If blocking potency of ivabradine is preserved under elevated endotoxin levels in human atrial myocytes

AbstractLower heart rate is associated with better survival in patients with multiple organ dysfunction syndrome (MODS), a disease mostly caused by sepsis. The benefits of heart rate reduction by ivabradine during MODS are currently being investigated in the MODIfY clinical trial. Ivabradine is a selective inhibitor of the pacemaker current If and since If is impaired by lipopolysaccharide (LPS, endotoxin), a trigger of sepsis, we aimed to explore If blocking potency of ivabradine under elevated endotoxin levels in human atrial cardiomyocytes. Treatment of myocytes with S-LPS (containing the lipid A moiety, a core oligosaccharide and an O-polysaccharide chain) but not R595 (an O-chain lacking LPS-form) caused If inhibition under acute and chronic septic conditions. The specific interaction of S-LPS but not R595 to pacemaker channels HCN2 and HCN4 proves the necessity of O-chain for S-LPS–HCN interaction. The efficacy of ivabradine to block If was reduced under septic conditions, an observation that correlated with lower intracellular ivabradine concentrations in S-LPS- but not R595-treated cardiomyocytes. Computational analysis using a sinoatrial pacemaker cell model revealed that despite a reduction of If under septic conditions, ivabradine further decelerated pacemaking activity. This novel finding, i.e. If inhibition by ivabradine under elevated endotoxin levels in vitro, may provide a molecular understanding for the efficacy of this drug on heart rate reduction under septic conditions in vivo, e.g. the MODIfY clinical trial

Distribution and diversity of Polyporaceae in Western India: An overview and addition to mycoflora of the Gujarat state

Extensive fieldwork in different climatic regimes of Gujarat state during last four years resulted in the collection of more than 349 fungal species. Out of these, 37 species from 20 genera were found to be from the family Polyporaceae. Among these, five species are being reported for the first time here as new distribution records. The highest number of species is represented by the genus Trametes while, Cerrena unicolo, Neolentinus kauffmanii, Dichomitus squalens, Panus conchatus and Laetiporus sulphureus possessed single species each

Research-Based Web Design & Usability Guidelines [2006 edition]

The new edition of the U.S. Department of Health and Human Services’ (HHS) Research-Based Web Design and Usability Guidelines. These guidelines reflect HHS’ commitment to identifying innovative, research-based approaches that result in highly responsive and easy-to-use Web sites for the public. These guidelines help move us in that direction by providing practical, yet authoritative, guidance on a broad range of Web design and communication issues. Having access to the best available research helps to ensure we make the right decisions the first time around and reduces the possibility of errors and costly mistakes

Saxagliptin but Not Sitagliptin Inhibits CaMKII and PKC via DPP9 Inhibition in Cardiomyocytes

Some oral anti-hyperglycemic drugs, including gliptins that inhibit dipeptidyl peptidase 4 (DPP4), have been linked to the increased risk of heart failure (HF) in type-2 diabetic patients. While the cardiovascular safety trial, TECOS, revealed no link between sitagliptin and the risk of HF, a substantial 27% increase in the hospitalization for HF was observed in type-2 diabetic patients treated with saxagliptin within the SAVOR-TIMI 53 trial. A previous in vitro study revealed that saxagliptin impairs the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-phospholamban (PLB)-sarcoplasmic reticulum Ca2+-ATPase 2a axis and protein kinase C (PKC) activity in cardiomyocytes leading to impaired cardiac contractility and electrophysiological function. However, the link between saxagliptin and its target proteins (CaMKII and PKC) remains to be explored. Since DPP8 and DPP9 (but not DPP4) are expressed by cardiomyocytes and saxagliptin is internalized by cardiomyocytes, we investigated whether DPP8/9 contribute to saxagliptin-mediated inhibition of CaMKII and PKC activity. Structural analysis revealed that the DPP4-saxagliptin interaction motif (S630, Y547) for the cyanopyrrolidine group is conserved in DPP8 (S755, Y669) and DPP9 (S730, Y644). Conversely, F357 that facilitates binding of the anchor lock domain of sitagliptin in the S2 extensive subsite of DPP4 is not conserved in DPP8/9. In parallel, unlike saxagliptin, sitagliptin did not affect phosphorylation of CaMKII/PLB or activity of PKC in HL-1 cardiomyocytes. These findings were recapitulated by pharmacological inhibition (TC-E-5007, a DPP8/9 antagonist) and knock-down of DPP9 (but not DPP8). In primary mouse ventricular cardiomyocytes, saxagliptin (but not sitagliptin) impaired Ca2+ transient relaxation and prolonged action potential duration (APD). These results suggest that saxagliptin-DPP9 interaction impairs the CaMKII-PLB and PKC signaling in cardiomyocytes. We reveal a novel and potential role of DPP9 in cardiac signaling. The interaction of saxagliptin with DPP9 may represent an underlying mechanism for the link between saxagliptin and HF. Elucidation of saxagliptin-DPP9 interaction and downstream events may foster a better understanding of the role of gliptins as modulators of cardiac signaling

