High pressure induces superoxide production in isolated arteries viaprotein kinase C-dependent activation of NAD(P)H oxidase

Background - Oxidative stress seems to be present in all forms of hypertension. Thus, we tested the hypothesis that high intraluminal pressure (P-i) itself, by activating vascular oxidases, elicits increased superoxide (O-2(.-)) production interfering with flow-induced dilation. Methods and Results - Isolated, cannulated rat femoral arterial branches were exposed in vitro ( for 30 minutes) to normal P-i (80 mm Hg) or high P-i (160 mm Hg). High P-i significantly increased vascular O-2(.-) production ( as measured by lucigenin chemiluminescence and ethidium bromide fluorescence) and impaired endothelium-dependent dilations to flow; these effects could be reversed by superoxide dismutase. Administration of the NAD(P)H oxidase inhibitor diphenyleneiodonium, apocynin, the protein kinase C (PKC) inhibitor chelerythrine or staurosporin or the removal of extracellular Ca2+ during high P-i treatment prevented the increases in O-2(.-) production, whereas administration of losartan or captopril had no effect. High P-i resulted in significant increases in intracellular Ca2+ ([Ca2+](i)) in the vascular wall ( fura 2 fluorescence) and phosphorylation of PKCalpha ( Western blotting). The PKC activator phorbol myristate acetate significantly increased vascular O-2(.-) production, which was inhibited by superoxide dismutase, diphenyleneiodonium, chelerythrine, or removal of extracellular Ca2+. Both high P-i and phorbol myristate acetate increased the phosphorylation of the NAD( P) H oxidase subunit p47(phox). Conclusion - High P-i itself elicits arterial O-2(.-) production, most likely by PKC-dependent activation of NAD( P) H oxidase, thus providing a potential explanation for the presence of oxidative stress and endothelial dysfunction in various forms of hypertension and the vasculoprotective effect of antihypertensive agents of different mechanisms of action

Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase.

Recent studies have uncovered important cross talk between inflammation, generation of reactive oxygen and nitrogen species, and lipid metabolism in the pathogenesis of cardiovascular aging. Inhibition of the endocannabinoid anandamide metabolizing enzyme, the fatty acid amide hydrolase (FAAH), is emerging as a promising novel approach for the treatment of various inflammatory disorders. In this study, we have investigated the age-associated decline of cardiac function and changes in inflammatory gene expression, nitrative stress, and apoptosis in FAAH knockout (FAAH(-/-)) mice and their wild-type (FAAH(+/+)) littermates. Additionally, we have explored the effects of anandamide on TNF-alpha-induced ICAM-1 and VCAM-1 expression and monocyte-endothelial adhesion in human coronary artery endothelial cells (HCAECs). There was no difference in the cardiac function (measured by the pressure-volume conductance catheter system) between 2- to 3-mo-old (young) FAAH(-/-) and FAAH(+/+) mice. In contrast, the aging-associated decline in cardiac function and increased myocardial gene expression of TNF-alpha, gp91phox, matrix metalloproteinase (MMP)-2, MMP-9, caspase-3 and caspase-9, myocardial inducible nitric oxide synthase protein expression, nitrotyrosine formation, poly (ADP-ribose)polymerase cleavage and caspase-3/9 activity, observed in 28- to 31-mo-old (aging) FAAH(+/+) mice, were largely attenuated in knockouts. There was no difference in the myocardial cannabinoid CB(1) and CB(2) receptor gene expression between young and aging FAAH(-/-) and FAAH(+/+) mice. Anandamide dose dependently attenuated the TNF-alpha-induced ICAM-1 and VCAM-1 expression, NF-kappaB activation in HCAECs, and the adhesion of monocytes to HCAECs in a CB(1)- and CB(2)-dependent manner. These findings suggest that pharmacological inhibition of FAAH may represent a novel protective strategy against chronic inflammation, oxidative/nitrative stress, and apoptosis associated with cardiovascular aging and atherosclerosis

Effects of aerobic workout on the changes in the characteristics of dynamics of the center of gravity in different age categories

