Sudden cardiac death in young athletes: Literature review of molecular basis

Intense athletic training and competition can rarely result in sudden cardiac death (SCD). Despite the introduction of pre-participation cardiovascular screening, especially among young competitive athletes, sport-related SCD remains a debated issue among medical personnel, sports communities and laypersons alike, and generates significant media attention. The most frequent cause of SCD is a hidden inherited cardiomyopathy, the athletes may not even be aware of. Predictive medicine, by searching the presence of pathogenic alterations in cardiac genes, may be an integrative tool, besides the conventional ones used in cardiology (mainly electro and echocardiogram), to reach a definitive diagnosis in athletes showing signs/symptoms, even borderline, of inherited cardiomyopathy/ channelopathy, and in athletes presenting family history of SCD and/or of hereditary cardiac disease. In this review, we revised the molecular basis of the major cardiac diseases associated to sudden cardiac death and the clinical molecular biology approach that can be used to perform risk assessment at DNA level of sudden cardiac death, contributing to the early implementation of adequate therapy. Alterations can occur in ion channel genes, in genes encoding desmosomal and junctional proteins, sarcomeric and Z-disc proteins, proteins for the cytoskeleton and the nuclear envelope. The advent of next generation sequencing (NGS) technology has provided the means to search for mutations in all these genes, at the same time. Therefore, this molecular approach should be the preferred methodology for the aforementioned purpose

Molecular Epidemiology of Mitochondrial Cardiomyopathy: A Search Among Mitochondrial and Nuclear Genes

Mitochondrial Cardiomyopathy (MCM) is a common manifestation of multi-organ Mitochondrial Diseases (MDs), occasionally present in non-syndromic cases. Diagnosis of MCM is complex because of wide clinical and genetic heterogeneity and requires medical, laboratory, and neuroimaging investigations. Currently, the molecular screening for MCM is fundamental part of MDs management and allows achieving the definitive diagnosis. In this article, we review the current genetic knowledge associated with MDs, focusing on diagnosis of MCM and MDs showing cardiac involvement. We searched for publications on mitochondrial and nuclear genes involved in MCM, mainly focusing on genetic screening based on targeted gene panels for the molecular diagnosis of the MCM, by using Next Generation Sequencing. Here we report twelve case reports, four case-control studies, eleven retrospective studies, and two prospective studies, for a total of twenty-nine papers concerning the evaluation of cardiac manifestations in mitochondrial diseases. From the analysis of published causal mutations, we identified 130 genes to be associated with mitochondrial heart diseases. A large proportion of these genes (34.3%) encode for key proteins involved in the oxidative phosphorylation system (OXPHOS), either as directly OXPHOS subunits (22.8%), and as OXPHOS assembly factors (11.5%). Mutations in several mitochondrial tRNA genes have been also reported in multi-organ or isolated MCM (15.3%). This review highlights the main disease-genes, identified by extensive genetic analysis, which could be included as target genes in next generation panels for the molecular diagnosis of patients with clinical suspect of mitochondrial cardiomyopathies

Mannose-binding lectin genetic analysis: possible protective role of the HYPA haplotype in the development of recurrent urinary tract infections in men

SummaryFactors related to bacterial virulence and/or to the host have been implicated in the pathogenesis of recurrent urinary tract infections (rUTI), but in most cases the cause is unknown. Mannose binding lectin (MBL) is an acute phase glycoprotein that exerts immunological functions by binding to the surface of a variety of pathogens. Some human gene variants reduce MBL activity thereby predisposing the host to bacterial and viral infections. The aim of this study was to investigate MBL2 gene variants in relation to rUTI risk. Six MBL gene variants and seven haplotypes were analyzed by PCR and direct sequencing in rUTI patients (n = 83) and in healthy subjects from southern Italy (n = 642). The frequencies of the L allele (−550) and the HYPA haplotype were higher in controls than in patients stratified according to sex (p < 0.05). Our data indicate that the HYPA haplotype in the MBL2 gene could be associated with a minor risk of developing rUTI in males

