Arrhythmogenic right ventricular cardiomyopathy (ARVC) termed a 'disease of the desmosome' is an inherited cardiomyopathy that recently underwent reclassification owing to the identification of ...left-dominant and biventricular disease forms. Homozygous loss-of-function mutations in the desmosomal component, desmoplakin, are found in patients exhibiting a biventricular form of ARVC; however, no models recapitulate the postnatal hallmarks of the disease as seen in these patients. To gain insights into the homozygous loss-of-function effects of desmoplakin in the heart, we generated cardiomyocyte-specific desmoplakin-deficient mice (DSP-cKO) using ventricular myosin light chain-2-Cre mice. Homozygous DSP-cKO mice are viable but display early ultrastructural defects in desmosomal integrity leading to a cardiomyopathy reminiscent of a biventricular form of ARVC, which includes cell death and fibro-fatty replacement within the ventricle leading to biventricular dysfunction, failure and premature death. DSP-cKO mice also exhibited ventricular arrhythmias that are exacerbated with exercise and catecholamine stimulation. Furthermore, DSP-cKO hearts exhibited right ventricular conduction defects associated with loss of connexin 40 expression and electrical wavefront propagation defects associated with loss of connexin 43 expression. Dose-dependent assessment of the effects of loss of desmoplakin in neonatal ventricular cardiomyocytes revealed primary loss of connexin 43 levels, phosphorylation and function independent of the molecular dissociation of the mechanical junction complex and fibro-fatty manifestation associated with ARVC, suggesting a role for desmoplakin as a primary stabilizer of connexin integrity. In summary, we provide evidence for a novel mouse model, which is reminiscent of the postnatal onset of ARVC while highlighting mechanisms underlying a biventricular form of human ARVC.
Understanding mechanisms underlying titin regulation in cardiac muscle function is of critical importance given recent compelling evidence that highlight titin mutations as major determinants of ...human cardiomyopathy. We previously identified a cardiac biomechanical stress-regulated complex at the cardiac-specific N2B region of titin that includes four-and-a-half LIM domain protein-1 (Fhl1) and components of the mitogen-activated protein signaling cascade, which impacted muscle compliance in Fhl1 knock-out cardiac muscle. However, direct regulation of these molecular components in mediating titin N2B function remained unresolved. Here we identify Fhl1 as a novel negative regulator of titin N2B levels and phosphorylation-mediated mechanics. We specifically identify titin N2B as a novel substrate of extracellular signal regulated-kinase-2 (Erk2) and demonstrate that Fhl1 directly interferes with Erk2-mediated titin-N2B phosphorylation. We highlight the critical region in titin-N2B that interacts with Fhl1 and residues that are dependent on Erk2-mediated phosphorylation in situ. We also propose a potential mechanism for a known titin-N2B cardiomyopathy-causing mutation that involves this regulatory complex. These studies shed light on a novel mechanism regulating titin-N2B mechano-signaling as well as suggest that dysfunction of these pathways could be important in cardiac disease states affecting muscle compliance.
Background: Titin is critical for cardiac muscle function; however, limited knowledge exists of mechanisms important for its regulation.
Results: A four-and-a-half LIM domain protein-1/extracellular signal-regulated kinase-2-associated complex modulates titin-N2B levels, phosphorylation, and mechanics.
Conclusion: We reveal new mechanisms underlying titin mechano-signaling.
Significance: We advance our understanding of how titin-associated complexes/mutations can impact cardiac muscle function and disease.
COVID-19, caused by SARS CoV-2, is an acute respiratory viral illness. We present the experience of treating patients hospitalized with COVID-19 in a Role 3 hospital in an active warzone.
This is a ...retrospective care series of patients treated for COVID-19 at Craig Joint Theater Hospital, Bagram, Afghanistan from May to August 2020. Data extracted included demographics, admission and disposition information, past medical history, comorbidities, Transportation Command (TRANSCOM) severity classification (i.e. Category A, Category B), and treatments received.
