Modelling the effects of disopyramide on short QT syndrome variant 1 in the human ventricles

The short QT syndrome (SQTS) is a recently identified genetic disorder associated with ventricular and/or atrial arrhythmias and increased risk of sudden cardiac death. The SQTS variant 1 (SQT1) N588K mutation to the hERG gene causes a gain-of-function to IKr which shortens the ventricular effective refractory period (ERP), as well as reducing the potency of several drugs which block the hERG channel. This study used computational modelling to assess the effects of disopyramide (DISO), a class 1a anti-arrhythmic agent, on human ventricular electro-physiology in SQT1. The O'Hara Rudy dynamic (ORd) model of the human ventricle action potential (AP) was modified to incorporate a Markov chain model of IKr/hERG including formulations for wild type (WT) and SQT1 N588K mutant hERG channels. The blocking effects of DISO on IKr, INa, ICaL, and Ito were modelled using IC50 and Hill coefficient values from the literature. The ability of DISO to prolong the QT interval was evaluated using a 1D model of human ventricular cells with transmural heterogeneities and the corresponding pseudo-ECG. At a clinically-relevant concentration of 10 μM DISO, the action potential duration (APD) at the single cell level was increased significantly through inhibition of mutant SQT1-hERG channels. The corrected QT interval in tissue was prolonged. This study provides further evidence that DISO is a suitable treatment for hERG-mediated SQTS

Modelling the effects of disopyramide on short QT syndrome variant 1 in the human ventricles

The short QT syndrome (SQTS) is a recently identified genetic disorder associated with ventricular and/or atrial arrhythmias and increased risk of sudden cardiac death. The SQTS variant 1 (SQT1) N588K mutation to the hERG gene causes a gain-of-function to IKr which shortens the ventricular effective refractory period (ERP), as well as reducing the potency of several drugs which block the hERG channel. This study used computational modelling to assess the effects of disopyramide (DISO), a class 1a anti-arrhythmic agent, on human ventricular electro-physiology in SQT1. The O'Hara Rudy dynamic (ORd) model of the human ventricle action potential (AP) was modified to incorporate a Markov chain model of IKr/hERG including formulations for wild type (WT) and SQT1 N588K mutant hERG channels. The blocking effects of DISO on IKr, INa, ICaL, and Ito were modelled using IC50 and Hill coefficient values from the literature. The ability of DISO to prolong the QT interval was evaluated using a 1D model of human ventricular cells with transmural heterogeneities and the corresponding pseudo-ECG. At a clinically-relevant concentration of 10 μM DISO, the action potential duration (APD) at the single cell level was increased significantly through inhibition of mutant SQT1-hERG channels. The corrected QT interval in tissue was prolonged. This study provides further evidence that DISO is a suitable treatment for hERG-mediated SQTS

Bisphenol A exposure and cardiac electrical conduction in excised rat hearts

BACKGROUND: Bisphenol A (BPA) is used to produce polycarbonate plastics and epoxy resins that are widely used in everyday products, such as food and beverage containers, toys and medical devices. Human biomonitoring studies have suggested that a large proportion of the population may be exposed to BPA. Recent epidemiological studies have reported correlations between increased BPA urinary concentrations and cardiovascular disease; yet the direct effects of BPA on the heart are unknown. OBJECTIVES: The goal of our studies was to measure BPA\u27s effect (0.1-100 μM) on cardiac impulse propagation ex vivo, using excised whole hearts from adult rats. METHODS: We measured atrial and ventricular activation times during sinus and paced rhythms using epicardial electrodes and optical mapping of transmembrane potential. Atrioventricular activation intervals and epicardial conduction velocities were computed using recorded activation times. RESULTS: Cardiac BPA exposure resulted in prolonged PR segment and decreased epicardial conduction velocity (0.1 - 100 μM), prolonged action potential duration (1 - 100 μM) and delayed atrioventricular conduction (10 - 100 μM). Importantly, these effects were observed after acute exposure (≤ 15 min), underscoring the potential detrimental effects of continuous BPA exposure. The highest BPA concentration used (100 μM) resulted in prolonged QRS intervals, dropped ventricular beats and eventually resulted in complete heart block. CONCLUSIONS: Our results show that acute BPA exposure slows electrical conduction in excised hearts from female rats. These findings emphasize the importance of examining BPA\u27s effect on heart electrophysiology and determining whether chronic in vivo exposure can cause/exacerbate conduction abnormalities in patients with pre-existing heart conditions and other high-risk populations

