[Cluster size polymorphism of active human ribosomal genes and simulation of the conditions of its stability through generations].

Based on selective silver nitrate staining of active ribosomal gene (AcRG) clusters in nucleolus organizer regions (NORs) of human metaphase chromosomes, a technique was developed earlier to estimate the AcRG dosage in individual genomes as a sum of arbitrary units (0-3) ascribed to the silver precipitate (AgNOR) on ten NORs. The AcRG dosage was considered to be an additive quantitative trait determined by five polymorphic autosomal loci (with for allelic forms for each locus). A database was created to contain the data on AcRG cluster variants for more than 1000 individual human genomes. In this study, the population frequencies of AcRG cluster variants were determined. The results agreed with the hypothesis that stabilizing selection acts at the zygotic and/or early embryogenetic stage to restrain the AcRG genomic dosage (copy number) within a range from 14.9 to 23.7 arbitrary units (the cell is unviable when the trait is beyond this range). The average zygotic losses due to selection were estimated at 9.1-9.9% for a real population. A computer model where the AcRG dosage of a progeny results from a random combination of the AgNORs of the five acrocentric chromosome pairs of the parents was developed and used to simulate the formation of a certain AcRG genomic dosage through generations in a human panmictic population with nonoverlapping generations. A combination of stabilizing selection by total AcRG copy number and a certain spontaneous mutation rate (the probability of changes in the cluster size of a NOR as a result of unequal crossingover in meiotic prophase) was shown to be a sufficient condition for the restrain of equilibrium population frequencies of AgNOR size variants in a human panmictic population. Using the model, the most probable spontaneous mutation frequency was predicted to be (2.1-2.3) x 10(-2) per NOR per generation for human AgNORs. The predicted frequency was within the 95% confidence interval of the experimental rate, which was determined by studying the inheritance of AgNOR variants in real families.

[Genetic markers of predisposition to infectious complications in neonatal infants with respiratory distress syndrome].

Neonatal respiratory distress syndrome (NRDS) is the commonest cause of death and morbidity of the newborn. A genetic risk for NRDS is currently recognized. The aim of this study was to determine whether there was an association of the polymorphisms of the SP-B, SP-D genes and the interleukins (IL)-1alpha, IL-10 genes with the development of infectious complications in neonatal infants with the respiratory distress syndrome. It was found that the certain genotypes by the polymorphic loci of surfactant proteins and interleukins might be associated with infectious diseases in the newborn with respiratory distress syndrome.

[Polymorphism of glutathione-S transferase M1 gene in patients with generalized forms of surgical infection]. / Polimorfism gena glutation-S-transferazy M1 u bol'nykh s generalizovannymi formami khirurgicheskoi infektsii.

Polymorphism of glutathione S-transferase M1 (GSTM1) locus was analyzed with PCR in patients with generalized forms of surgical infection (n = 47) and in healthy donors (n = 80). Reliable difference was revealed in distribution of zero genotype between patients with sepsis and septic shock (chi 2 = 8.37; p = 0.007) and also between patients with sepsis and organs insufficiency (chi 2 = 5.79; p = 0.02). There were no reliable differences between patients with sepsis and control group (chi 2 = 1.29; p = 0.32). It is concluded that patients--carriers of deletion of GSTM1 gene in homozygote have increased probability of septic shock and polyorganic insufficiency in surgical infection. It can be used as a negative prognostic criterion in clinical practice.

[Significance of hereditary factors in multiple organ dysfunction syndrome in children with infections]. / Znachenie nasledstvennykh faktorov v realizatsii sindromov organnoi disfunktsii pri khirurgicheskoi infektsii u detei.

In order to elucidate the contribution of hereditary factor (dose of ribosome genes) to the realization of organ dysfunction syndromes in children with surgical infection, the total size of silver nitrate-stained nucleoli-forming regions (Ag-NFR) of acrocentric chromosomes in karyotypes was assessed in 22 patients aged from 14 months to 12 years, 17 of these with appendicular peritonitis, 4 with destructive pneumonia, and 1 with acute hematogenic osteomyelitis. Pyoseptic diseases involved no organ dysfunction in 10 patients, and in 12, multiple organ dysfunction was diagnosed. Our findings indicate that the carriers of low-copy variants of ribosome genes are characterized by hereditary predisposition to lowered individual resistance of the organism. Therefore, children with surgical infection with a decreased size of Ag-NFR (low dose of ribosome genes) in the karyotype potentially represent a group at risk of multiple organ dysfunction realization.

