[Multifactor predictive model in patients with myocardial infarction based on modern biomarkers].

Objective To study the prognostic role of current serum biomarkers in patients with myocardial infarction (MI) by constructing a multifactorial model for prediction of cardiovascular complications (CVC) in remote MI. Acute coronary syndrome is a major cause of death and disability in the Russian Federation. Introduction of current biomarkers, such as N-terminal pro-brain natriuretic peptide, stimulating growth factor (ST2), and centraxin-2 (Pentraxin, Ptx-3), provides more possibilities for diagnostics and calculation of risk for CVC.Materials and Methods Concentrations of biomarkers were measured in 180 patients with MI (mean age, 61.4±1.7) upon admission. At one year, specific and composite endpoints were determined (MI, acute cerebrovascular disease, admission for CVD, and cardiovascular death). Based on this information, a prognostic model for subsequent events was developed.Results A mathematical model was created for computing the development of a composite endpoint. In this model, the biomarkers NT-proBNP, Ptx-3 and, to a lesser extent, ST2 demonstrated their prognostic significance in diagnosis of CVC with a sensitivity of 78.79 % and specificity of 86.67 % (area under the curve, AUC 0.73).Conclusion In patients with remote MI, the biomarkers NT-proBNP, ST2, and Ptx-3 improve prediction of CVC.

[Polymorphic Variants of Glutamate Receptor (GRIK5, GRIN2B) and Serotonin Receptor (HTR2A) Genes Are Associated with Chronic Obstructive Pulmonary Disease].

Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease of the respiratory system that affects primarily distal respiratory pathways and lung parenchyma. Smoking tobacco is a major risk factor for COPD. The relationship of HTR4 (rs3995090), HTR2A (rs6313), GRIK5 (rs8099939), GRIN2B (rs2268132), and CHRNB4 (rs1948) gene polymorphisms and COPD, as well as the contribution of these polymorphisms to the variations in quantitative characteristics that describe respiratory function, smoking behavior, and nicotine dependence was assessed in an ethnically homogeneous Tatar population. The polymorphisms of HTR2A (rs6313) (P = 0.026, OR = 1.42 for the CC genotype) and GRIN2B (rs2268132) (P = 0.0001, OR = 2.39 for the TT genotype) were significantly associated with increased risk of COPD. The AA genotype of GRIK5 (rs8099939) had a protective effect (P = 0.02, OR = 0.61). Importantly, the HTR2A (rs6313), GRIN2B (rs2268132), and GRIK5 (rs8099939) polymorphisms were only associated with COPD in smokers. Smoking index (pack-years) was significantly higher in carriers of the GRIK5 genotype AC (rs8099939) (P = 0.0027). The TT genotype of GRIN2B (rs2268132) was associated with COPD in subjects with high nicotine dependence according to the Fagerstrõm test (P = 0.002, OR = 2.98). The TT genotype of HTR2A (rs6313) was associated with a reduced risk of the disease in the group with moderate nicotine dependence (P = 0.02, OR = 0.22). The CC genotype of HTR2A (rs6313) and the TT genotype of GRIN2B (rs2268132) were associated with higher levels of nicotine dependence according to the Fagerstrõm test (P = 0.0011 and P = 0.037). Our results may provide insight into potential molecular mechanisms that involve the glutamate (GRIK5, GRIN2B) and serotonin (HTR2A) receptor genes in the pathogenesis of COPD.

Inflammatory and Immune Response Genes Polymorphisms are Associated with Susceptibility to Chronic Obstructive Pulmonary Disease in Tatars Population from Russia.

Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease of the respiratory system affecting primarily distal respiratory pathways and lung parenchyma. This work was designed as a case-control study aimed at investigating the association of COPD with polymorphisms in inflammatory and immune response genes (JAK1, JAK3, STAT1, STAT3, NFKB1, IL17A, ADIPOQ, ADIPOR1, etc.) in Tatar population from Russia. Ten SNPs (rs310216, rs3212780, rs12693591, rs2293152, rs28362491, rs4711998, rs1974226, rs1501299, rs266729, and rs12733285) were genotyped by the real-time polymerase chain reaction (TaqMan assays) in a case-control study (425 COPD patients and 457 in the control group, from Ufa, Russia). Logistic regression was used to detect the association of SNPs in different models. Linear regression analyses were performed to estimate the relationship between SNPs and lung function parameters and pack-years. In Tatar population, significant associations of JAK1 (rs310216) (P = 0.0002, OR 1.70 in additive model), JAK3 (rs3212780) (P = 0.001, OR 1.61 in dominant model), and IL17A (rs1974226) (P = 0.0037, OR 2.31 in recessive model) with COPD were revealed. The disease risk was higher in carriers of insertion allele of NFKB1 (rs28362491) (P = 0.045, OR 1.22). We found a significant gene-by-environment interaction of smoking status and IL17A (rs1974226) (P interact = 0.016), JAK3 (rs3212780) (P interact = 0.031), ADIPOQ (rs266729) (P interact = 0.013), and ADIPOR1 (rs12733285) (P interact = 0.018). The relationship between the rs4711998, rs1974226, rs310216, rs3212780, rs28362491, and smoking pack-years was found (P = 0.045, P = 0.004, P = 0.0005, P = 0.021, and P = 0.042). A significant genotype-dependent variation of forced vital capacity was observed for NFKB1 (rs28362491) (P = 0.017), ADIPOR1 (rs12733285) (P = 0.043), and STAT1 (rs12693591) (P = 0.048). The genotypes of STAT1 (rs12693591) (P = 0.013) and JAK1 (rs310216) (P = 0.048) were associated with forced expiratory volume in 1 s.

[Predictor Model of Acute Coronary Syndrome Outcomes].

Scores for assessment of risk of cardiovascular events in patients with acute coronary syndrome (ACS) became wide spread during last decade. Taking into consideration high level of ACS morbidity and mortality in Russia there is a need in creation of own national scores. Aim of this study was to investigate the value of risk factors of death and to create a multivariate model of survival of patients with ACS during hospitalization. MATERIALS AND METHODS: The non-randomized retrospective continuous study of 1000 case histories (medical records) of patients with ACS with assessment of value of risk factors was performed, and the multifactor model and computer program estimation of risk of death was created. While selecting risk factors emphasis was made on heart rhythm and presence of arrhythmia, and on anamnestic data. RESULTS: Most significant factors were age, history of myocardial infarction, atrial fibrillation, and ventricular tachycardia. The created regression model of estimation of risk of death by 51.4% was explained by these factors. Using this model, we developed a computer program "Kardiorisk" which predicts risk of death with 100% sensitivity and 80% specificity.

[Association of the nicotine and cigarette smoke toxicants metabolic (CHRNA3/5, CYP2A6, NQO1) and DNA repair genes (XRCC1, XRCC3, XPC, XPA) with chronic obstructive pulmonary disease].

The contribution of the polymorphic markers of the CHRNA5/A3, CYP2A6, NQO1, XPC, XRCC1, XRCC3, XPD, XPA genes to chronic obstructive pulmonary disease has been assessed. For this purpose, analysis of the gene polymorphisms in case/control groups in Tatar population has been performed. The CHRNA5 (rs16969968) (P = 0.0001, OR = 2.24), CHRNA3 (rs1051730) (P = 0.0001, OR = 2.72) were associated with significantly high risk of chronic obstructive pulmonary disease in recessive model. The disease risk was higher in homozygous carriers of normal allele of CYP2A6 (del) (P = 0.00001, OR = 2.77). Analysis showed an association of the NQO1 (rs1131341), XRCC1 (rs25487), XRCC3 (rs861539), XPC (rs2228001) and XPA (rs1800975) (P = 0.000001, OR = 2.67; P = 0.00001, OR = 0.51; P = 0.0003, OR = 1.76; P = 0.0004, OR = 0.54 and P = 0.007, OR = 0.74) in additive model with chronic obstructive pulmonary disease. We found a significant gene-by-environment interaction of smoking status and XPA (rs1800975) (Pinteract = 0.002); rs16969968, rs1051730 of CHRNA3/5 genes were significantly associated with chronic obstructive pulmonary disease only in smokers. The relationship between the CYP2A6(CYP2A6*4) and smoking pack-years was found (P = 0.0019). The TT genotype of XRCC3 (rs861539) were associated with decreased of lung function parameters: vital capacity % (P = 0.0487), forced vital capacity (%) (P = 0.0032) and forced expiratory volume in 1 s (%) (P = 0.02). The relationship between the XPA (rs1800975) and forced expiratory volume in 1 s (%) (P = 0.0028) was found.