Antimicrobial Peptides and Physical Activity: A Great Hope against COVID 19

Antimicrobial peptides (AMPs), α- and β-defensins, possess antiviral properties. These AMPs achieve viral inhibition through different mechanisms of action. For example, they can: (i) bind directly to virions; (ii) bind to and modulate host cell-surface receptors, disrupting intracellular signaling; (iii) function as chemokines to augment and alter adaptive immune responses. Given their antiviral properties and the fact that the development of an effective coronavirus disease 2019 (COVID-19) treatment is an urgent public health priority, they and their derivatives are being explored as potential therapies against COVID-19. These explorations using various strategies, range from their direct interaction with the virus to using them as vaccine adjuvants. However, AMPs do not work in isolation, specifically in their role as potent immune modulators, where they interact with toll-like receptors (TLRs) and chemokine receptors. Both of these receptors have been shown to play roles in COVID-19 pathogenesis. In addition, it is known that a healthy lifestyle accompanied by controlled physical activity can represent a natural weapon against COVID-19. In competitive athletes, an increase in serum defensins has been shown to function as self-protection from the attack of microorganisms, consequently a controlled physical activity could act as a support to any therapies in fighting COVID-19. Therefore, including information on all these players' interactions would produce a complete picture of AMP-based therapies' response

Combined MITOchondrial-NUCLEAR (MITO-NUCLEAR) Analysis for Mitochondrial Diseases Diagnosis: Validation and Implementation of a One-Step NGS Method

Background: Next-generation sequencing (NGS) technology is revolutionizing diagnostic screening for mitochondrial diseases (MDs). Moreover, an investigation by NGS still requires analyzing the mitochondrial genome and nuclear genes separately, with limitations in terms of time and costs. We describe the validation and implementation of a custom blended MITOchondrial-NUCLEAR (MITO-NUCLEAR) assay for the simultaneous identification of genetic variants both in whole mtDNA and in nuclear genes included in a clinic exome panel. Furthermore, the MITO-NUCLEAR assay, implemented in our diagnostic process, has allowed us to arrive at a molecular diagnosis in a young patient. Methods: Massive sequencing strategy was applied for the validation experiments, performed using multiple tissues (blood, buccal swab, fresh tissue, tissue from slide, and formalin-fixed paraffin-embedded tissue section) and two different blend-in ratios of the mitochondrial probes: nuclear probes; 1:900 and 1:300. Results: Data suggested that 1:300 was the optimal probe dilution, where 100% of the mtDNA was covered at least 3000×, the median coverage was >5000×, and 93.84% of nuclear regions were covered at least 100×. Conclusions: Our custom Agilent SureSelect MITO-NUCLEAR panel provides a potential "one-step" investigation that may be applied to both research and genetic diagnosis of MDs, allowing the simultaneous discovery of nuclear and mitochondrial mutations

Positive effects of physical activity in autism spectrum disorder: how influences behavior, metabolic disorder and gut microbiota

Autism spectrum disorder is a neurodevelopmental disorder characterized by social interactions and communication skills impairments that include intellectual disabilities, communication delays and self-injurious behaviors; often are present systemic comorbidities such as gastrointestinal disorders, obesity and cardiovascular disease. Moreover, in recent years has emerged a link between alterations in the intestinal microbiota and neurobehavioral symptoms in children with autism spectrum disorder. Recently, physical activity and exercise interventions are known to be beneficial for improving communication and social interaction and the composition of microbiota. In our review we intend to highlight how different types of sports can help to improve communication and social behaviors in children with autism and also show positive effects on gut microbiota composition

Diagnostic and Therapeutic Potential for HNP-1, HBD-1 and HBD-4 in Pregnant Women with COVID-19

Pregnancy is characterized by significant immunological changes and a cytokine profile, as well as vitamin deficiencies that can cause problems for the correct development of a fetus. Defensins are small antimicrobial peptides that are part of the innate immune system and are involved in several biological activities. Following that, this study aims to compare the levels of various cytokines and to investigate the role of defensins between pregnant women with confirmed COVID-19 infection and pregnant women without any defined risk factor. TNF-α, TGF-β, IL-2 and IL-10, β-defensins, have been evaluated by gene expression in our population. At the same time, by ELISA assay IL-6, IL-8, defensin alpha 1, defensin beta 1 and defensin beta 4 have been measured. The data obtained show that mothers affected by COVID-19 have an increase in pro-inflammatory factors (TNF-α, TGF-β, IL-2, IL-6, IL-8) compared to controls; this increase could generate a sort of "protection of the fetus" from virus attacks. Contemporarily, we have an increase in the anti-inflammatory cytokine IL-10 and an increase in AMPs, which highlights how the mother's body is responding to the viral attack. These results allow us to hypothesize a mechanism of "trafficking" of antimicrobial peptides from the mother to the fetus that would help the fetus to protect itself from the infection in progress

Distribution of human beta-defensin polymorphisms in various control and cystic fibrosis populations.

