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The innate immune system is the first to respond to invading pathogens. It is responsible for invader recognition, immune-cell recruitment, adaptive-immunity activation, and regulation of inflammation intensity. Previously, two single-nucleotide polymorphisms of innate-immunity genes - rs5743708 (Arg753Gln) of the TLR2 gene and rs8177374 (Ser180Leu) of the TIRAP gene - have been shown to be associated with both pneumonia and tuberculosis in humans, but the data are contradictory among different ethnic groups. It has also been reported that rs10902158 at the PKP3-SIGGIR-TMEM16J genetic locus belongs to a haplotype race-specifically associated with tuberculosis. Meanwhile, a gradient of its frequency is observed in Asia. The aim of this work was to assess the effect of selection for the genotypes of the above-mentioned SNPs on the gene pools of populations living in harsh climatic conditions that contribute to the development of infectious lung diseases. We estimated the prevalence of these variants in white and Asian (Chukchis and Yakuts) population samples from Northern Asia and among patients with community-acquired pneumonia (CAP). Carriage of the rs5743708 A allele was found to predispose to severe CAP (odds ratio 2.77, p = 0.021), whereas the GG/CT genotype of rs5743708/rs8177374 proved to be protective against it (odds ratio 0.478, p = 0.022) in white patients. No association of rs10902158 with CAP (total or severe) was found among whites. Stratification of CAP by causative pathogen may help eliminate the current discrepancies between different studies. No significant difference in rs5743708 or rs8177374 was found between adolescent and long-lived white samples. Carriage of the alleles studied is probably not associated with predisposition to longevity among whites in Siberia. Both white and Asian populations studied were different from Western European and East Asian populations in the variants' prevalence. The frequency of the rs8177374 T (Ser180Leu) variant was significantly higher in the Chukchi sample (p = 0, χ2 = 63.22) relative to the East Asian populations. This result may confirm the hypothesis about the selection of this allele in the course of human migration into areas with unfavorable climatic conditions., (Copyright © AUTHORS.)

The involvement of wortmannin (10 -5 M), phosphatidyl inositol 3-kinase (PI3K) blocker, in the implementation of the rapid nongenomic aldosterone (10 nM) effects on the intracellular sodium (Na i +) and the principal cell volume of cortical collecting duct (CCD) of 10-day and adult rat kidney CCD was studied. Using fluorescence microscopy with intracellular dye Na Green and Calcein we found that wortmannin weakened the effect of aldosterone on the Na i + at low sodium in the extracellular medium (14 mM NaCl), and slowed the rate of reduction of the principal cell volume in the presence of aldosterone at the hypoosmotic shock (240/140 mOsm) since 10 days of age. The findings suggest the participation of phosphatidylinositol pathway in the fast nongenomic aldosterone effects (seconds and minutes) at the early stage of postnatal ontogenesis.

The fast nongenomic aldosterone effect on intracellular sodium ([Na+]i) and cell volume was studied by the fluorescent microscopy in isolated cortical part of collecting duct of the rat kidney (CCD). It was shown that aldosterone (10 nM) raised [Na+]i in hyposodium outer medium (14 mM). The rate of [Na+]i changes in response to external sodium shift (137-14 mM) twice as low in the presence of aldosterone (p < 0.05). Corticosterone (100 nM) was unable to simulate aldosterone effect. Similarly to sodium channel blocker amiloride (10(-5) M), protein kinase C (PKC) inhibitor RO-31-8220 (10(-7) M) abolished aldosterone effect. Aldosterone (10 nM) significantly decreased the amplitude and increased the characteristic time of the cell volume restoration in hypotonic medium of the rat principle cells (p < 0.001). Corticosterone (50 nM) was also unable to reproduce aldosterone effect. Amiloride (10(-5) M) did not significantly influence either the amplitude or the characteristic time of cell volume restoration during hypoosmotic challenge (p > 0.05). For the first time the specificity and important role of Ca(2+)-dependent kinase in the nongenomic aldosterone effects on ENaC activity and cell volume regulation in rat CCD were demonstrated.

The polymorphism of the TNF A gene was studied in 89 asthmatic patients and their 162 relatives in order to estimate the contribution of this candidate gene to the predisposition to the development of asthma and allergic diseases. A control group comprised 258 individuals without bronchopulmonary pathology The polymerase chain reaction was used to study the 308 G/A polymorphism of the TNF A gene. The findings suggest that the asthmatic patients and their relatives have no association of the polymorphism of the TNF A gene in position 308 with their predisposition to the disease. Analysis of the distribution of the frequencies of alleles and genotypes among their probands, relatives, and the control group revealed no statistically significant differences between the groups.