[Prophylactic use of VFS in patients with coronary artery disease in the perioperative coronary artery bypass grafting].

Tachyarrhythmias (TA) - dangerous postoperative complications of coronary artery bypass grafting, threatening the lives of patients and found, according to different authors, in 13-40% of cases. VFS - an antiarrhythmic drug that belongs to a class 1C, is effective in the treatment and prevention of a variety of cardiac arrhythmias. The aim of the work was to study the clinical efficacy of VFS CHD patients with a history of tachyarrhythmias during the perioperative period of coronary bypass surgery, as well as its comparison with other antiarrhythmic drug (amiodarone). Clinical efficacy was evaluated in 218 patients with coronary heart disease at baseline with a history of tachyarrhythmia (paroxysmal atrial fibrillation or premature ventricular high grade (IV and V class on classification of Lown B. and Wolf M. in the modification of Ryan M.). Shown that the VFS is more effective than amiodarone, both in paroxysmal atrial fibrillation and ventricular arrhythmias when high gradation.

[Direct evidences of calcium traffic through pacemaker channel].

Recently, it was shown that pacemaker f/HCN channel might be permeable not only for Na+ and K+, but also for calcium ions. Pacemaker channel HCN2 was expressed in ovarian cell culture of Chinese hamster. In the patch clamp experiments the calcium current with low amplitude 0.06±-0.87 nA and open probability 0.48% (±3.02 at -110 mV, n = 6, Ca2+ 2 mmol) was measured. HCN2-Ca2+ current significantly activated with cyclic adenosinemonophosphate by increasing of open probability and inhibited by specific If-blocker ivabradine. The calcium ion current was also shown in f-channels of neonatal rats ventriculocytes. Thus, the calcium ions conduction through HCN2 and native f-channel at physiological concentrations of extracellular fluid and physiological membrane potentials of cardiomyocytes was demonstrated.

[Association of the MMP3, MMP9, ADAM33 and TIMP3 genes polymorphic markers with development and progression of chronic obstructive pulmonary disease].

The contribution of the polymorphic markers of the matrix metalloproteinases MMP1 (-1607G > GG, rs1799750; -519A > G, rs494379), MMP2 (-735C > T, rs2285053), MMP3 (-1171 5A > 6A, rs35068180), MMP9 (-1562C > T, rs3918242; 2660A > G, rs17576), MMP12 (-82A > G, rs2276109), the disintegrin and metalloprotease 33 ADAM33 (12418A > G, rs2280091; 13491C > G, rs2787094), the tissue inhibitors of metalloproteinases TIMP2 (-418G > C, rs8179090), TIMP3 (-1296T > C, rs9619311) genes to chronic obstructive pulmonary disease has been assessed. For this purpose, PCR-RFLP analysis of the gene polymorphisms in case (N = 391) and control (N = 514) groups has been performed. The 6A6A genotype of the MMP3--1171 5A > 6A polymorphism was associated with significantly high risk of chronic obstructive pulmonary disease (OR = 2.490, Padj = 0.003979, Pcor = 0.0358 adjusted for age, sex, smoke pack-years, ethnos). Analysis showed an association of the G-G haplotype of 13491C > G and 12418A > G ADAM33 gene polymorphisms (OR = 0.39, Padj = 0.0012, Pcor = 0.006)with chronic obstructive pulmonary disease. We found a significant interaction of the smoking status and ADAM33 12418A > G (Pinteraction = 0.026) and TIMP3--1296T > C (Pinteraction = 0.044). The relationship between the GG genotype of the ADAM33 13491C > G and emphysema risk was found (OR = 1.74, Padj = 0.013, Pcor = 0.117). Severity of chronic obstructive pulmonary disease was modified by MMP9 -1562C > T in additive model (OR = 1.883, Padj = 0.028, Pcor = 0.252). The MMP3, MMP9, ADAM33, TIMP3 genes polymorphism may be an important risk factor for the development and progression of chronic obstructive pulmonary disease, important gene and environmental interactions were determined.