Abstract Human beta defensins contribute to the first line of defense against infection of the lung. Polymorphisms in these genes are therefore potential modifiers of the severity of lung disease in cystic fibrosis. Polymorphisms were sought in the human beta-defensin genes DEFB1, DEFB4, DEFB103A, and DEFB104 in healthy individuals and cystic fibrosis (CF) patients living in various European countries. DEFB1, DEFB4, and DEFB104 were very polymorphic, but DEFB103A was not. Within Europe, differences between control populations were found for some of the frequent polymorphisms in DEFB1, with significant differences between South-Italian and Czech populations. Moreover, frequent polymorphisms located in DEFB4 and DEFB104 were not in Hardy Weinberg equilibrium in all populations studied, while those in DEFB1 were in Hardy Weinberg equilibrium. Sequencing of a monochromosomal chromosome 8 mouse-human hybrid cell line revealed signals for multiple alleles for some loci in DEFB4 and DEFB104, but not for DEFB1. This indicated that more than one DEFB4 and DEFB104 gene was present on this chromosome 8, in agreement with recent findings that DEFB4 and DEFB104 are part of a repeat region. Individual DEFB4 and DEFB104 PCR amplification products of various samples were cloned and sequenced. The results showed that one DNA sample could contain more than two haplotypes, indicating that the various repeats on one chromosome were not identical. Given the higher complexity found in the genomic organization of the DEFB4 and DEFB104 genes, association studies with CF lung disease severity were performed only for frequent polymorphisms located in DEFB1. No association with the age of first infection by Pseudomonas aeruginosa or with the FEV1 percentage at the age of 11-13 years could be found

Physical activity and sport performance: adiponectin in relation to different physio-pathological status

Adiponectin (Acrp30), and in particular its High Molecular Weight (HMW) oligomers, contributes to enhance insulin sensitivity and to reduce inflammation levels. Physical exercise improves body’s biochemical balance and metabolism resulting effective in the prevention and therapy of metabolic diseases. Whether improvement of metabolic features mediated by physical exercise is associated with changes in Acrp30 serum composition is not yet clarified. In the present study, we investigated total Acrp30 expression and its oligomeric status in two different metabolic status: professional Water Polo (WP) Players and adult patients affected by Cystic Fibrosis (CF) that performed regular physical exercise. CF is an inherited metabolic disease characterized by alterations in lipid and glucidic metabolism. Our results demonstrated significant elevated BMI, AST and LDH levels and, conversely, significantly lower concentrations of total cholesterol and VLD were present in WP players. No significant difference was found in total Acrp30 and/or HMW oligomers. Interestingly, in WP players, a direct relationship between total Acrp30 and monocytes as well as an inverse relationship between total Acrp30 and AST levels were found. ACDC molecular screening revealed previously described SNPs. In CF patients, physical exercise has significant effects on lipid and glycemic metabolism. Indeed, patients that performed exercise are characterized by significant decrease of either VLDL, cholesterol and triglycerides, border-line significant decrease of either total cholesterol/HDL and non-HDL cholesterol/HDL ratio and by trend decrease of total, LDL and non-HDL cholesterol, although not significant. It’s to highlight that physical exercise significantly reduces glycemia and HOMA-IR and increases serum albumin. However, physical exercise does not modify Acrp30 concentrations that, on the other hand, result significantly higher in all CF patients compared to controls. In conclusion, even if peripheral muscle abnormalities and respiratory factors limit exercise in patients with CF, our study indicated that physical activity has beneficial effects on lipid and glycemic metabolism in these patients not associated with Acrp30