Introduction The quality and function of movements undergo deterioration due to weight gain. Aerobic training normalizes body weight, improves the health status, and in addition, it is expected to improve the dynamics of movements. The aims of this study were to prove the beneficial effects of recreational physical activities on the movements. Methods Participants were divided into five different age categories: second childhood, adolescence, mature age I, mature age II, and aging. Squatting and vertical jumping of the participants were measured at the beginning and at the end of a 5-month training program. These movements simulated ordinary daily movements. Changes in the body were determined by InBody230. APAS 3D system was used for movement analysis. Results The results showed significant improvements in body weight, fat mass, muscle mass, fat mass–body weight ratio, muscle mass–body weight ratio, body mass index, body fat percentage, and waist–hip ratio. During jumping, the lifting and sinking of the center of gravity’s (CG) position and its velocity and acceleration were improved. In case of squatting, the results showed significant improvements in the velocity and acceleration of dynamical characteristics of the CG. Other correlations were observed between changes in body composition and the dynamics of movements. Discussion The research proved that recreational training optimized body composition and improved the characteristics of CG’s dynamics. The study suggests considerable connection between body composition and the characteristics of the movements’ dynamics. From this point of view, our training program was the most effective in the working age groups

Comparison of clinical characteristics of patients with pandemic SARS-CoV-2-related and community-acquired pneumonias in Hungary – a pilot historical case-control study

The distinction between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–related and community-acquired pneumonias poses significant difficulties, as both frequently involve the elderly. This study aimed to predict the risk of SARS-CoV-2-related pneumonia based on clinical characteristics at hospital presentation. Case-control study of all patients admitted for pneumonia at Semmelweis University Emergency Department. Cases (n = 30) were patients diagnosed with SARS-CoV-2-related pneumonia (based on polymerase chain reaction test) between 26 March 2020 and 30 April 2020; controls (n = 82) were historical pneumonia cases between 1 January 2019 and 30 April 2019. Logistic models were built with SARS-CoV-2 infection as outcome using clinical characteristics at presentation. Patients with SARS-CoV-2-related pneumonia were younger (mean difference, 95% CI: 9.3, 3.2–15.5 years) and had a higher lymphocyte count, lower C-reactive protein, presented more frequently with bilateral infiltrate, less frequently with abdominal pain, diarrhoea, and nausea in age- and sex-adjusted models. A logistic model using age, sex, abdominal pain, C-reactive protein, and the presence of bilateral infiltrate as predictors had an excellent discrimination (AUC 0.88, 95% CI: 0.81–0.96) and calibration (p = 0.27–Hosmer-Lemeshow test). The clinical use of our screening prediction model could improve the discrimination of SARS-CoV-2 related from other community-acquired pneumonias and thus help patient triage based on commonly used diagnostic approaches. However, external validation in independent datasets is required before its clinical use

A public health threat in Hungary: obesity, 2013

Background: In Hungary, the last wide-range evaluation about nutritional status of the population was completed in 1988. Since then, only limited data were available. Our aim was to collect, analyze and present updated prevalence data. Methods. Anthropometric, educational and morbidity data of persons above 18 y were registered in all geographical regions of Hungary, at primary care encounters and within community settings. Results: Data (BMI, waist circumference, educational level) of 40,331 individuals (16,544 men, 23,787 women) were analyzed. Overall prevalence for overweight was 40.4% among men, 31.3% among women, while for obesity 32.0% and 31.5%, respectively. Abdominal obesity was 37.1% in males, 60.9% in females. Among men, the prevalence of overweight-obesity was: under 35 y = 32.5%-16.2%, between 35-60 y = 40.6%-34.7%, over 60 y = 44.3%-36.7%. Among women, in the same age categories were: 17.8%-13.8%, 29.7%-29.0%, and 36.9%-39.0%. Data were presented according to age by decades as well. The highest odds ratio of overweight (OR: 1.079; 95% CI [1.026-1.135]) was registered by middle educational level, the lowest odds ratio of obesity (OR: 0.500; 95% CI [0.463-0.539]) by the highest educational level. The highest proportion of obese people lived in villages (35.4%) and in Budapest (28.9%). Distribution of overweighed persons were: Budapest (37.1%), other cities (35.8%), villages (33.8%). Registered metabolic morbidities were strongly correlated with BMIs and both were inversely related to the level of urbanization. Over the previous decades, there has been a shift in the distribution of population toward being overweight and moreover obese, it was most prominent among males, mainly in younger generation. Conclusions: Evaluation covered 0.53% of the total population over 18 y and could be very close to the proper national representativeness. The threat of obesity and related morbidities require higher public awareness and interventions

Roles of genetic polymorphisms in the folate pathway in childhood acute lymphoblastic leukemia evaluated by bayesian relevance and effect size analysis.

