Arrhythmic risk prediction in arrhythmogenic right ventricular cardiomyopathy : external validation of the arrhythmogenic right ventricular cardiomyopathy risk calculator

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus. Methods and results: In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05-7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65-0.75)] and calibration slope of 1.01 (95% CI 0.99-1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%. Conclusion: Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC

Lifespan extension without fertility reduction following dietary addition of the autophagy activator Torin1 in Drosophila melanogaster

Autophagy is a highly conserved mechanism for cellular repair that becomes progressively down-regulated during normal ageing. Hence, manipulations that activate autophagy could increase lifespan. Previous reports show that manipulations to the autophagy pathway can result in longevity extension in yeast, flies, worms and mammals. Under standard nutrition, autophagy is inhibited by the nutrient sensing kinase Target of Rapamycin (TOR). Therefore, manipulations of TOR that increase autophagy may offer a mechanism for extending lifespan. Ideally, such manipulations should be specific and minimise off-target effects, and it is important to discover additional methods for ‘clean’ lifespan manipulation. Here we report an initial study into the effect of up-regulating autophagy on lifespan and fertility in Drosophila melanogaster by dietary addition of Torin1. Activation of autophagy using this selective TOR inhibitor was associated with significantly increased lifespan in both sexes. Torin1 induced a dose-dependent increase in lifespan in once-mated females. There was no evidence of a trade-off between longevity and fecundity or fertility. Torin1-fed females exhibited significantly elevated fecundity, but also elevated egg infertility, resulting in no net change in overall fertility. This supports the idea that lifespan can be extended without trade-offs in fertility and suggest that Torin1 may be a useful tool with which to pursue anti-ageing research

A Functional Misexpression Screen Uncovers a Role for Enabled in Progressive Neurodegeneration

Drosophila is a well-established model to study the molecular basis of neurodegenerative diseases. We carried out a misexpression screen to identify genes involved in neurodegeneration examining locomotor behavior in young and aged flies. We hypothesized that a progressive loss of rhythmic activity could reveal novel genes involved in neurodegenerative mechanisms. One of the interesting candidates showing progressive arrhythmicity has reduced enabled (ena) levels. ena down-regulation gave rise to progressive vacuolization in specific regions of the adult brain. Abnormal staining of pre-synaptic markers such as cystein string protein (CSP) suggest that axonal transport could underlie the neurodegeneration observed in the mutant. Reduced ena levels correlated with increased apoptosis, which could be rescued in the presence of p35, a general Caspase inhibitor. Thus, this mutant recapitulates two important features of human neurodegenerative diseases, i.e., vulnerability of certain neuronal populations and progressive degeneration, offering a unique scenario in which to unravel the specific mechanisms in an easily tractable organism

Induction of autophagy by spermidine promotes longevity.

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L’exploration des Schémas Précoces Inadaptés (SPI) chez les personnes adultes atteintes de troubles bipolaires: une revue systématique de la littérature scientifique

