Evaluation of Antioxidant Defence Systems and Inflammatory Status in Basketball Elite Athletes.

Intense physical activity can induce metabolic changes that modify specific biochemical biomarkers. In this scenario, the purpose of our study was to evaluate how intense physical activity can affect oxidative metabolism. Following this, fifteen professional basketball players and fifteen sedentary controls were recruited and subjected to two samplings of serum and urine in the pre-season (September) and two months after the start of the competitive season (November). Our results have shown an increase in athletes compared to controls in CK and LDH in September (respectively, p-value 0.003 and p-value < 0.001) and in November (both p-value < 0.001), whereas ALT is increased only in November (p-value 0.09). GGT serum levels were decreased in athletes compared to controls in both months (in September p-value 0.001 and in November p-value < 0.001). A gene expression analysis, carried out using RT-PCR, has revealed that IL-2, IL-6, IL-8, xCT and GCLM are increased in athletes in both months (p-value < 0.0001), while IL-10 and CHAC1 are increased only in September if compared to the controls (respectively, p-value 0.040 and p-value < 0.001). In conclusion, physical activity creates an adaptation of the systems involved in oxidative metabolism but without causing damage to the liver or kidney. This information could be of help to sports doctors for the prevention of injuries and illnesses in professional athletes for the construction of the athlete's passport.

Salivary Complaints in Burning Mouth Syndrome: A Cross Sectional Study on 500 Patients.

BACKGROUND: Xerostomia and sialorrhea often accompany Burning Mouth Syndrome (BMS) despite no change in saliva quantity. This study analyzed BMS patients with different symptom combinations: burning only (B), burning and xerostomia (BX), burning and sialorrhea (BS), and burning with xerostomia and sialorrhea (BXS), using a large sample of 500 patients from the University of Naples Federico II. METHODS: After a medical evaluation, patients were divided into four groups based on their reported symptoms: B (140), BX (253), BS (49), and BXS (58). Patient data on education, BMI, smoking/alcohol habits, comorbidities, medication use, pain intensity, quality, and psychological profile were collected. RESULTS: The BX group showed a higher prevalence of patients taking blood thinners. Additional symptoms varied among groups, with the BX group experiencing more dysgeusia and globus, and the BS group reporting more tingling. Multivariate analysis identified BMI, dysgeusia, globus, and blood thinner use as significant factors in the B and BX groups, while male gender, tingling, alcohol use, and pain quality were significant in the BS and BXS groups. CONCLUSIONS: Overall, BMS patients display a complex range of symptoms, with xerostomia being the most frequent additional symptom. Sociodemographic, psychological, and medical factors cannot fully explain the variations in symptomatology among different patient subgroups. Further research is needed to understand the underlying causes and develop tailored treatment approaches.

Integrated Approach to Highlighting the Molecular Bases of a Deep Vein Thrombosis Event in an Elite Basketball Athlete.

Acute or intense exercise can result in metabolic imbalances, muscle injuries, or reveal hidden disorders. Laboratory medicine in sports is playing an increasingly crucial role in monitoring athletes' health conditions. In this study, we designed an integrated approach to explore the causes of a deep venous thrombosis event in an elite basketball player. Since the complete blood count revealed a marked platelet count (838 × 103 µL), and thrombophilia screening tests did not reveal any significant alteration, we evaluated the thrombin generation, which highlights a state of hypercoagulability. First-level haemostasis exams showed only a slight prolongation of the activated Partial Thromboplastin Time (aPTT). Thus, screening tests for von Willebrand Disease showed a reduction in vWF parameters. Therefore, we directed our hypothesis towards a diagnosis of acquired von Willebrand disease secondary to Essential Thrombocythemia (ET). To confirm this hypothesis and highlight the molecular mechanism underlying the observed phenotype, molecular tests were performed to evaluate the presence of the most common mutations associated with ET, revealing a 52-bp deletion in the coding region of CALR exon 9. This case report highlights the importance of an integrated approach to monitoring the athletes' health status to personalise training and treatments, thus avoiding the appearance of diseases and injuries that, if underestimated, can undermine the athlete's life.

