The clinical relevance of genetic variants in nonischemic dilated cardiomyopathy (DCM) is unsettled.
The study sought to assess the prognostic impact of disease-causing genetic variants in DCM.
...Baseline and longitudinal clinical data from 1,005 genotyped DCM probands were retrospectively collected at 20 centers. A total of 372 (37%) patients had pathogenic or likely pathogenic variants (genotype positive) and 633 (63%) were genotype negative. The primary endpoint was a composite of major adverse cardiovascular events. Secondary endpoints were end-stage heart failure (ESHF), malignant ventricular arrhythmia (MVA), and left ventricular reverse remodeling (LVRR).
After a median follow-up of 4.04 years (interquartile range: 1.70-7.50 years), the primary endpoint had occurred in 118 (31.7%) patients in the genotype-positive group and in 125 (19.8%) patients in the genotype-negative group (hazard ratio HR: 1.51; 95% confidence interval CI: 1.17-1.94; P = 0.001). ESHF occurred in 60 (16.1%) genotype-positive patients and in 55 (8.7%) genotype-negative patients (HR: 1.67; 95% CI: 1.16-2.41; P = 0.006). MVA occurred in 73 (19.6%) genotype-positive patients and in 77 (12.2%) genotype-negative patients (HR: 1.50; 95% CI: 1.09-2.07; P = 0.013). LVRR occurred in 39.6% in the genotype-positive group and in 46.2% in the genotype-negative group (P = 0.047). Among individuals with baseline left ventricular ejection fraction ≤35%, genotype-positive patients exhibited more major adverse cardiovascular events, ESHF, and MVA than their genotype-negative peers (all P < 0.02). LVRR and clinical outcomes varied depending on the underlying affected gene.
In this study, DCM patients with pathogenic or likely pathogenic variants had worse prognosis than genotype-negative individuals. Clinical course differed depending on the underlying affected gene.
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The clinical phenotype of LMNA-associated dilated cardiomyopathy (DCM) varies even among individuals who share the same mutation. LMNA encodes lamin AC, which interacts with the lamin-associated ...protein 2 alpha (LAP2α) encoded by the TMPO gene. The LAP2α/Arg690Cys polymorphism is frequent in Latin America and was previously found to disrupt LAP2α-Lamin AC interactions in vitro. We identified a DCM patient heterozygous for both a lamin AC truncating mutation (Ser431*) and the LAP2α/Arg690Cys polymorphism. We performed protein modeling and docking experiments, and used confocal microscopy to compare leukocyte nuclear morphology among family members with different genotype combinations (wild type, LAP2α Arg690Cys heterozygous, lamin AC/Ser431* heterozygous, and LAP2α Arg690Cys/lamin AC Ser431* double heterozygous). Protein modeling predicted that 690Cys destabilizes the LAP2α homodimer and impairs lamin AC-LAP2α docking. Lamin AC-deficient nuclei (Ser431* heterozygous) showed characteristic blebs and invaginations, significantly decreased nuclear area, and increased elongation, while LAP2α/Arg690Cys heterozygous nuclei showed a lower perimeter and higher circularity than wild-type nuclei. LAP2α Arg690Cys apparently attenuated the effect of LMNA Ser431* on the nuclear area and fully compensated for its effect on nuclear circularity. Altogether, the data suggest that LAP2α/Arg690Cys may be one of the many factors contributing to phenotype variation of LMNA-associated DCM.
El objetivo de este trabajo es el entrenamiento psicológico en el control del nivel óptimo de activación fisiológica para la mejora del rendimiento. En este estudio de caso único (N = 1), el ...participante es un jugador de fútbol de 23 años, perteneciente a la segunda categoría provincial de aficionados de la Federación Andaluza de Fútbol. El entrenamiento se dividió en tres fases en relación con el nivel de activación y el rendimiento, (1) autoconocimiento: el participante debía aprender a conocer su propio nivel de activación. En esta fase, realizaba diferentes ejercicios físicos y a continuación se le preguntaba por su Frecuencia Cardíaca (FC), brindándole, posteriormente, feedback de la misma; (2) definición del nivel de activación: en la que se trataba de averiguar con qué FC alcanzaba el mejor rendimiento al recorrer un circuito ad hoc (nivel de activación óptimo); (3) autorregulación: durante la que se le entrenó a autorregular su propia FC para que pudiera alcanzar su nivel de activación óptimo y alcanzar así un buen rendimiento. Los resultados indican un aprendizaje del autoconocimiento y autorregulación del nivel óptimo de activación del jugador, a través de la aplicación de feedback y la utilización del pulsómetro. El mejor rendimiento se produjo cuando las pulsaciones oscilaban entre 161 y 166 p/m. Se concluye que el entrenamiento psicológico en autorregulación del nivel óptimo de activación fisiológica contribuye a la mejora del rendimiento, tal y como ha quedado demostrado en el presente trabajo.
