1 ERAD is highly expressed in podocytes of both mouse and human kidneys. Mice with podocyte-specific Sel1L deficiency develop podocytopathy and severe congenital nephrotic syndrome with an impaired slit diaphragm shortly after weaning and die prematurely, with a median lifespan of approximately 3 months. We show mechanistically that nephrin, a type 1 membrane protein causally linked to congenital nephrotic syndrome, is an endogenous ERAD substrate. ERAD deficiency attenuated the maturation of nascent nephrin, leading to its retention in the ER. We also show that various autosomal-recessive nephrin disease mutants were highly unstable and broken down by SEL1L-HRD1 ERAD, which attenuated the pathogenicity of the mutants toward the WT allele. This study uncovers a critical role of SEL1L-HRD1 ERAD in glomerular filtration barrier function and provides insights into the pathogenesis associated with autosomal-recessive disease mutants., Introduction The key function of the kidneys is the ultrafiltration of blood in the glomerulus, where podocytes, specialized differentiated epithelial cells, wrap around capillaries of the glomerulus via a unique [...]

Using the Jamaica poverty line data as its base, the authors develop a formula for calculating the living wage for Jamaica. Using the formula, as well as economic and fiscal data, the living wage is found to be 27% higher than the 2012 minimum wage. The feasibility of implementing a living wage and issues that will curtail implementation are discussed. We also provide a comparative analysis of living wage models in both developed and developing countries. The general discussion shows that, while the living wage exists in several territories, the methodology for calculation varies by country. Findings from the study indicate that the living wage is a viable option for protecting the 'working poor' in Jamaica because, unlike the minimum wage (which is determined by negotiations), its calculation provides a methodological framework that is consistent with economic reality of the country. Keywords: Living Wage, Minimum Wage, Poverty Line, Trade Union, Working Poor, The living wage model has gained prominence over the last two decades in several countries seeking to reduce poverty, taxation, and welfare expenditure. A living wage is one that provides [...]

Author(s): Eunsil Hahm [1]; Changli Wei [1]; Isabel Fernandez [1]; Jing Li [1]; Nicholas J Tardi [1]; Melissa Tracy [1]; Shikha Wadhwani [1]; Yanxia Cao [1]; Vasil Peev [1]; Andrew [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2010.08.006 Byline: Audrey H. Wu, Jalal K. Ghali, Gerald W. Neuberg, Christopher M. O'Connor, Peter E. Carson, Wayne C. Levy Abstract: Previous studies have not extensively examined the association of hyperuricemia and adverse outcomes in systolic heart failure (HF) in relation to xanthine oxidase inhibitor therapy. Article History: Received 19 April 2010; Accepted 9 August 2010

A study was conducted to evaluate the effect and benefits of the use of rolofylline, an adenosine A1-receptor antagonist in improving dyspnea and reducing the risk of renal failure in the case of patients with acute heart failure. Results indicated that rolofylline did not have any kind of favorable outcome in the case of such patients.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2010.05.020 Byline: Ryenn L. West (a), Adrian F. Hernandez (a), Christopher M. O'Connor (a), Randall C. Starling (b), Robert M. Califf (c) Abstract: In acute heart failure syndrome (AHFS), dyspnea is one of the most common but least understood presenting symptoms for hospitalization. For this reason, dyspnea relief is increasingly becoming a focus in the development of therapies for the treatment of AHFS, and currently stands as an acceptable primary end point for regulatory approval by governmental agencies. This raises the question of how best to measure such a subjective symptom. In this review, we will describe the basis for dyspnea, provide a detailed description of the strengths and weaknesses of the current best tools used to measure it, and describe future directions for future development of dyspnea measurement in AHFS. Author Affiliation: (a) Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (b) Cleveland Clinic, Cleveland, OH (c) Duke Translational Medicine Institute, Duke University School of Medicine, Durham, NC Article History: Received 18 April 2010; Accepted 15 May 2010

Specific CheA-short (CheAs) residues, L123 and L126, were identified as critical for CheZ binding. In the Cbe[A.sub.s] 'P1-CheZ nuclear magnetic resonance structure, these residues form an interaction surface on [alpha]-helix E in the 'P1 domain. Both L123 and L126 are buried in CheA-long (Che[A.sub.L]), providing an explanation for why Che[A.sub.L] fails to bind CheZ.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2009.06.018 Byline: G. Michael Felker, Vic Hasselblad, Adrian F. Hernandez, Christopher M. O'Connor Abstract: Measurement of circulating natriuretic peptides has been shown to play an important role in diagnosis and prognosis in patients with chronic heart failure. Whether serial natriuretic peptide measurements to aid in the titration of therapy can improve heart failure outcomes remains uncertain. We performed a quantitative meta-analysis of available randomized controlled trials to determine whether titration of therapy based on natriuretic peptide measurements improves mortality in chronic heart failure. Author Affiliation: Duke Clinical Research Institute and the Division of Cardiology, Duke University Medical Center, Durham, NC Article History: Received 15 June 2009; Accepted 17 June 2009 Article Note: (footnote) Dr. James B. Young served as guest editor for this manuscript.