Contribution of Genetic Test to Early Diagnosis of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency: The Experience of a Reference Center in Southern Italy.

BACKGROUND: the deficiency of 5,10-Methylenetetrahydrofolate reductase (MTHFR) constitutes a rare and severe metabolic disease and is included in most expanded newborn screening (NBS) programs worldwide. Patients with severe MTHFR deficiency develop neurological disorders and premature vascular disease. Timely diagnosis through NBS allows early treatment, resulting in improved outcomes. METHODS: we report the diagnostic yield of genetic testing for MTHFR deficiency diagnosis, in a reference Centre of Southern Italy between 2017 and 2022. MTHFR deficiency was suspected in four newborns showing hypomethioninemia and hyperhomocysteinemia; otherwise, one patient born in pre-screening era showed clinical symptoms and laboratory signs that prompted to perform genetic testing for MTHFR deficiency. RESULTS: molecular analysis of the MTHFR gene revealed a genotype compatible with MTHFR deficiency in two NBS-positive newborns and in the symptomatic patient. This allowed for promptly beginning the adequate metabolic therapy. CONCLUSIONS: our results strongly support the need for genetic testing to quickly support the definitive diagnosis of MTHFR deficiency and start therapy. Furthermore, our study extends knowledge of the molecular epidemiology of MTHFR deficiency by identifying a novel mutation in the MTHFR gene.

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.

Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes.

The diffusion of next-generation sequencing (NGS)-based approaches allows for the identification of pathogenic mutations of cardiomyopathies and channelopathies in more than 200 different genes. Since genes considered uncommon for a clinical phenotype are also now included in molecular testing, the detection rate of disease-causing variants has increased. Here, we report the prevalence of genetic variants detected by using a NGS custom panel in a cohort of 133 patients with inherited cardiomyopathies (n = 77) or channelopathies (n = 56). We identified 82 variants, of which 50 (61%) were identified in genes without a strong or definitive evidence of disease association according to the NIH-funded Clinical Genome Resource (ClinGen; "uncommon genes"). Among these, 35 (70%) were variants of unknown significance (VUSs), 13 (26%) were pathogenic (P) or likely pathogenic (LP) mutations, and 2 (4%) benign (B) or likely benign (LB) variants according to American College of Medical Genetics (ACMG) classifications. These data reinforce the need for the screening of uncommon genes in order to increase the diagnostic sensitivity of the genetic testing of inherited cardiomyopathies and channelopathies by allowing for the identification of mutations in genes that are not usually explored due to a currently poor association with the clinical phenotype.

Metabolic Treatment of Wolfram Syndrome.

Wolfram Syndrome (WS) is a very rare genetic disorder characterized by several symptoms that occur from childhood to adulthood. Usually, the first clinical sign is non-autoimmune diabetes even if other clinical features (optic subatrophy, neurosensorial deafness, diabetes insipidus) may be present in an early state and may be diagnosed after diabetes' onset. Prognosis is poor, and the death occurs at the median age of 39 years as a consequence of progressive respiratory impairment, secondary to brain atrophy and neurological failure. The aim of this paper is the description of the metabolic treatment of the WS. We reported the experience of long treatment in patients with this syndrome diagnosed in pediatric age and followed also in adult age. It is known that there is a correlation between metabolic control of diabetes, the onset of other associated symptoms, and the progression of the neurodegenerative alterations. Therefore, a multidisciplinary approach is necessary in order to prevent, treat and carefully monitor all the comorbidities that may occur. An extensive understanding of WS from pathophysiology to novel possible therapy is fundamental and further studies are needed to better manage this devastating disease and to guarantee to patients a better quality of life and a longer life expectancy.

The Biological Role of Vitamins in Athletes' Muscle, Heart and Microbiota.