En raison des enjeux cliniques actuels concernant les troubles bipolaires et des arguments théoriques en faveur de l’approche centrée sur les schémas comme modèle de compréhension, cette revue systématique de la littérature a pour objectif d’évaluer la pertinence de ce modèle au regard des données empiriques. Méthodes. – Cette revue a été menée suivant la méthode Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) sur les bases de données électroniques Cochrane, PsycArticles, Psycho logy and Behavioral Sciences Collection, PsycInfo, PubMed, ScienceDirect et Scopus avec les mots-clés « early maladaptive schemas » et « bipolar disorder ». Seuls les articles répondant aux critères d’éligibilité pouvaient être inclus (ex. population et mesures). Résultats. – Parmi 39 publications, 10 articles ont été retenus après analyse de leur titre, résumé et contenu intégral. Malgré les biais identifiés limitant leur portée et l’absence d’un pattern homogène de schémas activés, les résultats suggèrent que les schémas précoces inadaptés permettent de distinguer les individus présentant des troubles bipolaires de ceux n’ayant aucun trouble, et de ceux souffrant de troubles dépres sifs ou de personnalité borderline, tout comme ils peuvent rendre compte de l’hétérogénéité clinique des troubles bipolaires. Enfin, leur retentissement est important sur le cours de la pathologie (suicidalité et handicap fonctionnel). Conclusions. – L’approche centrée sur les schémas s’avère pertinente bien que les données empiriques ne permettent pas encore de comprendre la disparité de profils durant la période intercritique et d’indiquer la thérapie des schémas de manière adaptée. Une perspective de recherche est alors envisagée afin de pallier ces manques identifiés dans la littérature.Objectives. – Clinical heterogeneity during euthymic states is a crucial issue in bipolar disorders. Indeed, actual data are not sufficient to understand why some patients are unharmed by subthreshold symptoms and have functional impairments whereas others have a functional remission but have subthreshold symptoms. Based on the Ball model, cognitive and schematic vulnerability interact with genetic vul nerability and trigger affective symptoms with the intervention of s according to this model, adjustment and adaptation to illness assessed by functional outcome and illiness experience are associated with this cognitive and schematic vulnerability. So, theoretical arguments support that childhood adversity and temperamental deregulation characterize patients with bipolar disorders. Thus, the aim of this study is to systematically review studies of Early Maladaptive Schemas in bipolar disorder, to determine whether Early Maladaptive Schemas have specificity in bipolar disorder in comparison with other populations, and to identify which Early Maladaptive Schemas could be activated. The challenge of this review is to identify if the taking of early maladaptive schemas into account could allow us to better identify, understand and manage bipolar disorders. Methods. – This systematic review was led according to the Preferred Reporting Items for Systematic review and Meta-Analysis statement on the electronic databases Cochrane, PsycArticles, Psychology and Behavioral Sciences Collection, PsycInfo, PubMed, ScienceDirect and Scopus with « early maladaptive schemas » AND « bipolar disorder » as keywords. Only studies meeting eligibility criteria concerning publication status, language, population and outcomes were included after several screenings on basis of title, abstract and full-text. Then, we carried out data extraction in accordance with criteria defined in principle (about characteristics of participants, objectives, materiel and methods, principle results and bias). Results. – Among 39 records identified, a total of 10 studies met eligibility criteria for inclusion in this review. Synthesizing findings across the studies revealed three important topics. First, early maladaptive schemas appear as potential cognitive characteristics that clinicians have to investigate in clinical practice. Indeed, patients with bipolar disorders present greater activation of the early maladaptive schemas in comparison with people who have no disorder. This point supports the first part of Ball’s theoretical model that considers schemas as a vulnerability to bipolarity. Secondly, early maladaptive schemas are relevant to distinguish bipolar disorders from unipolar depression and borderline personality disorder. A greater and a lower activation are respectively identified among bipolar disorders. Thirdly, supporting the second part of Ball’s model, early maladaptive schemas play a key role in recovery regarding their impact on the course of bipolarity, in particular on suicidality and functional impairment. Finally, these dysfunctional schemas allow us to understand the clinical heterogeneity of bipolar disorder, and among others, about the type of bipolarity. These results have several implications, but there are some limits in this systematic review. First, no French study has been done. Then, reduced sample sizes in these studies increased the risk to conclude wrongly to an activation difference between groups. Furthermore, probably due to the variety of methods and populations, we could not identify an homogeneous pattern of early activated maladaptive schemas. Overall, scientific approaches used in these studies are based on statistical models using mean and standard deviation. These types of statistical analyses are the main limit because they cannot represent the heterogeneity of early maladaptive schemas profiles. Conclusions. – Schema theory proves to be a relevant approach in bipolar disorders, and early maladaptive schemas appear to be important to take into account in clinical practice. Nevertheless, in order to propose schemas therapy appropriately, it is necessary to specify if early maladaptive schemas are activated and to specify therapeutic indications because of clinical heterogeneity. Moreover, data do not yet allow us to understand the disparity of profiles during the inter-episode period. Indeed, a French research perspective is being considered that will prefer a person-oriented approach

Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300

Ageing is the primary risk factor for osteoarthritis (OA). A decline in the ageing-associated process of autophagy is suggested as a potential contributor to OA development. Polyamines such as spermidine decrease during ageing, contributing to impaired autophagy and reduced cellular function. However, the role of polyamines and their effect on the regulatory mechanism governing autophagy in aged and arthritic cartilage tissue has not been established. Elucidating if polyamine regulation of autophagy is impaired during ageing and OA in chondrocytes may lead to improved treatment approaches to protect against cartilage degradation. Our results indicate that polyamine synthesis was decreased in aged and OA cartilage, along with reduced autophagy activity, evidenced by decreased autophagyrelated gene and protein expression and autophagosome formation. Importantly, spermidine treatment increased the expression of the acetyltransferase EP300, which binds to crucial autophagy proteins, Beclin1 and LC3, and elevates chondrocyte autophagy. Our data indicate spermidine prevents the ageing- and OA-related decrease in autophagy and may protect against OA development