[Genome-wide association study of bronchial asthma in the Volga-Ural region of Russia].

Bronchial asthma is a chronic inflammatory respiratory disease that is caused by the complex interaction of environmental influences and genetic susceptibility. The first genome-wide association study of bronchial asthma discovered a significant association between SNPs within 17q12-21 genomic region and childhood bronchial asthma in individuals of European descent. Association with this genomic region was then replicated in a number of independent samples of European and Asian descent. Here we report results of the first genome-wide association study of bronchial asthma in the Volga-Ural region of Russia. The present study includes 358 unrelated patients with physician-diagnosed bronchial asthma and 369 disease-free control subjects of different ethnic origin (Russians, Tatars and Bashkirs). Genotyping of DNA samples was carried out using the Illumina Human610 quad array as a part of GABRIEL project (contract from the EC No LSHB-CT-2006-018996). After QC filtering procedures, a final set of 550915 SNPs genotyped in 330 cases and 348 controls was tested for association with bronchial asthma. Five markers on chromosome 17q12-21 showed statistically significant association with bronchial asthma (p < or = 4.79 x 10(-7)). SNP rs7216389 with the strongest evidence for association (p = 1.01 x 10(-7)) is located within the first intron of the GSDMB gene. Evidence for association was stronger with childhood-onset asthma (p = 1.97 x 10(-6) for SNP rs7216389) compared to late-onset asthma (p = 1.8 x 10(-4) for SNP rs7216389). Our replication study using three SNPs within GSDMB gene confirmed association with only childhood-onset asthma. In summary, these results suggest an important role for genetic variants within 17q12-q21 region in the development of bronchial asthma in the Volga-Ural region of Russia.

[Value of endothelial dysfunction in cardiovascular diseases and methods of its correction with drugs].

Vascular endothelium is not simply a barrier between blood and extra vascular bed but is a source of large number of mediators regulating various functions of the body among which nitrous oxide appears to be one of most important. Endothelial dysfunction (ED) develops in a number of processes: diabetes mellitus, smoking, arterial hypertension, hypercholesterolemia. ED promotes increase of rate development of cardiovascular diseases. One of most well known markers of ED is microalbuminuria (MAU). Drug and nondrug means are used for the treatment of ED. Calcium antagonists and angiotensin converting enzyme inhibitors both separately and as components of combination therapy are able to maximally diminish MAU.

[Value of pleiotropic effects of angiotensin-converting enzyme inhibitors].

Recently the pleiotropic effects of angiotensin-converting enzyme inhibitors which lay beyond their pure antihypertensive effects are widely discussed. Antiproliferative, antiatherosclerotic, antiproliferative and antiarrhythmic properties, as well as positive effects on hemostasis and endothelial function allows angiotensin-converting enzyme inhibitors to occupy very important position among other cardiovascular medications and to have a number of indications: arterial hypertension, congestive heart failure, myocardial infarction, left ventricular hypertrophy and patients with high risk of cardiovascular disease.

[Polymorphism of the genes for antioxidant defense enzymes and their association with the development of chronic obstructive pulmonary disease in the population of Bashkortostan].