Hypochlorite-Modified LDL Induces Arrhythmia and Contractile Dysfunction in Cardiomyocytes

Neutrophil-derived myeloperoxidase (MPO) and its potent oxidant, hypochlorous acid (HOCl), gained attention as important oxidative mediators in cardiac damage and dysfunction. As cardiomyocytes generate low-density lipoprotein (LDL)-like particles, we aimed to identify the footprints of proatherogenic HOCl-LDL, which adversely affects cellular signalling cascades in various cell types, in the human infarcted myocardium. We performed immunohistochemistry for MPO and HOCl-LDL in human myocardial tissue, investigated the impact of HOCl-LDL on electrophysiology and contractility in primary cardiomyocytes, and explored underlying mechanisms in HL-1 cardiomyocytes and human atrial appendages using immunoblot analysis, qPCR, and silencing experiments. HOCl-LDL reduced ICa,L and IK1, and increased INaL, leading to altered action potential characteristics and arrhythmic events including early- and delayed-afterdepolarizations. HOCl-LDL altered the expression and function of CaV1.2, RyR2, NCX1, and SERCA2a, resulting in impaired contractility and Ca2+ homeostasis. Elevated superoxide anion levels and oxidation of CaMKII were mediated via LOX-1 signaling in HL-1 cardiomyocytes. Furthermore, HOCl-LDL-mediated alterations of cardiac contractility and electrophysiology, including arrhythmic events, were ameliorated by the CaMKII inhibitor KN93 and the INaL blocker, ranolazine. This study provides an explanatory framework for the detrimental effects of HOCl-LDL compared to native LDL and cardiac remodeling in patients with high MPO levels during the progression of cardiovascular disease

PHL1/341: Guidelines for Designing Education Resources for the World Wide Web: Strategies from the Field

INTRODUCTION: An increasing number of professionals, patients, and members of the general public are using the World Wide Web to obtain and/or deliver health information. Although the Web can serve as a highly effective medium for educating and informing, little information is available about how to design effective, accessible, and readable online health information. Additionally, few, if any, comprehensive standards exist on designing educational materials for a Web environment. In response, the National Cancer Institute's (NCI) Office of Cancer Information, Communication, and Education (OCICE) developed guidelines on how to design readable, intuitive, and easy-to-navigate health information for patients, the general public and health professionals. Using the guidelines as a framework, this presentation will include: guidance in identifying whether a resource is appropriate for the Web; design principles and technical considerations when developing online resources; demonstration of NCI publications designed for online viewing; examples of good and bad design; suggestions for implementing the guidelines in academic, community, and clinical settings. METHODS: The NCI Guidelines for Designing Educational Resources for the WWW are based on an extensive review of the literature for design, cognitive learning, and Web usability data; reviews of popular health Web sites; Web usability tests conducted by NCI with patients and health professionals; and discussions with experts in the field. RESULTS: Research data was used to develop the guidelines document, as well as online models of NCI education resources for cancer patients and the public. Initial results indicate improved readability and satisfaction. A plan will be set in place to design all NCI print and online education publications using these guidelines. Additionally, the guidelines will be updated on a continual basis following further testing and evaluation. DISCUSSION: Since the Internet is increasingly being used as a health information delivery and retrieval vehicle, it is imperative that information is optimally designed and presented to the user. Although the NCI guidelines are a starting point, more research is needed to identify changing user needs and trends, new delivery software, and strategies to tailor information based on the users' preference. The guidelines will continue to be refined and updated as new research and testing results become available