Background
Dilated cardiomyopathy (DCM) is a major cause of nonischemic heart failure and death in young adults. Next generation sequencing (NGS) has become part of the diagnostic workup in ...idiopathic and familial DCM. More than 50 DCM genes have been identified, revealing great molecular heterogeneity and variable diagnostic yield. Interpretation of variant pathogenicity is challenging particularly in underrepresented populations, as pathogenic variant databases include studies mainly from European/Caucasian populations. To date, no studies on genomic diagnosis of DCM have been conducted in Mexico.
Methods
We recruited 55 unrelated DCM patients, 22 familial (F‐DCM), and 33 idiopathic (I‐DCM), and performed site‐directed NGS seeking causal mutations. Diagnostic yield was defined as the proportion of individuals with at least one pathogenic (P) or likely pathogenic (LP) variant in DCM genes.
Results
Overall diagnostic yield was 47.3%, and higher in F‐DCM (63.6%) than in I‐DCM (36.4%, p = 0.047). Overall, NGS disclosed 41 variants of clinical interest (61.0% novel), 27 were classified as P/LP and 14 of unknown clinical significance. Of P/LP variants, 10 were A‐band region TTN truncating variants, five were found in DSP (18.5%), five in MYH7 (18.5%), two in LMNA (7.4%), and one in RBM20, ABCC9, FKTN, ACTA1, and TNNT2. NGS findings suggested autosomal recessive inheritance in three families, two with DSP loss of function mutations in affected individuals. The increasing number of mutation reports in DCM, increasing knowledge on the functional consequences of mutations, mutational hotspots and functional domains of DCM‐related proteins, the recent refinement ACMG/ClinGen Guidelines, and co‐segregation analysis in DCM families helped increase the diagnostic yield.
Conclusion
This is the first NGS study performed in a group of Mexican DCM patients, contributing to understand the mutational spectrum and complexity of DCM molecular diagnosis.
Molecular diagnosis in dilated cardiomyopathy (DCM) is challenging, particularly in underrepresented populations. We obtained a relatively high diagnostic yield in familial DCM (63.6%) and in idiopathic DCM (47.3%) in a group of Mexican patients. The increasing number of reports of mutations in DCM patients, the increasing knowledge on the functional consequences of mutations, mutational hotspots and functional domains of some DCM‐related proteins, the refinement ACMG/ClinGen Guidelines and co‐segregation analysis helped achieve this higher diagnostic yield.
The apparently regular and favourable climate that characterizes the Holocene as an interglacial period shows, however, important climatic instability well documented in the Northern Hemisphere. ...These fluctuations from colder to warmer or wetter to drier affected both biodiversity and human societies in the last 12,000 years, although the impact in Southern America is still poorly known. We are here investigating the biodiversity of small mammal faunas, more sensitive to climatic changes than large mammals, combining taphonomic and palaeoecological data in the Argentine Pampas to better understand the global nature and effect of these Holocene climatic fluctuations. This paper is pioneering applying in this region palaeoecological methodologies practised in European sites, such as the chorotype classification and biomes overlap analyses. The Pampean Region is an ecotone with a confluence of three climatic regions where any change in climatic conditions should be easily detected. Our results, based on the palaeoecological requirements of small mammals, do not indicate severe changes, and most of the sites show climatic stability except for one of them, in which a possible trend towards present conditions (temperate/humid) can be inferred.
•New palaeoecological methodologies are applied to the Pampean Region.•Microfauna is the best climatic indicator if multiproxy interpretations are considered.•Cave vs. open-air sites influence the composition of fossil small mammal assemblages.•Human activities in the past can distort palaeoecological interpretations.•Noticeable climatic events in the Northern hemisphere are soften/absent in the South.
The most frequent cytogenetic abnormality detected in chronic lymphocytic leukemia (CLL) patients is the presence of a deletion within the chromosome band 13q14. Deletions can be heterogeneous in ...size, generally encompassing the
and
genes (minimal deleted region), but at times also including the
gene. The latter, larger type of deletions are associated with worse prognosis.Genomic instability is a characteristic of most cancers and it has been observed in CLL patients mainly associated with telomere shortening.
Cytogenetic and fluorescence in situ hybridization studies of a CLL patient showed a chromosomal translocation t(12;13)(q15;q14), a mono-allelic 13q14 deletion encompassing both the
and
genes, and genomic instability manifested as chromosomal breaks, telomeric associations, binucleated cells, nucleoplasmic bridges, and micronucleated cells.In conclusion, our CLL patient showed genomic instability in conjunction with a 13q14 deletion of approximately 2.6 megabase pair involving the
and
genes, as well as other genes with potential for producing genomic instability due to haploinsufficiency.
Bicuspid aortic valve (BAV) disorder is the most common congenital heart disease. The aim of this study was to describe the characteristics of 0- to 18-year olds with BAV in a population-based ...registry.
Data from all pediatric patients were obtained from the Spanish registry for pediatric patients with bicuspid aortic valve (REVAB) (< 18 years). For data analysis, patients with BAV were divided into 2 groups by their features: isolated BAV and BAV with associated congenital heart disease.