A familial survey was conducted in 81 probands who were diagnosed as having bronchial asthma (BA) and their 183 first-, second-, and third-degree relatives (a study group). A control group comprised 263 apparently healthy individuals. The familial accumulation of BA was ascertained in the families of probands with this condition. Autosomal dominant inheritance of BA was established. The heterozygous variant of the macrophage-colony-stimulating factor receptor (MCSFR) gene genotype chi-fms may be considered as one of the genetic predictors of BA. The homozygous genotype in a rare allele of the MCSFR gene may be also a predictor of BA.

Aldosterone: a steroid hormone of adrenal cortex, has recently attracted much interest not only due to its great importance in regulation of salt and water balance, but also because of its key role in therapy of cardiovascular and renal pathology. The classical genomic mechanism of molecular action of aldosterone is mediated through interaction with mineral-corticoid receptors. Fast nongenomic pathway of cell signal transduction begins with interaction with hypothetic membrane receptors and includes activation of different kinase cascades. Interference of these two pathways of signal transduction assures abroad spectrum of aldosterone effects depending on the cell type, and also secures multycomponent regulation depending on the need of specific functional and stress situation. This review is dedicated to modern views of mechanisms of aldosterone molecular action, mostly of the level of aldosterone-sensitive segment of kidney nephron.

Developmental changes of mRNA alfa-subunit ENaC abundance in renal cortex of 10-day old and in adult rats and aldosterone (10 nM) influence on it were studied. The mRNA level was lower in young rat renal cortex and there was no aldosterone effect on it within 5 hours and 30 minutes, in contrast to adult rats. Intracellular sodium concentration [Na+ i] measured by fluorescent dye Na+ Green in CCD fragments micro-dissected from the kidneys was lower in fragments from immature kidneys, whereas fast nongenomic of aldosterone (10 nM) was the same at both ages. Aldosterone significantly raised [Na+ i] by 40 and 50% in conditions of low sodium concentration (14 mM) in outer medium in epithelial cells of both type of CCD fragments from 10-day old and adult animals, respectively (p < 0.05). We assume that heterochrony of fast and long time genomic effect takes place in aldosterone molecular mechanism maturation. Fast nongenomic effect on the [Na+ i] appeared earlier compared to delayed genomic effect of aldosterone mediated through the changes of the mRNA alpha-subunit ENaC abundance.

The reason of unresponsiveness of young 10-day rats kidney to aldosterone was explored. The aldosterone binding in distal segments of renal nephrons and the influence of hormonal induction on the mRNA of the alpha and beta subunits of the Na+, K(+)-ATPase in 10-day and 2-month old rats were investigated. There was no age related difference in the aldosterone specific binding in presence of RU-38486 (10(-7) M; Russel Uclaf) in the cortical collecting tubules: 0.26 +/- 0.04 (n = 9) and 0.22 +/- 0.03 (n = 8) mMol/mm of tubule lengths in 10 day and adult rats, respectively. By Nozern blot analysis and RT-PCR more then three and two fold increase of the mRNA abundance of both subunits was found in young and adult renal cortex compare to the adrenalectomized control after aldosterone induction (5 micrograms/100 g. v. b. w. 4 times i/p injections in 3 hour interval between injections) (p < 0.01). By RT-PCR no expression of the alpha 2, alpha 3 and beta 2 isoforms has been observed in all experimental conditions. The age difference was discovered when aldosterone was injected together with spironolactone (5 micrograms and 12 mg per 100 g. b. w. respectively). It was shown, that spironolactone inhibits the effect of aldosterone in adults whereas the latter was unaffected in young rats. The scheme of the age-related differences in the aldosterone regulation of the sodium pump induction in the target cell of the distal part of the rat nephrons is presented.