[The treatment of appendicular peritonitis complicated by septic shock in childhood]. / Lechenie appendikuliarnogo peritonita, oslozhnennogo septicheskim shokom, v detskom vozraste.

The article presents an analysis of results of treatment of 39 children from 1 to 14 years of age with diagnosis of appendicular peritonitis complicated by septic shock. It was shown that complex pathogenetic treatment with controlled laparostomy, necessary compulsory or subsidiary artificial pulmonary ventilation before and after operative intervention, associated use of afferent methods allowed to decrease the number of lethal outcomes from 54.5 to 11.1%.

[The metabolic and immunological changes in appendiceal peritonitis in children complicated by multiple organ failure]. / Metabolicheskie i immunologicheskie izmeneniia pri appendikuliarnom peritonite u detei, oslozhnennom poliorgannoi nedostatochnost'iu.

An investigation of 56 children with appendicular peritonitis complicated by multiple-organ failure has revealed typical, in the authors' opinion, metabolic and immunological changes such as the regulation of organism to minimization of the energy exchange with catabolism of the functionally important proteins and the formation of multiple-component secondary immunodeficient state. The data obtained facilitate earlier diagnosis of the multiple-organ failure and optimization of the management which resulted in 2 times less lethality among such patients.

[Analysis of chromosome aberrations and nucleolar organizer regions of chromosomes in workers producing pyromellitic dianhydride: the possibility of the adaptive role of Ag-NOR variants]. / Analiz khromosomnykh aberatsii i iadryshkoobrazuiushchikh raionov khromosom u rabochikh proizvodstva piromellitovogo diangidrida: O vozmozhnoi adaptivnoi roli variantov Ag-IaOR.

To assess the mutagenic danger of pyromellitic dianhydride (PMDA) production, the frequency of chromosome aberrations in peripheral blood lymphocytes from 56 workers and 37 control donors from Ufa was determined. A significant increase in the frequency of metaphases with aberrant chromosomes was found in the industrial group (5.3%) as compared with the control (2.9%). The effect of toxic factors on the functional state of acrocentric NORs was analyzed. No significant differences between PMDA-exposed workers and the control group in cumulative functional activity of 10 NORs (silver staining) was revealed. At the same time, a decreased proportion of cells with associations was found (76% in workers and 82% in donors), which may be a consequence of changes in immune status and in compensatory activation of cell proliferation, which leads to accumulation of young circulating lymphocytes with low associative capacity of acrocentrics. In addition, a significantly increased proportion of individuals carrying extreme Ag-NOR variants (grades 3.5-4.0) was observed in the industrial group (up to 37% vs 6% in the control), which may be due either to genotype selection at the number of active rRNA gene copies or to compensatory activation of repressed copies of ribosomal genes in some NORs.

Immunosuppressive action of cyclophosphamide in mice: contribution of some factors to determination of strain differences.

Mechanisms of strain differences in susceptibility to cyclophosphamide (CP) has been investigated with BALB/c, DBA/2, CC57BR, and C57BL/6 mice. It was shown that the final immunosuppressive effects of CP is a result of a combination of such factors as the level of CP alkylating metabolites in the bloodstream and the sensitivity of the target cells to antiproliferative action of these metabolites. The importance of the immune status peculiarities has been discussed.

[Interconnection of the functional activity of nucleolar organizer regions of chromosomes with human reproductive pathologies]. / Vzaimosviaz' funktsional'noi aktivnosti iadryshkoobrazuiushchikh raionov khromosom s reproduktivnoi patologiei cheloveka.

Comparative analysis of transcriptional activity of human nucleolus organizer regions (NOR) of the chromosomes in the group of the control phenotypically healthy individuals (I) and in the spouses with repeated spontaneous abortions (II) was conducted in an attempt to verify the hypothesis: whether elimination of zygotes having received a very large or very small number of the copies of active rRNA genes may serve as a factor decreasing the fecundity of some spouses? It has been shown that the groups I and II have no differences in total activity of 10 NOR (Ag staining, rating estimation). At the same time, the II group is characterized by higher, in comparison with the I, heterogeneity of Ag-NOR variants in homologues of 5 nucleolus-organizing chromosomes. As a result, in the individuals of the group II the gametes are formed which are more heterogenous than in the group I for the Ag-NOR pattern variants. The imitation computer experiments revealed that in the group II elimination of zygotes as a consequence of inherited Ag-NOR variants combination should occur more frequently (in 22.2% cases) than in the group I (15.9%), p < 0.05. Thus, the hypothesis under test was substantiated in the present study.

