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Background: Clinical studies have reported that epicardial adipose tissue (EpAT) accumulation associates with the progression of atrial fibrillation (AF) pathology and adversely affects AF management. The role of local cardiac EpAT deposition in disease progression is unclear, and the electrophysiological, cellular, and molecular mechanisms involved remain poorly defined.Objectives: The purpose of this study was to identify the underlying mechanisms by which EpAT influences the atrial substrate for AF.Methods: Patients without AF undergoing coronary artery bypass surgery were recruited. Computed tomography and high-density epicardial electrophysiological mapping of the anterior right atrium were utilized to quantify EpAT volumes and to assess association with the electrophysiological substrate in situ. Excised right atrial appendages were analyzed histologically to characterize EpAT infiltration, fibrosis, and gap junction localization. Co-culture experiments were used to evaluate the paracrine effects of EpAT on cardiomyocyte electrophysiology. Proteomic analyses were applied to identify molecular mediators of cellular electrophysiological disturbance.Results: Higher local EpAT volume clinically correlated with slowed conduction, greater electrogram fractionation, increased fibrosis, and lateralization of cardiomyocyte connexin-40. In addition, atrial conduction heterogeneity was increased with more extensive myocardial EpAT infiltration. Cardiomyocyte culture studies using multielectrode arrays showed that cardiac adipose tissue-secreted factors slowed conduction velocity and contained proteins with capacity to disrupt intermyocyte electromechanical integrity.Conclusions: These findings indicate that atrial pathophysiology is critically dependent on local EpAT accumulation and infiltration. In addition to myocardial architecture disruption, this effect can be attributed to an EpAT-cardiomyocyte paracrine axis. The focal adhesion group proteins are identified as new disease candidates potentially contributing to arrhythmogenic atrial substrate. [ABSTRACT FROM AUTHOR]

The air movement induced by a high-speed train (HST) as it passes, the slipstream, is a safety hazard to commuters and trackside workers, and can cause damage to infrastructure along track lines. Because of its importance, many numerical studies have been undertaken to investigate this phenomenon. However, to the authors' knowledge, a systematic comparison of the accuracy of different turbulence models applied to the prediction of slipstream has not yet been conducted. This study investigates and evaluates the performance of three widely used turbulence models: URANS, SAS and DES, to predict the slipstream of a full-featured generic train model, and the results are compared with wind-tunnel experimental data to determine the fidelity of the models. Specifically, this research aims to determine the suitability of different turbulence modelling approaches, involving significantly different computational resources, for modelling different aspects of slipstream. [ABSTRACT FROM AUTHOR]

Background Ischemia-related arrhythmic incidence is generally lower in females (vs males), though risk is selectively increased in women with underlying cardiopathology. Ca2 +/calmodulin dependent kinase II (CaMKII) has been implicated in ischemia/reperfusion arrhythmias, yet the role of CaMKII in the ischemic female heart has not been determined. The aim of this study was to define the role and molecular mechanism of CaMKII activation in reperfusion arrhythmias in male/female hearts. Methods and results Male and female rat hearts and cardiomyocytes were subjected to multiple arrhythmogenic challenges. An increased capacity to upregulate autophosphorylated CaMKII (P-CaMKII) in Ca2 +-challenged female hearts was associated with an enhanced ability to maintain diastolic function. In ischemia/reperfusion, female hearts (vs male) exhibited less arrhythmias (59 ± 18 vs 548 ± 9, s, p < 0.05), yet had augmented P-CaMKII (2.69 ± 0.30 vs 1.50 ± 0.14, rel. units, p < 0.05) and downstream phosphorylation of phospholamban (1.71 ± 0.42 vs 0.90 ± 0.10, p < 0.05). In contrast, hypertrophic female hearts had more reperfusion arrhythmias and lower phospholamban phosphorylation. Isolated myocyte experiments (fura-2) confirmed Ca2 +-handling arrhythmogenic involvement. Molecular analysis showed target specificity of CaMKII was determined by post-translational modification, with CaMKIIδB and CaMKIIδC splice variants selectively co-localized with autophosphorylation and oxidative modifications of CaMKII respectively. Conclusions This study provides new mechanistic evidence that CaMKIIδ splice variants are selectively susceptible to autophosphorylation/oxidation, and that augmented generation of P-CaMKIIδB(Thr287) is associated with arrhythmia suppression in the female heart. Collectively these findings indicate that therapeutic approaches based on selective CaMKII splice form targeting may have potential benefit, and that sex-selective CaMKII intervention strategies may be valid. [ABSTRACT FROM AUTHOR]