We included 1681 patients from 33 hospitals. Males accounted for 69.6% (n = 1158). Valve morphology was horizontal in 63.4% (n = 1012) and pure (Sievers type 0) in 28.4% (n=469). Isolated BAV was present in 63.7% (n=1060), and concomitant left-sided obstructive lesions in 23.4% (n=390). Interventions were required in 8.6% (n=145).
These data represent the first large, population-based description of the clinical presentations and outcomes of patients enrolled in the Spanish registry for pediatric patients with bicuspid aortic valve.
La válvula aórtica bicúspide (VAB) es la cardiopatía congénita más frecuente. El objetivo de este estudio es describir las características de los pacientes en edad pediátrica con VAB en un registro poblacional.
Los datos de los pacientes se obtuvieron del Registro español de válvula aórtica bicúspide (REVAB) en pediatría (menores de 18 años). Para el análisis de datos, se dividió a los pacientes en 2 grupos según sus características: pacientes con VAB solo y pacientes con VAB y cardiopatía congénita concomitantes.
Se analizó a un total de 1.681 pacientes de 33 hospitales. La mayoría (1.158, 69,6%) eran varones. La morfología de la válvula fue horizontal en el 63,4% (1.012), y puras (tipo 0 Sievers), el 28,4% (469). El 63,7% (1.060) tenían solo VAB y en el 23,4% (390) concurrían lesiones obstructivas del lado izquierdo. Del total, el 8,6% (145) precisó alguna intervención en la válvula aórtica.
Estos datos representan la primera descripción de base poblacional de la presentación clínica y los resultados en los pacientes del REVAB Pediátrico.
Background
Poor adherence to clinical practice guidelines for eosinophilic esophagitis (EoE) has been described and the diagnostic delay of the disease continues to be unacceptable in many settings.
...Objective
To analyze the impact of improved knowledge provided by the successive international clinical practice guidelines on reducing diagnostic delay and improving the diagnostic process for European patients with EoE.
Methods
Cross‐sectional analysis of the EoE CONNECT registry based on clinical practice. Time periods defined by the publication dates of four major sets of guidelines over 10 years were considered. Patients were grouped per time period according to date of symptom onset.
Results
Data from 1,132 patients was analyzed and median (IQR) diagnostic delay in the whole series was 2.1 (0.7‐6.2) years. This gradually decreased over time with subsequent release of new guidelines (p < 0.001), from 12.7 years up to 2007 to 0.7 years after 2017. The proportion of patients with stricturing of mixed phenotypes at the point of EoE diagnosis also decreased over time (41.3% vs. 16%; p < 0.001), as did EREFS scores. The fibrotic sub‐score decreased from a median (IQR) of 2 (1‐2) to 0 (0‐1) when patients whose symptoms started up to 2007 and after 2017 were compared (p < 0.001). In parallel, symptoms measured with the Dysphagia Symptoms Score reduced significantly when patients with symptoms starting before 2007 and after 2012 were compared. A reduction in the number of endoscopies patients underwent before the one that achieved an EoE diagnosis, and the use of allergy testing as part of the diagnostic workout of EoE, also reduced significantly over time (p = 0.010 and p < 0.001, respectively).
Conclusion
The diagnostic work‐up of EoE patients improved substantially over time at the European sites contributing to EoE CONNECT, with a dramatic reduction in diagnostic delay.
Carbon-flow-regulator A (CfrA) adapts carbon flux to nitrogen conditions in nondiazotrophic cyanobacteria. Under nitrogen deficiency, CfrA leads to the storage of excess carbon, which cannot combine ...with nitrogen, mainly as glycogen. cfrA overexpression from the arsenite-inducible, nitrogen-independent ParsB promoter allows analysis of the metabolic effects of CfrA accumulation. Considering that the main consequence of cfrA overexpression is glycogen accumulation, we examined carbon distribution in response to cfrA expression in Synechocystis sp. PCC 6803 strains impaired in synthesizing this polymer. We carried out a comparative phenotypic analysis to evaluate cfrA overexpression in the wild-type strain and in a mutant of ADP-glucose pyrophosphorylase (ΔglgC), which is unable to synthesize glycogen. The accumulation of CfrA in the wild-type background caused a photosynthetic readjustment although growth was not affected. However, in a ΔglgC strain, growth decreased depending on CfrA accumulation and photosynthesis was severely affected. An elemental analysis of the H, C, and N content of cells revealed that cfrA expression in the wild-type caused an increase in the C/N ratio, due to decreased nitrogen assimilation. Metabolomic study indicated that these cells store sucrose and glycosylglycerol, in addition to the previously described glycogen accumulation. However, cells deficient in glycogen synthesis accumulated large amounts of Calvin-Benson cycle intermediates as cfrA was expressed. These cells also showed increased levels of some amino acids, mainly alanine, serine, valine, isoleucine, and leucine. The findings suggest that by controlling cfrA expression, in different conditions and strains, we could change the distribution of fixed carbon, with potential biotechnological benefits.
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