Physical activity, combined with adequate nutrition, is considered a protective factor against cardiovascular disease, musculoskeletal disorders, and intestinal dysbiosis. Achieving optimal performance requires a significantly high energy expenditure, which must be correctly supplied to avoid the occurrence of diseases such as muscle injuries, oxidative stress, and heart pathologies, and a decrease in physical performance during competition. Moreover, in sports activities, the replenishment of water, vitamins, and minerals consumed during training is essential for safeguarding athletes' health. In this scenario, vitamins play a pivotal role in numerous metabolic reactions and some muscle biochemical adaptation processes induced by sports activity. Vitamins are introduced to the diet because the human body is unable to produce these micronutrients. The aim of this review is to highlight the fundamental role of vitamin supplementation in physical activity. Above all, we focus on the roles of vitamins A, B6, D, E, and K in the prevention and treatment of cardiovascular disorders, muscle injuries, and regulation of the microbiome.

Cardiovascular Involvement in mtDNA Disease: Diagnosis, Management, and Therapeutic Options.

Mitochondrial diseases (MD) include an heterogenous group of systemic disorders caused by sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA), causing impairment of oxidative phosphorylation system. Hypertrophic cardiomyopathy is the dominant pattern of cardiomyopathy in all forms of mtDNA disease, being observed in almost 40% of the patients. Dilated cardiomyopathy, left ventricular noncompaction, and conduction system disturbances have been also reported. In this article, the authors discuss the current clinical knowledge on MD, focusing on diagnosis and management of mitochondrial diseases caused by mtDNA mutations.

Prevalence of hypertension and correlation with mental health in women with burning mouth syndrome: A case-control study.

Background: The relationship between hypertension (HTN) and chronic pain is still a matter of debate, and its prevalence in patients with burning mouth syndrome (BMS) has never been evaluated. This study aimed to assess the prevalence of HTN in women with BMS and to evaluate its relationship with potential predictors such as risk factors for cardiovascular diseases, pain, and mental health status analyzing differences with healthy women. Methods: In total, 250 women with BMS (WBMS) were prospectively recruited and compared with an equal number of healthy women (HW) matched for age. Education, body mass index, smoke and alcohol consumption, intensity and quality of pain, and psychological profile were further investigated to identify the potential predictors of HTN. Specifically, pain assessment [the Numeric Rating Scale (NRS) and Short-Form McGill Pain Questionnaire (SF-MPQ)] and psychological assessment [Hamilton Rating Scale for Depression and Anxiety (HAM-D and HAM-A), Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS)] was carried out for the participants. Results: HTN was found in 128 (51.2%) WBMS and 76 (30.4%) HW (p < 0.001**). The scores of the NRS, SF-MPQ, HAM-D, HAM-A, and PSQI were statistically significantly higher in the WBMS than in the HW (p < 0.001**). A strongly linear correlation between HTN and employment status, systemic diseases, and education level (p < 0.001**) was found in WBMS, while a strong correlation between HTN and employment status, hypercholesterolemia, systemic diseases, and drug consumption was found in HW (p < 0.001**). No statistically significant correlation was found between HTN and pain, anxiety, depression, and sleep disturbances. Conclusion: These results suggest that WBMS showed a higher prevalence of HTN compared with controls. Unemployed WBMS with lower education and other systemic comorbidities are at an increased risk of developing HTN. HTN is associated with alteration in the vascular structure and function of the brain, and these processes accelerate brain aging, which contributes to a reduction in intracortical connectivity, thus affecting the modulatory system of control of pain in patients with BMS, independently of their mental health assessment. Predictors that may underlie this association remain unclear, taking into account the differences found in HW, and should be further elucidated.

Multidisciplinary In-Depth Investigation in a Young Athlete Suffering from Syncope Caused by Myocardial Bridge.