Highlights: [•] Important sex differences are evident in cardiac stress responses. [•] Cardiac androgen/estrogen receptor activation modulates basal contractile function. [•] Sex steroids exhibit complex & context dependent actions in cardiac stress. [•] Both estrogens and androgens can have beneficial and detrimental effects in cardiac stress scenarios. [•] Greater mechanistic understanding required to develop sex-specific cardiac therapies. [Copyright &y& Elsevier]

Abstract: Background: Ca2+/calmodulin-dependent protein kinase (CaMKII) activation is known to be associated with conditions where the incidence of arrhythmias is increased, and where cardiomyocyte Ca2+-overload occurs. The goal of this study was to determine whether CaMKII inhibition in the intact heart may be linked to the suppression of ventricular arrhythmias occurring during reperfusion after an ischemic insult. Methods: Non-paced male rat hearts (n =8–11) were treated with a CaMKII inhibitor (KN93, 2.5μmol/L) 10min prior to global ischemia (20min) and for the initial 10min of reperfusion. Cardiac mechanical and arrhythmic responses were evaluated under constant pressure perfusion conditions and myocyte damage assessed by measurement of coronary effluent lactate dehydrogenase (LDH). Results: Under basal conditions, KN93 increased coronary flow (41±8% increase, p <0.05) and was negatively inotropic (29±7% decrease, p <0.05), but did not affect heart rate. Ischemic contracture was significantly diminished in KN93-treated hearts (onset, min: 11.48±0.50 vs 16.27±1.23, p <0.05). CaMKII inhibition in early reperfusion almost completely abolished the incidence of ventricular tachycardia/fibrillation in reperfusion (11/11 control vs 1/8 KN93). In the absence of ventricular arrhythmias, heart rate was substantially reduced (% basal; 100±3% vs 46±8%, p <0.05) throughout reperfusion. Left ventricular developed pressure was initially low in KN93 hearts post-ischemia, but recovered to control levels by the end of 60min reperfusion (68±5% vs 56±5%, p =ns). LDH was significantly reduced in KN93-treated hearts. Conclusion: Although CaMKII inhibition diminishes contractile performance of the intact heart in the initial post-ischemic period, it provides crucial benefits through protection against potentially lethal reperfusion-induced arrhythmias and cardiomyocyte sarcolemmal rupture. [Copyright &y& Elsevier]

Abstract: Aim: To compare overdose mortality associated with methadone and buprenorphine treatment for opioid dependence. Methods: Data linkage study. Since 1 April 2006, the Division of Analytic Laboratories (DAL) has routinely tested all New South Wales (NSW) coronial post-mortem samples for both methadone and buprenorphine. Names of all methadone or buprenorphine-positive cases between April and December 2006 inclusive were linked to the National Coroners Information System (NCIS) database, which provided information on cause of death, autopsy findings and circumstances of death. Names were linked to the Pharmaceutical Services Branch Drugs of Addiction System (PHDAS) database to identify whether people were in treatment, and in decedents not registered in treatment, the source of methadone or buprenorphine was presumed to be diversion from treatment programs. Mean number in treatment during 2006 for methadone and buprenorphine were derived from the PHDAS database. Rate of opioid overdose per thousand people in treatment were calculated for methadone and buprenorphine. Results: In the 9-month period there were 13,718 in methadone treatment and 2716 people in buprenorphine. There were 60 sudden deaths positive for methadone (32 in-treatment) and 7 buprenorphine-positive decedents (none in treatment). Most out-of-treatment deaths occurred in people with known histories of drug misuse. Forty-three methadone positive cases – 19/32 in treatment, and 24/28 out-of-treatment – and 2 of the 7 buprenorphine-positive deaths were due to overdose. The risk of overdose death per thousand people in treatment was lower for buprenorphine than for methadone (RR 4.25 [1.03, 17.54]). Conclusion: In this short-term study, buprenorphine was associated with lower overdose risk than methadone. [Copyright &y& Elsevier]