In this study, frequencies of the polymorphic variants of the genes encoding antioxidant enzymes, GSTM1, GSTT1, GSTP1, CAT, GPX1, NQO1, SOD1, and SOD3 were examined in three ethnic groups of healthy subjects from the Republic of Bashkortostan (Russians, Tatars, and Bashkirs). An association of these markers with the development of chronic obstructive pulmonary disease (COPD) was tested. Interethnic differences relative to the distribution of the polymorphic variants of the GSTP1 locus Ile105Val and the NQO1 locus 609C/T were revealed. Relative to the genotype distribution at the Ile 105Val locus of the GSTP1 gene, ethnic group of Bashkirs was found to be statistically significantly different from Tatars (chi2 = 8.819; d.f. = 2; P = 0.012). Relative to the genotype frequency distribution pattern at the NQO1 locus 609C/T, the group of Bashkirs differed from Russians (chi2 = 8.913; df. = 2; P = 0.012). An association of genotype Val/Val of the GSTP1 Ile105Val locus with the risk of COPD in Russians (chi2 = 5.25; P = 0.022; Pcor = 0.044; OR = 4.09), and of the GSTP1 haplotype *D in Tatars, was demonstrated (chi2 = 11.575; P = 0.0014; Pcor = 0.0042; OR = 3.178). Genotype TT of the CAT -262C/T locus marked resistance to the COPD development in Russians (chi2 = 6.82; P = 0.0098; Pcor = = 0.0196; OR = 0.31; 95% CI, 0.119 to 0.77). The risk for COPD in the ethnic group of Tatars was associated with the CAT haplotype (-262)C(1167)T (chi2 = 6.038; P = 0.0147; Pcor = 0.044; OR = 1.71). Analysis of the NQO1 haplotypes at the 465C/T and6009C/T loci showed that haplotype 465C/609T was associated with COPD in Russians (chi2 = 4.571; P = 0.0328; Pcor = 0.01; OR = 1.799). It was demonstrated that Gly allele of the Arg213Gly polymorphic locus of the SOD3 gene marked the risk for COPD in the ethnic group of Tatars (OR = 2.23; 95% CI, 1.22 to 4.1). Thus, GSTP1, CAT, NQO1, and SOD3 polymorphisms play an important role in the development of COPD among the population of Bashkortostan.

[Methodology of management of a sanatorium and spa facility based on the integration of scientifically-sound approaches].

Methodology of building up a managerial system for a sanatorium and spa facility is proposed based on the integration of known general scientifically-grounded approaches, each concerned with a selected aspect of the system. Taken together, they give a complete picture of the mechanisms underlying functioning of the system and help to increase efficiency of its operation.

[Current state of a mineral water spa and a health resort complex in the Republic of Bashkortostan and prospects for its further development].

The objective of this study was to consider natural conditions and mechanisms of formation of mineral water sources in the Republic of Baskortostan. A map showing their location within the bounds of the Republic lying at the junction of Europe and Asia is presented. The distribution of mineral water springs is highly non-uniform and dictated by the landscape patterns, climatic, geologic and tectonic history of the territory, its climatic and hydrological conditions. It is concluded that most part of Bshkortostan has very promising prospects for the further development of its spa and resort complex.

[Association of cytochrome P450 genes polymorphisms (CYP1A1 and CYP1A2) with the development of chronic obstructive pulmonary disease in Bashkortostan].

To assess the role that polymorphisms of cytochrome P450 genes play in genetic predisposition to chronic obstructive pulmonary disease (COPD), the allele and genotype distributions of CYPIA1 (2455 A/G, 3801T/C) and CYP1A2 (-2464T/delT, -163C/A) genes were studied in Tatar and Russian COPD patients and in cases of healthy individuals (Russian, Tatar and Bashkir), residents of Bashkortostan. It was shown that the CYP1A1 and CYP1A2 genes haplotypes frequency distribution patterns do not differed between Tatars and Russians ethnic groups (chi2 = 0.973, df = 3, p = 1.00 and chi2 = 1.546, df = 3, p = 0.92, respectively). Analysis of the the CYP1A1 and CYP1A2 genes haplotypes revealed statistically significant differences in the haplotypes frequency distributions between Bashkirs versus Russians and Tatars (chi2 = 12.328, df= 3,p = 0.008; chi2 = 9.218, df=3, p = 0.034, respectively for CYP1A1 gene and (chi2 = 18.779, df=3, p = 0.0001, chi = 14.326, df=3, p = 0.003, respectively for CYP1A2 gene). The (-2467)delT allele and CYP1A2*1D haplotype of CYPIA2 gene was associated with higher risk of COPD in Tatar ethnic group (OR = 1.83, 95% CI 1.24-2.71, chi2 = 9.48, p = 0.003 and chi2 = 9.733, p = 0.0027, Pcor = 0.008; OR = 3.908, 95% CI 1.56-10.19, respectively). On the other hand the CYP1A2*1A haplotype had protective effect (chi2 = 6.319, p = 0.0127, Pcor = 0.038; OR = 0.6012, 95% CI 0.402-0.898). But at the same time we did not find any differences in the genotypes and haplotypes frequency distributions of the CYP1A2 gene within the patients and healthy groups in Russian ethnic group. We also did not find any association of CYP1A1 gene with COPD in ethnic groups of Bashkortostan.