Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B

Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a β-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-β-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae-dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Evaluation of LHP® (1% hydrogen peroxide) cream versus petrolatum and untreated controls in open wounds in healthy horses: a randomized, blinded control study

<p>Abstract</p> <p>Background</p> <p>Treatment and protection of wounds in horses can be challenging; protecting bandages may be difficult to apply on the proximal extremities and the body. Unprotected wounds carry an increased risk of bacterial contamination and subsequent infection which can lead to delayed wound healing. Topical treatment with antimicrobials is one possibility to prevent bacterial colonization or infection, but the frequent use of antimicrobials ultimately leads to development of bacterial resistance which is an increasing concern in both human and veterinary medicine.</p> <p>Methods</p> <p>Standardized wounds were created in 10 Standardbred mares. Three wounds were made in each horse. Two wounds were randomly treated with LHP^®or petrolatum and the third wound served as untreated control. All wounds were assessed daily until complete epithelization. Protocol data were recorded on day 2, 6, 11, 16, 21 and 28. Data included clinical scores for inflammation and healing, photoplanimetry for calculating wound areas and swab cytology to assess bacterial colonization and inflammation. Bacterial cultures were obtained on day 2, 6 and 16.</p> <p>Results</p> <p>Mean time to complete healing for LHP^®treated wounds was 32 days (95%CI = 26.9-37.7). Mean time to complete healing for petrolatum and untreated control wounds were 41.6 days (95%CI = 36.2-47.0) and 44.0 days (95%CI = 38.6-49.4) respectively. Wound healing occurred significantly faster in LHP^®wounds compared to both petrolatum (p = 0.0004) and untreated controls (p < 0.0001). There was no significant difference in time for healing between petrolatum and untreated controls. Total scores for bacteria and neutrophils were significantly (p < 0.0001) lower for LHP^®treated wounds compared to petrolatum from day 16 and onwards. <it>Staphylococcus aureus </it>and <it>Streptococcus zooepidemicus </it>were only found in cultures from petrolatum treated wounds and untreated controls.</p> <p>Conclusions</p> <p>Treatment with LHP^®reduced bacterial colonization and was associated with earlier complete wound healing. LHP^®cream appears to be safe and effective for topical wound treatment or wound protection.</p

Marking their own homework: The pragmatic and moral legitimacy of industry self-regulation

When is industry self-regulation (ISR) a legitimate form of governance? In principle, ISR can serve the interests of participating companies, regulators and other stakeholders. However, in practice, empirical evidence shows that ISR schemes often under-perform, leading to criticism that such schemes are tantamount to firms marking their own homework. In response, this paper explains how current management theory on ISR has failed to separate the pragmatic legitimacy of ISR based on self-interested calculations, from moral legitimacy based on normative approval. The paper traces three families of management theory on ISR and uses these to map the pragmatic and moral legitimacy of ISR schemes. It identifies tensions between the pragmatic and moral legitimacy of ISR schemes, which the current ISR literature does not address, and draws implications for the future theory and practice of ISR

Visuospatial Integration: Paleoanthropological and Archaeological Perspectives

The visuospatial system integrates inner and outer functional processes, organizing spatial, temporal, and social interactions between the brain, body, and environment. These processes involve sensorimotor networks like the eye–hand circuit, which is especially important to primates, given their reliance on vision and touch as primary sensory modalities and the use of the hands in social and environmental interactions. At the same time, visuospatial cognition is intimately connected with memory, self-awareness, and simulation capacity. In the present article, we review issues associated with investigating visuospatial integration in extinct human groups through the use of anatomical and behavioral data gleaned from the paleontological and archaeological records. In modern humans, paleoneurological analyses have demonstrated noticeable and unique morphological changes in the parietal cortex, a region crucial to visuospatial management. Archaeological data provides information on hand–tool interaction, the spatial behavior of past populations, and their interaction with the environment. Visuospatial integration may represent a critical bridge between extended cognition, self-awareness, and social perception. As such, visuospatial functions are relevant to the hypothesis that human evolution is characterized by changes in brain–body–environment interactions and relations, which enhance integration between internal and external cognitive components through neural plasticity and the development of a specialized embodiment capacity. We therefore advocate the investigation of visuospatial functions in past populations through the paleoneurological study of anatomical elements and archaeological analysis of visuospatial behaviors