This series included 15 Category A and 55 Category B patients. Most patients were non-US contractors with one chronic condition. Most patients received medical treatments in accordance with Department of Defense Practice Management Guidelines. For Category A patients, mechanical ventilation use declined from a mean average of 10.67 days to 2.83 days following the introduction of high-flow nasal cannula. Average hospital length of stay was 6 days (range 2-23). One death occurred in a patient greater than 60 years old with three known prior medical conditions. Most patients were discharged to a non-medical isolation facility. Aeromedically evacuated patients were mostly US military and US contractors.
We faced several challenges including retrofitting a Role 3 facility designed for trauma care for management of a highly contagious respiratory viral illness. Logistics constraints impacted timely delivery of medical therapies and equipment and decreased efficiency of aeromedical evacuation. Despite these challenges and the simultaneous trauma mission, most patients received medical care in accordance with treatment guidelines with a low mortality rate.
El estudio tiene por objetivo presentar la validación de un instrumento formulado racionalmente para evaluar, mediante auto-reporte, el comportamiento social en adolescentes chilenos (CACSA) y ...describir el comportamiento social de dos grupos: adolescentes escolarizados (N=1914) y adolescentes infractores de ley (N=264). El cuestionario posee 56 ítemes que exploran tres dimensiones generales, a) Comportamiento Prosocial (CPRO), b) Comportamiento Antisocial Total (CAT); y c) Víctima de Abuso de Poder (VAP); CAT contiene seis dimensiones específicas: Delitos (D), Transgresiones Contra la Propiedad (TPRO), Transgresiones Contra las Personas (TPER), Comportamiento Abusivo con Pares (CAP), Consumo de Alcohol y Drogas (OHD); y Transgresiones Sociales Leves (TSL). El estudio incluye también una escala de deseabilidad social y otra actitudinal. Los resultados revelan importantes fortalezas psicométricas del instrumento y capacidad de discriminación entre adolescentes escolarizados e infractores de ley. Se discute la importancia de reconocer por auto-reporte la prevalencia de comportamientos antisociales y la relación entre conductas prosociales y antisociales en adolescentes chilenos.
This paper reports the validation of a rationally built self-report instrument to assess social behavior in Chilean adolescents (CACSA) and presents the findings on social behavior from two samples: school attending adolescents (N=1914) and juvenile offenders (N=264). The questionnaire consists of 56 items, which explore three general behavioral dimensions: Prosocial (CPRO) and Antisocial (CAT) behavior, and Victims of Abuse of Power (VAP); CAT contains six specific dimensions: Crimes (D), Transgressions Against Property (TPRO), Transgressions Against Persons (TPER); Abusive Behavior with Peers (CAP), Substance Abuse (OHD); and Minor Social Transgressions (TSL). The study also includes a social desirability scale and an attitudinal scale. Results revealed the questionnaire has important psychometric strengths, as well as discriminative properties between the school attending adolescents and the juvenile offenders. The importance and reliability of self-report data for building indices of antisocial behavior is discussed, as well as the relationship between prosocial and antisocial behavior among Chilean adolescents.
O estudo tem por objetivos apresentar a validação de um instrumento formulado racionalmente para avaliar, mediante auto-relato, o comportamento social de adolescentes chilenos (CACSA) e descrever o comportamento social de dois grupos: adolescentes escolarizados (N=1914) e adolescentes infratores da lei (N=264). O questionário consiste de 56 itens que exploram três dimensões gerais: a) Comportamento Pró-social (CPRO), b) Anti-Social (CAT) c) Vítimas de Abuso de Poder (VAP). CAT contém seis dimensões específicas: Delitos (D), Transgressões de Ofensa à Propriedade (TPRO), Transgressões Contra as Pessoas (TPER), Comportamentos Abusivos entre Pares (CAP), Consumo do Álcool e Drogas (OHD) e Transgressões Sociais Leves (TSL). O estudo incluiu também uma escala de desejabilidade social e outra atitudinal. Os resultados revelam que o instrumento mostra excelentes qualidades psicométricas e capacidade de discriminação entre os adolescentes escolarizados e os infratores da lei. Discute-se a importância de reconhecer a prevalência de comportamentos anti-sociais por meio de auto-relato e a relação entre condutas pró-sociais e anti-sociais em adolescentes chilenos.
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