Television viewing in Thai infants and toddlers: impacts to language development and parental perceptions

<p>Abstract</p> <p>Background</p> <p>Effects of television to language development in infants and toddlers, especially in the Asian children, are inconclusive. This study aimed to (a) study time spent on television in Thai infants and toddlers (age < 2 years), (b) investigate the association between time spent on television (as recommended by the American Academy of Paediatrics (AAP), < 2 hours per day) and language development in Thai 2-year-old children, and (c) explore parental perceptions on television toward their child's development.</p> <p>Methods</p> <p>Two hundred and sixty children and their parents were recruited into the study. Time spent on television and parental perceptions on television viewing toward their child's development were recorded during face-to-face and telephone interviews. Language development was assessed at the age of 2 years using the Clinical Linguistic Auditory Milestone Scale (CLAMS), and parents' report. Association between delayed language development and time spent on television viewing, as well as other various parameters such as gender, maternal education and family income, were analysed using a multivariate logistic regression model.</p> <p>Results</p> <p>Most Thai infants and toddlers watched television at the age of 6 months, 1 year and 2 years old (98.0, 95.3 and 96.7%, respectively). On average, 1-year-old children watched television 1.23 ± 1.42 hours per day. This increased to 1.69 ± 1.56 hours per day when they were 2 years old. However, watching television longer than 2 hours per day did not associate with delayed language development. On multivariate logistic regression analysis, gender (male) was the only significant factor associated with delayed language development (OR = 6.9, 95% CI = 1.5–31.3). Moreover, 75%, 71%, and 66% of Thai parents believed that television viewing yielded benefits to children's developments.</p> <p>Conclusion</p> <p>Thai children commenced watching television at an early age and the amount of television viewing time increased by age. Most parents had positive perceptions to television viewing. The study found no association between time spent on television viewing (≥ 2 hours per day) and delayed language development at the age of 2 years.</p> <p>Gender (male) was the only variable associated with delayed language development.</p

The Concise Guide to PHARMACOLOGY 2023/24: Transporters

\ua9 2023 The Authors. British Journal of Pharmacology published by John Wiley &amp; Sons Ltd on behalf of The British Pharmacological Society.The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16182. Transporters are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

Use of television, videogames, and computer among children and adolescents in Italy

<p>Abstract</p> <p>Background</p> <p>This survey determined the practices about television (video inclusive), videogames, and computer use in children and adolescents in Italy.</p> <p>Methods</p> <p>A self-administered anonymous questionnaire covered socio-demographics; behaviour about television, videogames, computer, and sports; parental control over television, videogames, and computer.</p> <p>Results</p> <p>Overall, 54.1% and 61% always ate lunch or dinner in front of the television, 89.5% had a television in the bedroom while 52.5% of them always watched television there, and 49% indicated that parents controlled the content of what was watched on television. The overall mean length of time daily spent on television viewing (2.8 hours) and the frequency of watching for at least two hours per day (74.9%) were significantly associated with older age, always ate lunch or dinner while watching television, spent more time playing videogames and using computer. Those with parents from a lower socio-economic level were also more likely to spend more minutes viewing television. Two-thirds played videogames for 1.6 daily hours and more time was spent by those younger, males, with parents that do not control them, who watched more television, and who spent more time at the computer. The computer was used by 85% of the sample for 1.6 daily hours and those older, with a computer in the bedroom, with a higher number of computers in home, who view more television and play videogames were more likely to use the computer.</p> <p>Conclusion</p> <p>Immediate and comprehensive actions are needed in order to diminish time spent at the television, videogames, and computer.</p

