Diagnosis of lipomatous hypertrophy of the atrial septum by two-dimensional echocardiography

Originally described in 1964, lipomatous hypertrophy of the atrial septum currently remains a diagnosis established primarily at autopsy. Clinical interest in this disorder has centered on the reported association with supraventricular arrhythmias and sudden death. Because two-dimensional echocardiography allows detailed assessment of atrial septal configuration, we reviewed two-dimensional echocardiographic reports obtained over a 1 year period and identified 17 patients who had features consistent with lipomatous hypertrophy of the atrial septum. Nine were men and the average age was 70 years. Autopsy confirmation of the echographic findings was possible in one patient. In nine patients, ideal body weight was exceeded by 10% or more. The atrial septum viewed from the subcostal transducer position showed a distinctive echo-dense globular thickening sparing the valve of the fossa ovalis. The resultant tomographic image of the atrial septum had a characteristic dumbbell appearance. The mean thickness of the atrial septum was 21 mm (range 15 to 29). Seven patients had supraventricular arrhythmias, and eight had P wave abnormalities.The two-dimensional echocardiographic features described are distinctive and suggest that this technique is the procedure of choice not only for establishing the diagnosis of lipomatous hypertrophy of the atrial septum but also for providing a means for prospective follow-up of patients with this little known entity

Cells

Phytocannabinoids, including the non-addictive cannabis component cannabidivarin (CBDV), have been reported to hold therapeutic potential in several neurodevelopmental disorders (NDDs). Nonetheless, the therapeutic value of phytocannabinoids for treating Fragile X syndrome (FXS), a major NDD, remains unexplored. Here, we characterized the neurobehavioral effects of CBDV at doses of 20 or 100 mg/kg in the Fmr1-knockout (Fmr1-KO) mouse model of FXS using two temporally different intraperitoneal regimens: subchronic 10-day delivery during adulthood (Study 1: rescue treatment) or chronic 5-week delivery at adolescence (Study 2: preventive treatment). Behavioral tests assessing FXS-like abnormalities included anxiety, locomotor, cognitive, social and sensory alterations. Expression of inflammatory and plasticity markers was investigated in the hippocampus and prefrontal cortex. When administered during adulthood (Study 1), the effects of CBDV were marginal, rescuing at the lower dose only the acoustic hyper-responsiveness of Fmr1-KO mice and at both doses their altered hippocampal expression of neurotrophins. When administered during adolescence (Study 2), CBDV at both doses prevented the cognitive, social and acoustic alterations of adult Fmr1-KO mice and modified the expression of several inflammatory brain markers in both wild-type littermates and mutants. These findings warrant the therapeutic potential of CBDV for preventing neurobehavioral alterations associated with FXS, highlighting the relevance of its early administration.Bordeaux Region Aquitaine Initiative for Neuroscienc

Description and Demonstration of the Coupled Community Earth System Model v2-Community Ice Sheet Model v2 (CESM2-CISM2)

Earth system/ice-sheet coupling is an area of recent, major Earth System Model (ESM) development. This work occurs at the intersection of glaciology and climate science and is motivated by a need for robust projections of sea-level rise. The Community Ice Sheet Model version 2 (CISM2) is the newest component model of the Community Earth System Model version 2 (CESM2). This study describes the coupling and novel capabilities of the model, including: (1) an advanced energy-balance-based surface mass balance calculation in the land component with downscaling via elevation classes; (2) a closed freshwater budget from ice sheet to the ocean from surface runoff, basal melting, and ice discharge; (3) dynamic land surface types; and (4) dynamic atmospheric topography. The Earth system/ice-sheet coupling is demonstrated in a simulation with an evolving Greenland Ice Sheet (GrIS) under an idealized high CO2 scenario. The model simulates a large expansion of ablation areas (where surface ablation exceeds snow accumulation) and a large increase in surface runoff. This results in an elevated freshwater flux to the ocean, as well as thinning of the ice sheet and area retreat. These GrIS changes result in reduced Greenland surface albedo, changes in the sign and magnitude of sensible and latent heat fluxes, and modified surface roughness and overall ice sheet topography. Representation of these couplings between climate and ice sheets is key for the simulation of ice and climate interactions. </div

The DOE E3SM Coupled Model Version 1: Overview and Evaluation at Standard Resolution