Laboratory medicine, along with genetic investigations in sports medicine, is taking on an increasingly important role in monitoring athletes' health conditions. Acute or intense exercise can result in metabolic imbalances, muscle injuries or reveal cardiovascular disorders. This study aimed to monitor the health status of a basketball player with an integrated approach, including biochemical and genetic investigations and advanced imaging techniques, to shed light on the causes of recurrent syncope he experienced during exercise. Biochemical analyses showed that the athlete had abnormal iron, ferritin and bilirubin levels. Coronary Computed Tomographic Angiography highlighted the presence of an intramyocardial bridge, suggesting this may be the cause of the observed syncopes. The athlete was excluded from competitive activity. In order to understand if this cardiac malformation could be caused by an inherited genetic condition, both array-CGH and whole exome sequencing were performed. Array-CGH showed two intronic deletions involving MACROD2 and COMMD10 genes, which could be related to a congenital heart defect; whole exome sequencing highlighted the genotype compatible with Gilbert syndrome. However, no clear pathogenic mutations related to the patient's cardiological phenotype were detected, even after applying machine learning methods. This case report highlights the importance and the need to provide exhaustive personalized diagnostic work up for the athletes in order to cover the cause of their malaise and for safeguarding their health. This multidisciplinary approach can be useful to create ad personam training and treatments, thus avoiding the appearance of diseases and injuries which, if underestimated, can become irreversible disorders and sometimes can result in the death of the athlete.

Yield and clinical significance of genetic screening in elite and amateur athletes.

AIMS: The purpose of this study was to assess the value of genetic testing in addition to a comprehensive clinical evaluation, as part of the diagnostic work-up of elite and/or amateur Italian athletes referred for suspicion of inherited cardiac disease, following a pre-participation screening programme. METHODS: Between January 2009-December 2018, of 5892 consecutive participants, 61 athletes were investigated: 30 elite and 31 amateur athletes. Elite and amateur athletes were selected, on the basis of clinical suspicion for inherited cardiac disease, from two experienced centres for a comprehensive cardiovascular evaluation. Furthermore, the elite and amateur athletes were investigated for variants at DNA level up to 138 genes suspected to bear predisposition for possible cardiac arrest or even sudden cardiac death. RESULTS: Of these 61 selected subjects, six (10%) had diagnosis made possible by a deeper clinical evaluation, while genetic testing allowed a definite diagnosis in eight (13%). The presence of >3 clinical markers (i.e. family history, electrocardiogram and/or echocardiographic abnormalities, exercise-induced ventricular arrhythmias) was associated with a higher probability of positive genetic diagnosis (75%), compared with the presence of two or one clinical markers (14.2%, 8.1%, respectively, p-value = 0.004). CONCLUSION: A combined clinical and genetic evaluation, based on the subtle evidence of clinical markers for inherited disease, was able to identify an inherited cardiac disease in about one-quarter of the examined athletes.

NGS Analysis Revealed Digenic Heterozygous GCK and HNF1A Variants in a Child with Mild Hyperglycemia: A Case Report.

Monogenic diabetes (MD) represents a heterogeneous group of disorders whose most frequent form is maturity-onset diabetes of the young (MODY). MD is predominantly caused by a mutation in a single gene. We report a case of a female patient with suspected MD and a positive family history for diabetes and obesity. In this patient, two gene variants have been identified by next-generation sequencing (NGS): one in the Glucokinase (GCK) gene reported in the Human Gene Mutation Database (HGMD) and in the literature associated with GCK/MODY, and the other in the hepatocyte nuclear factor 1A (HNF1A) gene not previously described. The GCK variant was also identified in the hyperglycemic father, whereas the HNF1A variant was present in the mother. This new case of digenic GCK/HNF1A variants identified in a hyperglycemic subject, evidences the importance of NGS analysis in patients with suspected MD. In fact, this methodology will allow us to both increase the number of diagnoses and to identify mutations in more than one gene, with a better understanding of the genetic cause, and the clinical course, of the disease.

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.

Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review.