The isolated Langendorff-mode perfused heart has become a valuable experimental model, used extensively to examine cardiac function, pathophysiology and pharmacology. For the clinical cardiologist an ECG is often a simple practicality, however in experimental circumstances, particularly with ex vivo murine hearts it is not always possible to obtain an ECG due to experimental recording constraints. However, the mechanical record of ventricular contractile function can be highly informative in relation to electrical state. It is difficult though to achieve consistency in these evaluations of arrhythmia as a validated common reference framework is lacking. In 1988, a group of investigators developed the ‘Lambeth Conventions’—a standardised reference for the definition and classification of arrhythmias in animal experimental models of ischaemia, infarction and reperfusion in vivo. Now, two decades later it is timely to revisit the Lambeth Conventions, and to update the guidelines in the context of the marked increase in murine heart study in experimental cardiac pathophysiology. Here we describe an adjunct to the Lambeth Conventions for the reporting of ventricular arrhythmias post-ischaemia in ex vivo mouse hearts when ECG recordings are not employed. Of seven discrete and identifiable patterns of mechanical dysrhythmia observed in reperfusion, five could be classified using conventional ECG terminology: ventricular premature beat, bigeminy, trigeminy, ventricular tachycardia and ventricular fibrillation. Two additional rhythm variations detected from the pressure record are described (potentiated contraction and alternans). [Copyright &y& Elsevier]

Abstract: Background: The registration of combination buprenorphine/naloxone, a formulation designed to reduce risk of diversion, has led some Australian jurisdictional authorities to allow treatment without direct observation of dosing for stable, opioid-dependent patients. Aim: To compare two approaches (1) initiating treatment with observed dosing, then allowing patients who demonstrate stability to change to unobserved dosing; or (2) initiating patients with unobserved dosing, subsequently requiring those who fail to stabilize to change to observed treatment. Methods: This study builds on an RCT comparing efficacy of observed and unobserved treatment at 3 months. At the conclusion of the RCT, clinically “stable” subjects were allocated to continue without observed dosing, while those who did not demonstrate stability were allocated to observed dosing. Subjects were followed for a further 3 months. Primary end-point was retention in treatment. Results: Of 119 subjects randomised, 70 were retained in treatment to 3 months. Forty-five stable subjects were allocated to unobserved dosing, 25 to observation. Unstable subjects allocated to observed treatment were more likely to drop out thereafter (OR 2.14, 95% CI 1.09–4.19). There was a non-significant trend for people initiated with observed dosing to be better retained during the allocation phase; at 6 months, 13 subjects (22%) from the original unobserved group, and 22 (34%) from the observed group, were retained in treatment (χ 2 =2.10, 1df, p =0.15). Conclusions: Withdrawal of unobserved doses led to marked attrition from treatment. If access to unobserved dosing is to be restricted to stable patients, it appears preferable to initiate dosing with observation and allow unobserved doses for people who successfully stabilize, than to initiate with unobserved doses and transfer unstable patients to observation. [Copyright &y& Elsevier]

Aim: To investigate the efficacy of low doses of naltrexone in relapse prevention for heroin dependence. Design: Double blind, randomised comparison of three groups—Group 1 taking 50 mg per day, Group 2: 0.5 mg per day, and Group 3: 0.05 mg per day. Participants: Sixty-six dependent heroin users. Interventions: After detoxification followed by 1 week on 50 mg per day naltrexone, participants were randomised to trial medication. All were offered counselling and monitored with weekly clinical reviews. Research interviews were conducted at three and 6 months. Outcome measures: Retention in treatment and heroin use at 3 and 6 months. Secondary outcome measures were side effects and craving. Findings: Mean days retained in randomised treatment were—Group 1: 58.9 days; Group 2: 46.6 days; and Group 3: 47.8 days. Differences in retention were not significant using survival analysis. However, nine of the first 60 participants, transferred to the 50 mg dose, and one transferred to a lower dose (chi-square=0.142; P=0.018). At follow-up, there was no relationship between abstinence from heroin and naltrexone dose, nor between level of heroin use and dose. There were no differences between groups in craving or depression. Conclusion: Low doses of naltrexone had no discernible advantage, and participants preferred 50 mg per day. Despite preference for blocking doses of naltrexone, outcomes appeared to be independent of naltrexone dose. [Copyright &y& Elsevier]