This work documents the first version of the U.S. Department of Energy (DOE) new Energy Exascale Earth System Model (E3SMv1). We focus on the standard resolution of the fully coupled physical model designed to address DOE mission-relevant water cycle questions. Its components include atmosphere and land (110-km grid spacing), ocean and sea ice (60 km in the midlatitudes and 30 km at the equator and poles), and river transport (55 km) models. This base configuration will also serve as a foundation for additional configurations exploring higher horizontal resolution as well as augmented capabilities in the form of biogeochemistry and cryosphere configurations. The performance of E3SMv1 is evaluated by means of a standard set of Coupled Model Intercomparison Project Phase 6 (CMIP6) Diagnosis, Evaluation, and Characterization of Klima simulations consisting of a long preindustrial control, historical simulations (ensembles of fully coupled and prescribed SSTs) as well as idealized CO2 forcing simulations. The model performs well overall with biases typical of other CMIP-class models, although the simulated Atlantic Meridional Overturning Circulation is weaker than many CMIP-class models. While the E3SMv1 historical ensemble captures the bulk of the observed warming between preindustrial (1850) and present day, the trajectory of the warming diverges from observations in the second half of the twentieth century with a period of delayed warming followed by an excessive warming trend. Using a two-layer energy balance model, we attribute this divergence to the model’s strong aerosol-related effective radiative forcing (ERFari+aci = -1.65 W/m2) and high equilibrium climate sensitivity (ECS = 5.3 K).Plain Language SummaryThe U.S. Department of Energy funded the development of a new state-of-the-art Earth system model for research and applications relevant to its mission. The Energy Exascale Earth System Model version 1 (E3SMv1) consists of five interacting components for the global atmosphere, land surface, ocean, sea ice, and rivers. Three of these components (ocean, sea ice, and river) are new and have not been coupled into an Earth system model previously. The atmosphere and land surface components were created by extending existing components part of the Community Earth System Model, Version 1. E3SMv1’s capabilities are demonstrated by performing a set of standardized simulation experiments described by the Coupled Model Intercomparison Project Phase 6 (CMIP6) Diagnosis, Evaluation, and Characterization of Klima protocol at standard horizontal spatial resolution of approximately 1° latitude and longitude. The model reproduces global and regional climate features well compared to observations. Simulated warming between 1850 and 2015 matches observations, but the model is too cold by about 0.5 °C between 1960 and 1990 and later warms at a rate greater than observed. A thermodynamic analysis of the model’s response to greenhouse gas and aerosol radiative affects may explain the reasons for the discrepancy.Key PointsThis work documents E3SMv1, the first version of the U.S. DOE Energy Exascale Earth System ModelThe performance of E3SMv1 is documented with a set of standard CMIP6 DECK and historical simulations comprising nearly 3,000 yearsE3SMv1 has a high equilibrium climate sensitivity (5.3 K) and strong aerosol-related effective radiative forcing (-1.65 W/m2)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151288/1/jame20860_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151288/2/jame20860.pd

Identification de cibles thérapeutiques pour le traitement du syndrome de l'X fragile : conséquences pour le spectre de l'autisme