The structure of people's conceptual knowledge of concrete nouns has traditionally been viewed as hierarchical (Collins & Quillian, 1969). For example, superordinate concepts (vegetable) are assumed to reside at a higher level than basic-level concepts (carrot). A feature-based attractor network with a single layer of semantic features developed representations of both basic-level and superordinate concepts. No hierarchical structure was built into the network. In Experiment and Simulation 1, the graded structure of categories (typicality ratings) is accounted for by the flat attractor network. Experiment and Simulation 2 show that, as with basic-level concepts, such a network predicts feature verification latencies for superordinate concepts (vegetable ). In Experiment and Simulation 3, counterintuitive results regarding the temporal dynamics of similarity in semantic priming are explained by the model. By treating both types of concepts the same in terms of representation, learning, and computations, the model provides new insights into semantic memory. Keywords: Superordinate concepts; Attractor networks; Temporal dynamics; Semantic memory

A study was carried out to compare the outcome of ventricular surgical reconstruction along with coronary-artery grafting (CABG) and CABG alone which could decrease the incidence of death or hospitalization in cardiac patients. Results revealed that surgical reconstruction along with CABG reduced the left ventricular volume but did not significantly reduce the incidence of death or hospitalization.

The study aims to investigate the effects of exercise training on the health of patients with chronic heart failure. The results indicate that exercise training brought about modest and significant improvements in the health of patients prone to heart conditions, wherein there were early improvements and they persisted over time.

A study was conducted to evaluate the efficacy and safety of using exercise training in improving the condition of patients with chronic heart failure. Results indicated that exercise training was effective in modest significant reductions in hospitalization and mortality associated with cardiac failure.

A study was conducted to ascertain the long-term results among beneficiaries of Medicare who had received only ventricular devices for mechanical circulation or after open-heart surgery. Results showed that Medicare beneficiaries who received a mechanical ventricular assist device risked early mortality and morbidity among other factors.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2006.02.038 Byline: Gad Cotter (a), G. Michael Felker (a), Kirkwood F. Adams (b), Olga Milo-Cotter (a), Christopher M. O'Connor (a) Abstract: Despite significant advancement in chronic heart failure (HF), no breakthroughs have occurred in the last 2 decades in our understanding of the pathophysiology, classification, and treatment of acute HF (AHF). Traditional thinking, which has been that this disorder is a result of gradual fluid accumulation on a background of chronic HF, has been called into question by recent large registries enrolling less selected patient populations. It is increasingly recognized that many patients with this syndrome are elderly, have relatively preserved ejection fraction, and have mild or no preexisting chronic HF. In this review, we propose 2 primary subtypes of AHF: (1) acute decompensated cardiac failure, characterized by deterioration of cardiac performance over days to weeks leading to decompensation; and (2) acute vascular failure, characterized by acute hypertension and increased vascular stiffness. Registry data suggest that the latter is the more common form of AHF in the general population, although the former is often overrepresented in studies focused in academic tertiary care centers. Regardless of the clinical subtype, a variety of pathophysiologic mechanisms may play a role in this disorder, many of which remain poorly understood. In this review, we describe current understanding of the pathophysiology of AHF, including a critical evaluation of the data supporting both traditional and novel mechanisms, and suggest a framework for integrating these mechanisms into an overall model of AHF. Author Affiliation: (a) Duke University Medical Center, the Duke Clinical Research Institute, Durham, NC (b) University of North Carolina, Chapel Hill, NC Article History: Received 19 October 2005; Accepted 12 February 2006