Analysis of deletion polymorphism of human c-fms gene intron 11 (approximately 425-bp deletion) is of particular interest because of the increased proportion of the deletion heterozygotes among the infants born from the parents, one of which lacks the deletion allele, and the other is heterozygous for the deletion. In this study, allele and haplotype frequencies of the polymorphism examined were assessed in a number of Caucasoid and Mongoloid populations of Russia. In all populations tested, relatively high prevalence of the deletion-bearing allele, ranging from 9.45% in ethnic Germans to 20.75% in Altaians, was detected. Russians and Kazakhs were characterized by intermediate frequencies of the rare allele, constituting in these populations 12.89 and 14.93%, respectively. Hardy-Weinberg expectations were met in all populations examined, pointing to a stable level of polymorphism at the c-fms intron 11. It was established by the context analysis of DNA of the deleted fragment along with the flanking sequences that this region contained a number of transcription factor motifs (Ets, SRF, and Myc), potentially capable of the regulation of the M-CFF-dependant c-fms transcription. The deletion breakpoint was localized within the CArG motif, which, together with the neighboring ets motif, form the potential CArG/ets composite element. It was suggested that allele lacking the fragment of intron 11 could be restricted in its ability to modulate the level of the c-fms transcription in response to the action of M-CSF. The data of molecular epidemiological survey serve as the indirect evidence favoring the suggestion on the possible functional value of this gene fragment. It was demonstrated that in the samples of acute bronchitis and trichomoniasis patients allelic and genotype frequencies were statistically significantly different from those in the population sample. In case of trichmoniasis, the frequency of rare allele was 2.4 times lower, and in case of acute bronchitis it was 2.1 times higher than in the control sample.

Phosphorylation was shown to lead to a change in the conformational equilibrium toward E1 form associated with a decrease in apparent affinity for the K+ in alpha-1 subunit of the rat kidney Na+, K(+)-ATPase. Rate of transition from E2 to E1 was apparently unaffected by phosphorylation. ATP hydrolysis by the protein kinase C-phosphorylated Na+, K(+)-ATPase shows a decrease in the Vmax and Km for K+.

The development of the multiorgan dysfunction syndrome, directly determining the severity of the septic process, is characterized by not only inverse ratio of the energy and plastic material, but by metabolic changes which are still unclear and cannot yet be explained. Our purpose was to detect some features of amino acid metabolism in patients with grave sepsis and septic shock. The concentrations of plasma free amino acids were measured on days 1, 3, and 5 in 37 patients with grave sepsis and septic shock. The diagnosis of grave sepsis, septic shock, and organ dysfunction was made proceeding from the criteria defined by R. Bone. The study revealed reliably increased (p < 0.05) levels of arginine, proline, alanine, and the arginine-ornithine index reflecting the direction of arginine transformation in patients with septic shock and grave organ dysfunction (for at least 3 systems). This may be explained by active degradation of endogenous proteins of skeletal muscles, which is characteristic of septic hypermetabolism. Strong correlations were revealed between arginine level and the APACHE-II score (r = 0.57), proline and the same score (r = 0.51), mean arterial pressure and the arginine-ornithine index (r = -0.72), APACHE-II score and the arginine-ornithine index (r = 0.79), arterial lactate and the arginine-ornithine index (r = 0.64). Hence, amino acid metabolism apparently mediates the effects of septic cascade mediators on the following cell.

The aldosterone binding in isolated distal convoluted and cortical collecting tubules of renal nephrons and the influence of hormonal induction on the Na, K-ATPase activity in membrane fraction of kidney cortex were studied in 10-day- and 2-month-old rats. No reliable difference in aldosterone-specific binding was revealed (0.26 +/- 0.04 and 0.22 +/- 0.03 fmol/mm of tubule length, respectively, at the age of 10 days and 2 months). It was found that Na, K-ATPase activity increased with age from 0.39 +/- 0.06 to 0.72 +/- 0.10 mumol Pi/mg of protein.1 hour.100 microliters. Aldosterone induction caused approximately a 3-fold increase of the enzyme activity in both age groups comparing to the control level. Co-induction of aldosterone and spironolactone resulted in a 50% decrease of Na, K-ATPase activity in adult rats, but did not influence that in young rats. The revealed age-related differences in the mechanism of hormonal Na, K-ATPase regulation are supposed to underlie the absence of physiological reaction of the kidney to aldosterone in early postnatal ontogenesis.

The effect of aldosterone on the cAMP level, the state of inositol-phosphate pool and the intracellular free Ca2+ activity in the rat kidney, were studied. The cAMP level in the kidney cortex homogenate was not changed after i.p. injection of aldosterone. Reliable changes in the content of inositol-phosphates in the kidney cell suspension was not revealed after aldosterone treatment. A short-term enhancement of the intracellular Ca2+ activity in the isolated distal convoluted and cortical collecting tubules under the influence of aldosterone, was revealed. The participation of the second messenger systems in the realisation of aldosterone effects in kidney and the role of Ca2+ in the mechanism of aldosterone action, are discussed.