Fragile X syndrome (FXS) is a neurodevelopmental disorder due to an X-linked mutation in the FMR1 gene that results in intellectual disability (ID), autism spectrum disorder (ASD), anxiety, attention deficit hyperactivity disorder (ADHD) and sensory processing deficits. There is substantial overlap between FXS and ASD as approximately 30 to 50% of individuals diagnosed with FXS also meet the diagnostic criteria for ASD. Furthermore FXS-ASD patients represent approximately 5% of all cases of ASD. Since there is currently no targeted therapeutic approach, novel pharmacological agents addressing the neurobiological underpinnings of these disorders are crucially needed. Due to the overlap between the two conditions, systems which are disrupted in FXS and ASD patients may provide targets for treating the ASD symptoms observed in FXS-ASD patients and some non-syndromic ASD patients. FMRP, the protein lost by the FMR1 mutation, is a potent regulator of the endocannabinoid system (ECS) and BKCa channels. These function to regulate presynaptic excitability. Dysfunction in these systems is found in FXS patients and some ASD patients. The presynaptic role of these agents conceptualizes the “presynaptic hypothesis of FXS-ASD”. This project used genetic and pharmacological approaches which target FMRP, the ECS or BKCa channels in combination with an extensive behavioral characterization of FXS and ASD-relevant phenotypes, in order to assess the therapeutic value of these targets. This work demonstrates that the ECS and BKCa channels contribute to behavioral domains affected in neurodevelopmental disorders and offer several targets for therapeutics which should be explored.Le Syndrome de l’X fragile (FXS) est un trouble du neurodéveloppement causé par la mutation du chromosome X dans le gène FMR1. Les manifestations de cette mutation sont un déficit intellectuel, le trouble du spectre de l’autisme (TSA), trouble d'hyperactivité avec ou sans déficit de l'attention (TDHA), et les défauts du traitement de l’information sensorielle. Il existe un lien entre FXS et TSA. Environ 30 à 50% des individuels qui sont diagnostiqué avec FXS aussi remplir le critère pour TSA. En plus, les patients qui ont FXS-TSA compte pour environ 5% de toutes les personnes qui ont TSA. Étant donné qu’il n’existe actuellement aucune approche thérapeutique ciblée, de nouveaux agents pharmacologiques trainant les bases neurobiologiques de ce trouble sont indispensables. Parce qu’il y a un lien entre ces conditions, les systèmes qui sont perturbés pour les patients qui ont FXS ou TSA pourraient fournir des cibles pour le traitement des symptômes de TSA observés en les patients FXS-TSA et certains patients TSA non-syndromiques. FMRP, la protéine perdue par la mutation du gène FMR1, est un régulateur puissant du système endocannabinoid (ECS) et les canaux de conductance potassique qui sont calcique et voltage dépendantes (BKCa). Ces travaillent pour réguler l’excitabilité du neurone présynaptique. Le dysfonctionnement de ces systèmes est observé avec les patients de FXS et quelques patients de TSA. Le rôle presynaptique de ces agents conceptualise « l’hypothèse présynaptique de FXS-TSA ». Ce projet a utilisé des approches génétiques et pharmacologiques qui ciblent FMRP, l’ECS, or les canaux BKCa en combinaison avec une caractérisation comportementale des phénotypes FXS et TSA pertinents, afin d’évaluer la valeur thérapeutique de ces cibles. Ces travaux démontrent que les canaux ECS et BKCa contribuent aux domaines comportementaux affectés dans les troubles neurodéveloppementaux et offrent plusieurs cibles thérapeutiques qui devraient être explorées

Identifying therapeutic targets for the treatment of Fragile X Syndrome : Implications for Autism Spectrum Disorders

Le Syndrome de l’X fragile (FXS) est un trouble du neurodéveloppement causé par la mutation du chromosome X dans le gène FMR1. Les manifestations de cette mutation sont un déficit intellectuel, le trouble du spectre de l’autisme (TSA), trouble d'hyperactivité avec ou sans déficit de l'attention (TDHA), et les défauts du traitement de l’information sensorielle. Il existe un lien entre FXS et TSA. Environ 30 à 50% des individuels qui sont diagnostiqué avec FXS aussi remplir le critère pour TSA. En plus, les patients qui ont FXS-TSA compte pour environ 5% de toutes les personnes qui ont TSA. Étant donné qu’il n’existe actuellement aucune approche thérapeutique ciblée, de nouveaux agents pharmacologiques trainant les bases neurobiologiques de ce trouble sont indispensables. Parce qu’il y a un lien entre ces conditions, les systèmes qui sont perturbés pour les patients qui ont FXS ou TSA pourraient fournir des cibles pour le traitement des symptômes de TSA observés en les patients FXS-TSA et certains patients TSA non-syndromiques. FMRP, la protéine perdue par la mutation du gène FMR1, est un régulateur puissant du système endocannabinoid (ECS) et les canaux de conductance potassique qui sont calcique et voltage dépendantes (BKCa). Ces travaillent pour réguler l’excitabilité du neurone présynaptique. Le dysfonctionnement de ces systèmes est observé avec les patients de FXS et quelques patients de TSA. Le rôle presynaptique de ces agents conceptualise « l’hypothèse présynaptique de FXS-TSA ». Ce projet a utilisé des approches génétiques et pharmacologiques qui ciblent FMRP, l’ECS, or les canaux BKCa en combinaison avec une caractérisation comportementale des phénotypes FXS et TSA pertinents, afin d’évaluer la valeur thérapeutique de ces cibles. Ces travaux démontrent que les canaux ECS et BKCa contribuent aux domaines comportementaux affectés dans les troubles neurodéveloppementaux et offrent plusieurs cibles thérapeutiques qui devraient être explorées.Fragile X syndrome (FXS) is a neurodevelopmental disorder due to an X-linked mutation in the FMR1 gene that results in intellectual disability (ID), autism spectrum disorder (ASD), anxiety, attention deficit hyperactivity disorder (ADHD) and sensory processing deficits. There is substantial overlap between FXS and ASD as approximately 30 to 50% of individuals diagnosed with FXS also meet the diagnostic criteria for ASD. Furthermore FXS-ASD patients represent approximately 5% of all cases of ASD. Since there is currently no targeted therapeutic approach, novel pharmacological agents addressing the neurobiological underpinnings of these disorders are crucially needed. Due to the overlap between the two conditions, systems which are disrupted in FXS and ASD patients may provide targets for treating the ASD symptoms observed in FXS-ASD patients and some non-syndromic ASD patients. FMRP, the protein lost by the FMR1 mutation, is a potent regulator of the endocannabinoid system (ECS) and BKCa channels. These function to regulate presynaptic excitability. Dysfunction in these systems is found in FXS patients and some ASD patients. The presynaptic role of these agents conceptualizes the “presynaptic hypothesis of FXS-ASD”. This project used genetic and pharmacological approaches which target FMRP, the ECS or BKCa channels in combination with an extensive behavioral characterization of FXS and ASD-relevant phenotypes, in order to assess the therapeutic value of these targets. This work demonstrates that the ECS and BKCa channels contribute to behavioral domains affected in neurodevelopmental disorders and offer several targets for therapeutics which should be explored