A study is conducted to find if endothelin receptor antagonist tezosentan improves outcomes in patients with acute heart failure. The results suggest that tezosentan did not improve symptoms or clinical outcomes in patients with acute heart failure.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2007.01.026 Byline: Harry R. Phillips, Christopher M. O'Connor, Joseph Rogers Abstract: Coronary artery disease is the most common underlying cause of heart failure, yet there is little consensus on the role of revascularization in the management of patients with ischemic cardiomyopathy. The concept of recovery of dysfunctional but viable myocardium forms the pathophysiologic basis for the benefit of revascularization. Data from observational studies suggest that patients with coronary disease and left ventricular dysfunction may have improved outcomes after surgical revascularization or percutaneous coronary intervention (PCI) compared to medical treatment. Viability testing may be useful in selecting a population of patients who will receive differential benefit. In the clinical management of patients with heart failure, clinicians face challenging decisions about whether to recommend revascularization especially in patients who do not have angina. As data from randomized trials are awaited, PCI and coronary artery bypass grafting may be considered as complimentary revascularization approaches. Registry data suggest a benefit of coronary artery bypass grafting over PCI in patients with reduced ejection fraction; however, in patients with focal disease and comorbidities including previous surgery, PCI is reasonable, especially if complete revascularization is possible. Author Affiliation: Duke University Medical Center, Durham, NC

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2007.01.010 Byline: Christopher M. O'Connor Abstract: Several life-prolonging therapies are available for the treatment of heart failure, yet they are underutilized in many patients. A treatment gap exists between patients who are eligible for a therapy and the number of patients who actually receive them. Suboptimal prescribing rates for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, [beta]-blockers, and aldosterone antagonists have been reported. Strategies are needed to increase the proportion of patients who are receiving evidence-based therapies. Predischarge initiation of evidence-based therapies has effectively increased utilization in the acute coronary syndrome population. Predischarge initiation of [beta]-blockade in patients hospitalized for heart failure has also been shown to be safe and effective for improving [beta]-blocker use at 60 days. Larger registry initiatives have demonstrated improved use of evidence-based therapies associated with implementation of a performance improvement process system. The mortality and morbidity associated with heart failure is strikingly high, and it is critical that proven therapies are prescribed to all eligible patients so that clinical outcomes can be improved. Systematic processes are effective approaches to ensuring appropriate evidence-based therapies are prescribed in most patients. Author Affiliation: Division of Clinical Pharmacology, Duke University Medical Center, Durham, NC

A cohort study is conducted to evaluate the relationship between systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. The results suggest that systolic hypertension is common in patients hospitalized for heart failure and systolic blood pressure is an independent predictor of morbidity and mortality in patients with heart failure with either reduced or relatively preserved systolic function.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2005.03.056 Byline: G. Michael Felker, Linda K. Shaw, Wendy Gattis Stough, Christopher M. O'Connor Abstract: Anemia has been shown to be a predictor of mortality in patients with heart failure and impaired left ventricular systolic function (ISF). Although heart failure in the setting of preserved systolic function (PSF) is an important clinical problem, the relationship between anemia and outcomes in patients with PSF has not been carefully evaluated. Author Affiliation: Duke Clinical Research Institute, Durham, NC Article History: Received 12 November 2004; Accepted 30 March 2005 Article Note: (footnote) Dr Felker is supported in part by NIH K23 HL72357-01A1. This research was funded independently by the Duke Clinical Research Institute.

A meta-analysis of thirteen published clinical trials was performed to estimate the impact of the pulmonary artery catheter (PAC) device in critically ill patients. Use of the PAC was found to neither increase overall mortality or days in hospital nor confer any benefit, indicating the lack of a clear strategy leading to improved survival with the PAC.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2005.04.012 Byline: Wei Jiang (a), Alexander Glassman (b), Ranga Krishnan (c), Christopher M. O'Connor (d), Robert M. Califf (e) Author Affiliation: (a) Department of Internal Medicine and Psychiatry and Behavioral Sciences, Duke University, Medical Center, Durham, NC (b) Department of Clinical Psychopharmacology, New York State Psychiatric Institute, New York, NY (c) Division of Biological Psychiatry, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC (d) Department of Medicine, Duke University Medical Center, Durham, NC (e) Duke Clinical Research Institute, Durham, NC Article History: Received 18 April 2005; Accepted 18 April 2005 Article Note: (footnote) Sponsors: Aventis Pharmaceuticals, Inc; Forest Laboratories, Inc; GlaxoSmithKline; Pfizer, Inc; and Wyeth-Ayerst Pharmaceuticals.

The CheZ binding domain of CheA(sub s) is identified by testing the various fragments of CheA(sub s) that contain cysteine residues for CheZ binding activity in an ELISA-based CheA(sub s)-CheZ binding assay. It is shown that both the CheZ binding and activity enhancing functions of CheA(sub s) are located in its truncated P1 domain and the accessibility of the cysteine residue in P1 domain is important for the interaction between P1 domain and CheZ.

The antibiotic azithromycin did not reduce the risk of a second heart attack or premature death in 7,747 heart attack patients. All of the patients also tested positive for Chlamydia pneumoniae, a bacteria that has been linked to coronary artery disease. For this reason, doctors believed an antibiotic might benefit these patients. In this particular study, it did not.