Effects of tv time and other sedentary pursuits

Television (TV) viewing is the dominant recreational pastime at all ages, especially for children and adolescents. Many studies have shown that higher TV viewing hours are associated with higher body mass index (BMI), lower levels of fitness and higher blood cholesterol levels. Although the effect size estimated from observational studies is small (with TV viewing explaining very little of the variance in BMI), the results of intervention studies show large effect sizes. The potential mediators of the effect of higher TV viewing on higher BMI include less time for physical activity, reduced resting metabolic rate (for which there is little supporting evidence) and increased energy intake (from more eating while watching TV and a greater exposure to marketing of energy dense foods). Electronic games may have an effect on unhealthy weight gain, but are less related to increased energy intake and their usage is relatively new, making effect size difficult to determine. Thus, TV viewing does not explain much of the differences in body size between individuals or the rise in obesity over time, perhaps because of the uniformly high, but relatively stable, TV viewing hours. Reducing TV viewing hours is a difficult prospect because potential actions, such as social marketing and education, are likely to be relatively weak interventions, although the evidence would suggest that, if viewing could be reduced, it could have a significant impact on reducing obesity prevalence. Regulations to reduce the heavy marketing of energy dense foods and beverages on TV may be the most effective public health measure available to minimize the impact of TV viewing on unhealthy weight gain.<br /

Longitudinal associations between television in the bedroom and body fatness in a UK cohort study.

OBJECTIVE: To assess longitudinal associations between screen-based media use (television (TV) and computer hours, having a TV in the bedroom) and body fatness among UK children. METHODS: Participants were 12 556 children from the UK Millennium Cohort Study who were followed from age 7 to age 11 years. Associations were assessed between screen-based media use and the following outcomes: body mass index (BMI), fat mass index (FMI), and overweight. RESULTS: In fully adjusted models, having a bedroom TV at age 7 years was associated with significantly higher BMI and FMI (excess BMI for boys=0.29, 95% confidence interval (CI) 0.06-0.52; excess BMI for girls=0.57, 95% CI 0.31-0.84; excess FMI for boys=0.20, 95% CI 0.04-0.37; excess FMI for girls=0.39, 95% CI 0.21-0.57) and increased risk of being overweight (relative risk (RR) for boys=1.21, 95% CI 1.07-1.36; RR for girls=1.31, 95% CI 1.15-1.48) at age 11 years, compared with having no bedroom TV. Hours spent watching TV or digital versatile disks were associated with increased risk of overweight among girls only. Computer use at age 7 years was not related to later body fatness for either gender. CONCLUSION: Having a TV in the child's bedroom was an independent risk factor for overweight and increased body fatness in this nationally representative sample of UK children. Childhood obesity prevention strategies should consider TVs in children's bedrooms as a risk factor for obesity.International Journal of Obesity advance online publication, 27 June 2017; doi:10.1038/ijo.2017.129

Global Taxonomic Diversity of Anomodonts (Tetrapoda, Therapsida) and the Terrestrial Rock Record Across the Permian-Triassic Boundary

The end-Permian biotic crisis (∼252.5 Ma) represents the most severe extinction event in Earth's history. This paper investigates diversity patterns in Anomodontia, an extinct group of therapsid synapsids (‘mammal-like reptiles’), through time and in particular across this event. As herbivores and the dominant terrestrial tetrapods of their time, anomodonts play a central role in assessing the impact of the end-Permian extinction on terrestrial ecosystems. Taxonomic diversity analysis reveals that anomodonts experienced three distinct phases of diversification interrupted by the same number of extinctions, i.e. an end-Guadalupian, an end-Permian, and a mid-Triassic extinction. A positive correlation between the number of taxa and the number of formations per time interval shows that anomodont diversity is biased by the Permian-Triassic terrestrial rock record. Normalized diversity curves indicate that anomodont richness continuously declines from the Middle Permian to the Late Triassic, but also reveals all three extinction events. Taxonomic rates (origination and extinction) indicate that the end-Guadalupian and end-Permian extinctions were driven by increased rates of extinction as well as low origination rates. However, this pattern is not evident at the final decline of anomodont diversity during the Middle Triassic. Therefore, it remains unclear whether the Middle Triassic extinction represents a gradual or abrupt event that is unique to anomodonts or more common among terrestrial tetrapods. The end-Permian extinction represents the most distinct event in terms of decline in anomodont richness and turnover rates