FMR1 and Autism, an Intriguing Connection Revisited

Autism Spectrum Disorder (ASD) represents a distinct phenotype of behavioral dysfunction that includes deficiencies in communication and stereotypic behaviors. ASD affects about 2% of the US population. It is a highly heritable spectrum of conditions with substantial genetic heterogeneity. To date, mutations in over 100 genes have been reported in association with ASD phenotypes. Fragile X syndrome (FXS) is the most common single-gene disorder associated with ASD. The gene associated with FXS, FMR1 is located on chromosome X. Accordingly, the condition has more severe manifestations in males. FXS results from the loss of function of FMR1 due to the expansion of an unstable CGG repeat located in the 5′′ untranslated region of the gene. About 50% of the FXS males and 20% of the FXS females meet the Diagnostic Statistical Manual 5 (DSM-5) criteria for ASD. Among the individuals with ASD, about 3% test positive for FXS. FMRP, the protein product of FMR1, is a major gene regulator in the central nervous system. Multiple pathways regulated by FMRP are found to be dysfunctional in ASD patients who do not have FXS. Thus, FXS presents the opportunity to study cellular phenomena that may have wider applications in the management of ASD and to develop new strategies for ASD therapy

An Efficient Ice Sheet/Earth System Model Spin-up Procedure for CESM2-CISM2: Description, Evaluation, and Broader Applicability

Spinning up a highly complex, coupled Earth system model (ESM) is a time consuming and computationally demanding exercise. For models with interactive ice sheet components, this becomes a major challenge, as ice sheets are sensitive to bidirectional feedback processes and equilibrate over glacial timescales of up to many millennia. This work describes and demonstrates a computationally tractable, iterative procedure for spinning up a contemporary, highly complex ESM that includes an interactive ice sheet component. The procedure alternates between a computationally expensive coupled configuration and a computationally cheaper configuration where the atmospheric component is replaced by a data model. By periodically regenerating atmospheric forcing consistent with the coupled system, the data atmosphere remains adequately constrained to ensure that the broader model state evolves realistically. The applicability of the method is demonstrated by spinning up the preindustrial climate in the Community Earth System Model Version 2 (CESM2), coupled to the Community Ice Sheet Model Version 2 (CISM2) over Greenland. The equilibrium climate state is similar to the control climate from a coupled simulation with a prescribed Greenland ice sheet, indicating that the iterative procedure is consistent with a traditional spin-up approach without interactive ice sheets. These results suggest that the iterative method presented here provides a faster and computationally cheaper method for spinning up a highly complex ESM, with or without interactive ice sheet components. The method described here has been used to develop the climate/ice sheet initial conditions for transient, ice sheet-enabled simulations with CESM2-CISM2 in the Coupled Model Intercomparison Project Phase 6 (CMIP6).Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Communication and social interaction in the cannabinoid‐type 1 receptor null mouse: Implications for autism spectrum disorder

International audienceClinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1-/- , CB1+/- , and CB1+/+ males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3 months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1-/- than CB1+/- mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains