[Genetic Predisposition to Early Myocardial Infarction].

The aim of the study was to identify the features of the genetic structure of myocardial infarction (MI) susceptibility depending on age ("early MI" denoting individuals who had the first MI before the age of 60 years, and "late MI" the group of patients with the first "MI after 60 years"). A total of 355 patients were examined (n = 121 early MI and n = 234 late MI) and 285 residents of the Siberian region (as a control group). Genotyping of 58 single nucleotide variants (SNPs) was performed using mass spectrometry using the Agena (ex Sequenom) MassARRAY® System. Statistical analysis was performed using Statistica 8.0 ("StatSoft Inc.", USA), as well as the "stats" and "genetics" packages in the R environment. The regulatory potential of SNPs was evaluated using the rSNPBase online service (http://rsnp.psych.ac.cn/). eQTL loci were identified using data from the Genotype-Tissue Expression (GTEx) project (http://www.gtexportal.org/) and the Blood eQTL online service (https://genenetwork.nl/bloodeqtlbrowser/). The GG genotype of ITGA4 rs1143674, the CC genotype of CDKN2B-AS1 rs1333049, and the CC genotype of KIAA1462 rs3739998, are generally associated with MI. The AA genotype of ADAMDEC1 rs3765124 (OR = 2.03; 95% CI 1.23-3.33; p = 0.004) and the GG genotype of AQP2 rs2878771 (OR = 2.24; 95% CI 1.23-4.09; p = 0.006) are associated with the development of MI at an early age, and the TT genotype of TAS2R38 rs1726866 (OR = 1.82; 95% CI 1.11-2.89; p = 0.009) was the high-risk genotype for the late MI. Genetic variants associated with MI are regulatory SNP (rSNP) and affect the affinity of DNA binding to transcription factors, carry out post-transcriptional control of gene activity and change the level of gene expression in various tissues. Thus, early and late MI are based on both common genetic variants of ITGA4, CDKN2B-AS1, KIAA1462 genes and specific ones (ADAMDEC1 and AQP2 for early MI and TAS2R38 for late MI).

[Fibrogenesis Genes and Susceptibility to Coronary Atherosclerosis].

OBJECTIVES: To study associations between genes of different functional classes, including fibrogenesis genes, with coronary atherosclerosis and specific features of its course. METHODS: We included in this study 404 patients with confirmed chronic ischemic heart disease (IHD) who had undergone coronary artery bypass grafting. Two groups of participants were distinguished - those with (n=188) and without (n=216) history of myocardial infarction (MI). Control group consisted of inhabitants of the Siberia region (n=285). Associations were analyzed using 48 single nucleotide polymorphisms (SNP) located in genes earlier determined as associated with diseases of the cardiovascular continuum (diabetes mellitus, MI, atherosclerosis). Multiplex genotyping was performed using mass spectrometry. For statistical analyses we used Statistica v8.0 and R-language with "stats" and "genetics" packages. RESULTS: We identified several genetic markers contributing to susceptibility to development of atherosclerosis. Same markers were identified as determinants of the character of the course of atherosclerotic disease. Risk of development of atherosclerosis was higher in carriers of the following genotypes: TT of ITGB5 gene (rs1007856) - by 1.6 times (OR=1.59; р=0.0153); GG of ITGA4 gene - by 1.85 times (OR=1.85; р=0.0016); GG of IGFBP7 gene (rs11133482) - by 2.4 times (OR=2.36; р=0.0031). The following genotypes were identified as protective against MI and determining stable course of the disease: AA of TLR4 gene (rs4986790) (OR=0.47; р=0.0104).; CC of LDLR gene (rs2738446) (OR=0,53; р=0.0041); GG of OAS1 gene (rs1131454) (OR=0.50; р=0.0274). CONCLUSION: Susceptibility to coronary atherosclerosis and prognosis of disease progression were found to be associated with polymorphism of certain genes, involved in metabolism of the extracellular matrix and processes of fibrogenesis (ADAMDEC1, ITGA4, ITGB5, CDKN2B-AS1, IGFBP7), lipid metabolism (LDLR), immune system functioning (TLR4, OAS1) and DNA repair (LIG1).

[Genes for Fibrogenesis in the Determination of Susceptibility to Myocardial Infarction].