Monitoring networks are improved by additional sensors. Optimal configurations of sensors give better representations of the process of interest, maximising its exploration while minimising the need for costly infrastructure. By modelling the monitored process, we can identify gaps in its representation, i.e. uncertain predictions, where additional sensors should be located. Here, with data collected from the Rothamsted Insect Survey network, we train an artificial neural network to predict the seasonal aphid arrival from environmental variables. We focus on estimating prediction uncertainty across the UK to guide the addition of a sensor to the network. We first illustrate how to estimate uncertainty in neural networks, hence making them relevant for model-based monitoring network optimisation. Then we highlight critical areas of agricultural importance where additional traps would improve decision support and crop protection in the UK. Possible applications include most ecological monitoring and surveillance activities, but also the weather or pollution monitoring. • Sensor networks are used to monitor biological processes, such as aphid arrival. • Artificial neural networks can provide spatial predictions from point observations. • We show how artificial neural networks can also provide uncertainty estimates. • Model uncertainty highlights gaps where new sensors should be located. [ABSTRACT FROM AUTHOR]

Insect pests now pose a greater threat to crop production given the recent emergence of insecticide resistance, the removal of effective compounds from the market (e.g. neonicotinoids) and the changing climate that promotes successful overwintering and earlier migration of pests. As surveillance tools, predictive models are important to mitigate against pest outbreaks. Currently they provide decision support on species emergence, distribution, and migration patterns and their use effectively gives growers more time to take strategic crop interventions such as delayed sowing or targeted insecticide use. Existing techniques may have met their optimal usefulness, particularly in complex systems and changing climates. Machine learning (ML) arguably is an advance over current capabilities because it has the potential to efficiently identify the most informative time-windows whilst simultaneously improving species predictions. In doing so, ML is likely to advance the length of any integrated pest management opportunity when growers can intervene. As an example, we studied the migration of 51 species of aphids, which include some of the most economically important pests worldwide. We used a combination of entropy and C5.0 boosted decision trees to identify the most informative time windows to link meteorological variables to aphid migration patterns across the UK. Decision trees significantly improved the accuracy of first flight prediction by 20% compared to general additive models; further, meteorological variables that were selected by entropy significantly improved the accuracy by a further 3–5% compared to expert derived variables. Coarser (e.g. monthly) weather variables resulted in similar accuracies to finer (e.g. daily) variables but the most accurate model included multiple temporal resolutions with different period lengths. This combined resolution model alone highlights the ability of machine learning to accurately predict complex relationships between species and their meteorological drivers, largely beyond the experience of experts in the field. Finally, we identified the potential of these models to predict long-term first flight patterns in which machine learning attained equally high predictive ability as shorter-term forecasts. Whilst machine learning is a statistical advance, it is not necessarily a panacea: experts will be needed to underpin results with a mechanistic understanding, thus avoiding spurious relationships. The results of this study should provide researchers with an automated methodology to derive and select the most appropriate environmental variables when predicting ecological phenomena, while simultaneously improving the accuracy of such models. [ABSTRACT FROM AUTHOR]

Regulation of protein function by reversible cysteine-targeted oxidation can be achieved by multiple mechanisms, such as S-glutathiolation, S-nitrosylation, sulfenic acid, sulfinic acid, and sulfenyl amide formation, as well as intramolecular disulfide bonding of vicinal thiols. Another cysteine oxidation state with regulatory potential involves the formation of intermolecular protein disulfides. We utilized two-dimensional sequential non-reducing/reducing SDS-PAGE (diagonal electrophoresis) to investigate intermolecular protein disulfide formation in adult cardiac myocytes subjected to a series of interventions (hydrogen peroxide, S-nitroso-N-acetylpenicillamine, doxorubicin, simulated ischemia, or metabolic inhibition) that alter the redox status of the cell. More detailed experiments were undertaken with the thiol-specific oxidant diamide (5 mM), a concentration that induces a mild non-injurious oxidative stress. This increase in cellular oxidation potential caused global intermolecular protein disulfide formation in cytosolic, membrane, and myofilament/cytoskeletal compartments. A large number of proteins that undergo these associations were identified using liquid chromatography-mass spectrometry/mass spectrometry. These associations, which involve metabolic and antioxidant enzymes, structural proteins, signaling molecules, and molecular chaperones, were confirmed by assessing “shifts” on non-reducing immunoblots. The observation of widespread protein-protein disulfides indicates that these oxidative associations are likely to be fundamental in how cells respond to redox changes. [ABSTRACT FROM AUTHOR]