Diagnosis of pediatric steatohepatitis is a challenging issue due to a vast number of established and novel causes. Here, we report a child with Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) presenting with an underrated muscle weakness, exercise intolerance and an atypically severe steatotic liver involvement. A systematic literature review of liver involvement in MADD was performed as well. Our patient is a 11-year-old otherwise healthy, non-obese, male child admitted for some weakness/asthenia, vomiting and recurrent severe hypertransaminasemia (aspartate and alanine aminotransferases up to ×20 times upper limit of normal). Hepatic ultrasound showed a bright liver. MRI detected mild lipid storage of thighs muscles. A liver biopsy showed a micro-macrovacuolar steatohepatitis with minimal fibrosis. Main causes of hypertransaminasemia were ruled out. Serum aminoacids (increased proline), acylcarnitines (increased C4-C18) and a large excretion of urinary glutaric acid, ethylmalonic, butyric, isobutyric, 2-methyl-butyric and isovaleric acids suggested a diagnosis of MADD. Serum acylcarnitines and urinary organic acids fluctuated overtime paralleling serum transaminases during periods of illness/catabolic stress, confirming their recurrent nature. Genetic testing confirmed the diagnosis [homozygous c.1658A > G (p.Tyr553Cys) in exon 12 of the ETFDH gene]. Lipid-restricted diet and riboflavin treatment rapidly ameliorated symptoms, hepatic ultrasonography/enzymes, and metabolic profiles. Literature review (37 retrieved eligible studies, 283 patients) showed that liver is an extramuscular organ rarely involved in late-onset MADD (70 patients), and that amongst 45 patients who had fatty liver only nine had severe presentation. Conclusion: MADD is a disorder with a clinically heterogeneous phenotype. Our study suggests that MADD warrants consideration in the work-up of obesity-unrelated severe steatohepatitis.

Exercise, Immune System, Nutrition, Respiratory and Cardiovascular Diseases during COVID-19: A Complex Combination.

Coronaviruses (CoVs) represent a large family of RNA viruses that can infect different living species, posing a global threat to human health. CoVs can evade the immune response, replicate within the host, and cause a rapid immune compromise culminating in severe acute respiratory syndrome. In humans, the immune system functions are influenced by physical activity, nutrition, and the absence of respiratory or cardiovascular diseases. This review provides an in-depth study between the interactions of the immune system and coronaviruses in the host to defend against CoVs disease.

First trimester ultrasound features of X-linked Opitz syndrome and early molecular diagnosis: case report and review of the literature.

X-linked Opitz G/BBB syndrome (XLOS) is a multiple congenital disorder inherited in an X-linked manner. XLOS may be suspected, in prenatal age, on the basis of sonographic findings in the second and/or third trimester of gestation. Pathogenetic variants in MID1 gene have been reported in individuals with XLOS. Prenatal genetic testing is offered for pregnancies at risk, in which the mutation in the family has been identified. To date no cases of prenatal diagnosis, based on first-trimester ultrasound data, have been reported. We present a case of a fetus at 12 gestational weeks with ultrasound multiple anomalies, including increased nuchal translucency, heart defects, cleft lip and palate, enlarged fourth ventricle absence of ductus venosus and family hystory of XLOS. The genetic prenatal test detected the c(0).1286-1G > T mutation of MID1 gene. Data about prenatal ultrasonographic findings consistent with XLOS are limited to second and third trimester. This is the first case reporting ultrasound detectable midline defects suggestive of XLOS as early as the first trimester of gestation. This case also suggests that when multiple anomalies are detected in a fetus with normal chromosomal structure, the possibility of a monogenic disorder must be considered.

Potential role of imaging markers in predicting future disease expression of arrhythmogenic cardiomyopathy.

Aim: To evaluate the predictive accuracy of trabecular hypertrophy/derangement and late gadolinium enhancement in predicting diagnosis of arrhythmogenic cardiomyopathy (AC). Materials & methods: Fifty-nine suspected AC patients were evaluated. To evaluate the ability of these markers to detect patients fulfilling definite diagnosis at 4-year follow-up, sensitivity (Se), specificity (Sp), positive and negative predictive value (PPV and NPV) and predictive accuracy (PA) were calculated. Results: Presence of trabecular hypertrophy/derangement showed high NPV, while late gadolinium enhancement at cardiac MRI high Sp, NPV and PA. Their combination with symptoms and/or revised Task Force Criteria showed a high Sp, NPV and PA for definitive diagnosis during follow-up. Conclusion: In suspected AC patients, the absence of these markers allows to identify those with lower risk of disease progression.