A group of patients with ischemic heart disease and myocardial infarction (N = 156) and a reference population sample (N = 300) were genotyped for 58 single nucleotide polymorphisms (SNPs) in the genes involved in extracellular matrix function and collagen metabolism or associated with cardiovascular diseases and atherosclerotic plaque stability. Genotyping was performed by mass-spectrometry with two multiplex sets of 27 and 31 SNPs. The study revealed different genetic composition of predisposition to cardiovascular disease continuum (CVDC) syntropy (patients with concomitant conditions: hypercholesterolemia, hypertension, and type-II diabetes mellitus, N = 96) and to isolated myocardial infarction (without these conditions, N = 60). Only the KIAA1462 gene (rs3739998) showed associations with both CVDC syntropy (OR = 1.71; 95% CI 1.19-2.45; р = 0.003) and isolated infarction (OR = 1.58; 95% CI 1.05-2.40; р = 0.028). Isolated myocardial infarction was also associated with LIG1 (rs20579) (OR = 2.08; 95% CI 1.06-4.17; р = 0.028) and ADAMDEC1 (rs3765124) (OR = 1.63; 95% CI 1.07-2.50; р = 0.020). CVDC syntropy was associated with CDKN2BAS1 (rs1333049) (OR = 1.48; 95% CI 1.03-2.12; р = 0.029) and APOA2 (rs5082) (OR = 1.47; 95% CI 1.02-2.11; р = 0.035). So, genes involved in fibrogenesis contribute to predisposition to the myocardial infarction as well. Isolated myocardial infarction and CVDC syntropy can be considered as pathogenetically different cardiovascular conditions, with different genes that contribute to the susceptibility.

A histone deacetylase inhibitory prodrug - butyroyloxymethyl diethyl phosphate - protects the heart and cardiomyocytes against ischemia injury.

Butyroyloxymethyl diethylphosphate (AN-7) is a prodrug of butyric acid effective in reducing cardiotoxicity caused by chemotherapy. In this study, we tested whether AN-7 protects the heart and cardiomyocytes against ischemia injury. A single oral dose of AN-7 was given to mice or rats. Animals were sacrificed 1.5 or 24 h later and the hearts were subjected to ischemia and reperfusion ex-vivo (Langendorff). The mechanical performance was recorded throughout and the infarct size was measured at the end of reperfusion. Neonatal rat cardiomyocytes were subjected to 24-48 h hypoxia (1% O(2)) in the absence or presence of AN-7 and mitochondria damage and cell death were assessed. Proteins were analyzed by Western immunoblotting. In the two rodents, a single dose of AN-7 given in vivo preconditioned the hearts for improved functional recovery from ischemia and reperfusion performed ex-vivo. Both 1.5 h and 24 h treatments improved the pressure-related parameters whereas the coronary flow was ameliorated in the 24 h treatment only. Infarct size was smaller in the AN-7 treated hearts. In cardiomyocytes, AN-7 diminished the hypoxia induced dissipation of mitochondria membrane potential and cell death. Compared with untreated controls, AN-7-treated hearts recovering from global ischemia and cardiomyocytes undergoing hypoxia, displayed significantly higher levels of the cytoprotective heme oxygenase-1. Our findings indicate that AN-7 imparts cardioprotection against ischemia both in vivo and in vitro and emerges as a potential treatment modality for cardiac injury.

Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity.

Formaldehyde has been previously shown to play a dominant role in promoting synergy between doxorubicin (Dox) and formaldehyde-releasing butyric acid (BA) prodrugs in killing cancer cells. In this work, we report that these prodrugs also protect neonatal rat cardiomyocytes and adult mice against toxicity elicited by Dox. In cardiomyocytes treated with Dox, the formaldehyde releasing prodrugs butyroyloxymethyl diethylphosphate (AN-7) and butyroyloxymethyl butyrate (AN-1), but not the corresponding acetaldehyde-releasing butyroyloxydiethyl phosphate (AN-88) or butyroyloxyethyl butyrate (AN-11), reduced lactate dehydrogenase leakage, prevented loss of mitochondrial membrane potential (DeltaPsim) and attenuated upregulation of the proapoptotic gene Bax. In Dox-treated mice, AN-7 but not AN-88 attenuated weight-loss and mortality, and increase in serum lactate dehydrogenase. These findings show that BA prodrugs that release formaldehyde and augment Dox anticancer activity also protect against Dox cardiotoxicity. Based on these observations, clinical applications of these prodrugs for patients treated with Dox warrant further investigation.

[The genetic and biochemical mechanisms of the development of diabetic nephropathy in children].

The mechanisms responsible for the development of microangiopathies in type diabetes mellitus (DM1) are complex and under extensive study. Fresh data on the pathogenesis of DM1 make it possible to direct actual ways to the studies aimed at preventing the complications of this disease. The purpose of this study was to examine the contribution of the polymorphic types of the VNTR polymorphism of endothelial NO-synthase gene (NOS3) and the I/D polymorphism of angiotensin-converting enzyme (ACE), the status of the proteolytic systems and lipid metabolic disturbances to the development of diabetic neuropathy (DN). A total of 197 children Работа выполнена при финансовой поддержке гранта РГНФ № 00-06-00- 162а. who had DM1 in 1996-2002 were examined. Their mean age was 13.1 ±0.3 years. A control group comprised 32 apparently healthy children whose mean age was 12.8±0.1 years. DN was present in 44 children (19 boys and 25 girls). It has been established that allele A of endothelial NO-synthase is less common in diabetic patients with nephropathy (p < 0.05) and that it is a factor that reduces, while insignificantly, the risk for nephropathy (RR = 0.13). Analyzing the association with pathology by using the transmission/disequilibrium test has indicated the association of allele В of the gene NOS3 (TDT = 4.5, p - 0.034) and allele D of the gene ACE (TDT = 3.6, p < 0.05) with DN. The activity of plasma kallikrein was increased at the early stages of nephropathy (hyper-function). The higher activity of angiotensin-converting enzyme (57.0±2.9 µmol/min·l in the patients with nephropathy versus 38.1±2.8 µmol/min·/ in those without this disease) and the substantial suppression of α-proteinase inhibitor (21.1+-1.2 IU/ml in nephropathy at the stage of proteinuria versus 27.6±1.6 IU/ml without nephropathy) make a contribution to the development of nephropathy at the stages of microalbuminuria and proteinuria. ffyperlipidemia that manifests itself by the increased levels of cholesterol, triglycerides, and low-density lipoprotein cholesterol and by the decreased levels of high-density lipoprotein cholesterol is one of the mechanisms responsible for the development of DN in DM1.

