Search

Abstract: Background: The pathogenesis of MYBPC3-associated hypertrophic cardiomyopathy (HCM) is still unresolved. In our HCM patient cohort, a large and well-characterized population carrying the MYBPC3:c772G>A variant (p.Glu258Lys, E258K) provides the unique opportunity to study the basic mechanisms of MYBPC3-HCM with a comprehensive translational approach. Methods: We collected clinical and genetic data from 93 HCM patients carrying the MYBPC3:c772G>A variant. Functional perturbations were investigated using different biophysical techniques in left ventricular samples from 4 patients who underwent myectomy for refractory outflow obstruction, compared with samples from non-failing non-hypertrophic surgical patients and healthy donors. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and engineered heart tissues (EHTs) were also investigated. Results: Haplotype analysis revealed MYBPC3:c772G>A as a founder mutation in Tuscany. In ventricular myocardium, the mutation leads to reduced cMyBP-C (cardiac myosin binding protein-C) expression, supporting haploinsufficiency as the main primary disease mechanism. Mechanical studies in single myofibrils and permeabilized muscle strips highlighted faster cross-bridge cycling, and higher energy cost of tension generation. A novel approach based on tissue clearing and advanced optical microscopy supported the idea that the sarcomere energetics dysfunction is intrinsically related with the reduction in cMyBP-C. Studies in single cardiomyocytes (native and hiPSC-derived), intact trabeculae and hiPSC-EHTs revealed prolonged action potentials, slower Ca2+ transients and preserved twitch duration, suggesting that the slower excitation-contraction coupling counterbalanced the faster sarcomere kinetics. This conclusion was strengthened by in silico simulations. Conclusions: HCM-related MYBPC3:c772G>A mutation invariably impairs sarcomere energetics and cross-bridge cycling. Compensatory electrophysiological changes (eg, reduced potassium channel expression) appear to preserve twitch contraction parameters, but may expose patients to greater arrhythmic propensity and disease progression. Therapeutic approaches correcting the primary sarcomeric defects may prevent secondary cardiomyocyte remodeling

Book in Spanish.Tras casi 500 largos años, la pequeña urbe que encabezó la Provincia de Coro, una de las primeras unidades territoriales de Venezuela, situada en el septentrión de Suramérica, posiblemente ha generado más significación histórica que muchas localidades con mayor abolengo en el Sur o el Norte del continente.Como asienta esta extraordinaria antología del eminente poeta coriano Luis Alfonso Bueno, que Fundamemoria Documental presenta orgullosamente en esta edición especial, la historia de Coro y por extensión la del estado Falcón, se lee igual como una novela de suspenso (Octavio Petit, El Judas que Vendió a José Leonardo Chirinos), una reportaje de forajidos (Ildemaro Alguíndigue, Dos Guerrilleros Muertos en la Sierra de Coro), un relato costumbrista (Misael Salazar Leydenz, Las bodas del mulato Juan Joseph), un estudio sociológico (Aníbal Martínez, Gumersindo Torres, el Petróleo) un poema sonoro (Alí Primera, El Pueblo es un Gran Poeta), un diario de aventuras (Heberto Petit Arnáez, Bisabuelo y Biznieto Aventureros), una reflexión sobre la erudicción (Juvenal López Ruiz, La Biblioteca Arcaya: magia, religión y ciencia), una crónica de viajes (Virgilio Medina, Visita de Pablo Neruda a Coro), o una nota gastronómica (Juan Alonso Molina Morales, La Cocina Según Chento Cuervo).Esta obra, que consideramos esencial para quienes desean adentrarse en los misterios de la historia cotidiana de Falcón, fue escrita a dos tiempos: la primera parte publicada en el ya lejano 1983, como parte de la legendaria Biblioteca de Autores y Temas Falconianos, fundada por el propio Luis Alfonso; y la segunda, escrita exclusivamente para esta edición de Fundamemoria Documental.

We are very pleased to provide you with this book dealing with abdominal surgery. The chapters in the book are written by surgeons, radiologists, anesthesiologists and oncologists from different hospitals in Tunisia, Turkey, Denmark, Spain and Italy. Together with basic surgical principles, the unique local experiences and perspectives are presented. Although it does not cover all the aspects related to the abdominal surgery, it is intended for at least two kinds of readers: a) Residents of intermediate and advanced courses in medicine; b) Anesthesiologists, oncologists, surgeons, radiologists and all doctors whatever the specialty.