In this study we investigated whether polymorphisms in the folate pathway influenced the risk of childhood acute lymphoblastic leukemia (ALL) or the survival rate of the patients. For this we selected and genotyped 67 SNPs in 15 genes in the folate pathway in 543 children with ALL and 529 controls. The results were evaluated by gender adjusted logistic regression and by the Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) methods. Bayesian structure based odds ratios for the relevant variables and interactions were also calculated. Altogether 9 SNPs in 8 genes were associated with altered susceptibility to ALL. After correction for multiple testing, two associations remained significant. The genotype distribution of the MTHFD1 rs1076991 differed significantly between the ALL and control population. Analyzing the subtypes of the disease the GG genotype increased only the risk of B-cell ALL (p = 3.52x10(-4); OR = 2.00). The GG genotype of the rs3776455 SNP in the MTRR gene was associated with a significantly reduced risk to ALL (p = 1.21x10(-3); OR = 0.55), which resulted mainly from the reduced risk to B-cell and hyperdiploid-ALL. The TC genotype of the rs9909104 SNP in the SHMT1 gene was associated with a lower survival rate comparing it to the TT genotype (80.2% vs. 88.8%; p = 0.01). The BN-BMLA confirmed the main findings of the frequentist-based analysis and showed structural interactional maps and the probabilities of the different structural association types of the relevant SNPs especially in the hyperdiploid-ALL, involving additional SNPs in genes like TYMS, DHFR and GGH. We also investigated the statistical interactions and redundancies using structural model properties. These results gave further evidence that polymorphisms in the folate pathway could influence the ALL risk and the effectiveness of the therapy. It was also shown that in gene association studies the BN-BMLA could be a useful supplementary to the traditional frequentist-based statistical method

Rule-Based Models of the Interplay between Genetic and Environmental Factors in Childhood Allergy

Peer reviewe

Evaluation of a Partial Genome Screening of Two Asthma Susceptibility Regions Using Bayesian Network Based Bayesian Multilevel Analysis of Relevance

Genetic studies indicate high number of potential factors related to asthma. Based on earlier linkage analyses we selected the 11q13 and 14q22 asthma susceptibility regions, for which we designed a partial genome screening study using 145 SNPs in 1201 individuals (436 asthmatic children and 765 controls). The results were evaluated with traditional frequentist methods and we applied a new statistical method, called Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA). This method uses Bayesian network representation to provide detailed characterization of the relevance of factors, such as joint significance, the type of dependency, and multi-target aspects. We estimated posteriors for these relations within the Bayesian statistical framework, in order to estimate the posteriors whether a variable is directly relevant or its association is only mediated. With frequentist methods one SNP (rs3751464 in the FRMD6 gene) provided evidence for an association with asthma (OR = 1.43(1.2–1.8); p = 3×10−4). The possible role of the FRMD6 gene in asthma was also confirmed in an animal model and human asthmatics. In the BN-BMLA analysis altogether 5 SNPs in 4 genes were found relevant in connection with asthma phenotype: PRPF19 on chromosome 11, and FRMD6, PTGER2 and PTGDR on chromosome 14. In a subsequent step a partial dataset containing rhinitis and further clinical parameters was used, which allowed the analysis of relevance of SNPs for asthma and multiple targets. These analyses suggested that SNPs in the AHNAK and MS4A2 genes were indirectly associated with asthma. This paper indicates that BN-BMLA explores the relevant factors more comprehensively than traditional statistical methods and extends the scope of strong relevance based methods to include partial relevance, global characterization of relevance and multi-target relevance