[Preschool children's health in towns with different levels of environmental pollution]. / Zdorov'e detei doshkol'nogo vozrasta v gorodakh s raznym urovnem zagriazneniia okruzhaiushchei sredy.

A total of 3497 preschool children residing in the towns having with different man-made burden were examined. The study showed that most children referred to Health Groups 2 and 3. In the town with higher environmental pollution there were a larger proportion of children with dysfunctions of different organs and systems and higher incidence of diseases, including respiratory allergoses, etc.

[Evaluation of the function of mitral valve prosthesis by non-invasive methods]. / Otsenka funktsii protezov mitral'nogo klapana serdtsa neinvazivnymi metodami.

The study was undertaken to examine the correlation between the parameters of central hemodynamics and mitral valve prosthesis functions which were obtained by invasive techniques, as well as these of physical working capacity, hemodynamics, and blood by noninvasive methods at rest and during bicycle ergometry in the graded exercise test. An examination was made of 24 patients every 0.5-8 years (mean 3.2 years) after replacement of mitral valves by xenobioprostheses. "Oxygen pulse" and cardiac index defined during exercise highly correlated with prosthetic mid-diastolic pressure gradients. A moderate correlation was found between dry erythrocytic mass and total pulmonary blood flow resistance. The findings may be useful for the early diagnosis of prosthetic dysfunctions.

[Evaluation of the effectiveness of health-related improvement in working conditions of postal services employees]. / Otsenka éffektivnosti ozdorovleniia truda rabotnikov pochtovoi sviazi.

Basing on the physiological and hygienic research performed after a series of prophylactic measures, it was established that the introduction of rational working conditions in combination with physically active rest influences most postively the functional neuro-muscular state of upper extremities in telephone operators and mail sorters, and has a positive bearing on the hemodynamic indices, CNS and regulatory mechanisms status of operators and mail sorters.

[Experimental and clinical study of the use of lysozyme in combination with chemotherapeutic agents]. / Eksperimental'no-klinicheskoe izuchenie primeneniia lizotsima v kombinatsii s khimioterapevticheskimi sredstvami.

Antimicrobial effect of lysozyme in combination with a wide set of antimicrobial drugs (38) was studied with respect to 74 bacterial cultures. It was shown that synergism of the antimicrobial effect in the presence of lysozyme was variable for drugs differing in the mechanism of their action and depended on the pathogen species. The most pronounced synergistic effect was observed with respect to grampositive bacteria with the use of many drugs such as benzylpenicillin, ampiox, morphocycline, erythromycin and others. The potentiation effect of lysozyme was less pronounced with respect to Coli bacteria and Pseudomonas. Combination of lysozyme with aminoglycosides such as gentamicin, tobramycin, sisomicin and amikacin resulted in increasing antimicrobial effect with respect to practically all the microbial cultures tested. The clinical trials of the efficient combinations of the antibiotics and lysozyme studied experimentally proved their high efficacy in combined therapy of patients with pneumonia and pyelonephritis of bacterial genesis. Thus, in children with acute pneumonia (92 observations) it resulted in more rapid elimination of the temperature reaction, toxic and cardiorespiratiry syndromes, cough and physical signs of the disease. In treatment of 83 children with pyelonephritis complete clinico-laboratory remission was observed in 81 per cent of the cases against 56.4 per cent in the patients treated with the antibiotics without lysozyme.

[Effect of heart valve prostheses on hemolytic processes in patients with acquired heart diseases]. / Vliianie bioprotezov klapanov serdtsa ma gemoliticheskie protsessy u bol'nykh priobretennymi porokami serdtsa.

Parameters of intravascular hemolysis (erythrocyte count, hemoglobin concentration and circulating blood volume, acid erythrograms, plasma free hemoglobin and haptoglobin levels) were examined in 44 patients with acquired heart diseases controlled with the aid of bioprostheses. As shown by 2 years' follow-up, successfully implanted mitral and aortal bioprostheses did not significantly affect the activity of intravascular hemolysis. Yet developing stenosis and incompetence of the bioprostheses may be accompanied with a significant intravascular hemolysis.