Pharmacokinetics of alkylating metabolites of cyclophosphamide in different strains of mice.

Determination of the amount of alkylating (NBP) metabolites of cyclophosphamide (CP) in blood serum of BALB/c and DBA/2 mice has revealed that the shape of the curve describing the accumulation of NBP-metabolites, depends on the administered drug dose and animals' genotype. The experimental data obtained made it possible to suggest an improved pharmacokinetic model which takes into account a possible switching in of factors conditioning non-linear changes in the intensity of the accumulation processes in blood and elimination of CP alkylating metabolites from blood. The effect of different CP alkylating metabolite kinetics in BALB/c and DBA/2 mice on a different sensitivity of these mice to the immunodepressive action of CP in vivo, has been discussed.

[The induction and elimination of cytogenetic disorders in monkey lymphocytes following thiophosphamide action]. / Induktsiia i éliminatsiia tsitogeneticheskikh narushenii v limfotsitakh obez'ian posle vozdeistviia tiofosfamidom.

The dynamics of sister chromatid exchanges and chromosome aberrations in lymphocyte of monkey has been investigated after a thiophosphamide exposure. The process of induction and elimination of cytogenetic damages was described by the mathematical model. Developing the model in detail will allow to make a cytogenetic prognosis of remote consequences of mutagenic exposure.

[Evaluation of the incidence of congenital developmental defects in newborn infants based on an analysis of archival documentation]. / Otsenka rasprostranennosti vrozhdennykh porokov razvitiia u novorozhdennykh na osnove analiza arkhivnoi dokumentatsii.

Incidence of congenital malformations in the newborn was analyzed on the basis of the medical archives, thus the possibility of using the obtained data for genetic monitoring being established.

[Effect of chromosomal constitution with respect to the sex chromosomes on the proliferative activity of human lymphocytes]. / Vliianie khromosomnoi konstitutsii po polovym khromosomam na proliferativnuiu aktivnost' limfotsitov cheloveka.

Rate division of human lymphocytes was studied in 85 healthy siblings and 142 normal non-related individuals using sister chromatid differential staining in standard conditions of cell culturing. It was shown that proliferation of male lymphocytes exceeds that of female cells. This sexual dimorphism does not depend on the time of fixation of cell cultures and probably is conditioned by differential chromosomal constitution of the two sexes. The study of sex chromosome mosaics revealed rate modification of cell proliferation in the line: 45,X greater than 46,XY greater than 46,XX. The possibility of influence of heterochromatin and sex chromosomal genes on control of cell division is discussed.

[Interindividual and intercellular differences in the total activity of ribosomal genes detectable by the Ag staining of nucleolus organizer regions in human acrocentric chromosomes]. / Mezhindividual'nye i mezhkletochnye razlichiia summarnoi aktivnosti ribosomnykh genov, vyiavliaemye AG-okraskoi iadryshkoobrazuiushchikh raionov akrotsentricheskikh khromosom cheloveka.

Selectively Ag-stained nucleolar organizing regions (NORs) of human chromosomes were analysed using four size categories: 0, 1, 2 or 3 grades. A criterion of NORs' total activity has been proposed as a sum of grades (sigma (+]. On this basis, interindividual polymorphism was defined in 60 healthy individuals with normal karyotypes. The reaction norm of sigma (+) was determined (from 16 to 22 grades). In the cells of the patients with two nucleolar organizing chromosomes involved in Robertsonian translocations the sigma (+) was within the reaction norm (16-19). The total NORs activity was determined in a patient having both normal karyotype cells and two cell clones with one or two small bisatellited chromosomes: sigma (+) in three cell clones amounted to 20.5, 23.0 and 26.3. In the clones with additional NORs, the silver staining intensity for 10 NORs of the main set did not change, which leads to a suggestion that no compensatory change in the number of rRNA gene copies working takes place in man. The data obtained allow to suppose that zygotic selection operates in man, which ensures maintainance of the number of the ribosomal gene's copies necessary for viability of an individual.

[Ratio of the frequency of chromosome aberrations and sister chromatid exchanges to the dose of the mutagenic exposure to cyclophosphamide in vivo and in vitro]. / Zavisimost' chastot khromosomnykh aberratsii i sestrinskikh khromatidnykh obmenov ot dozy mutagennogo vozdeistviia tsiklofosfamida in vivo i vitro.

Cyclophosphamide (CP) and its metabolites were used to compare the rate of chromosomal aberrations (CA) and sister chromatid exchange (SCE) in the rabbit lymphocytes in vivo and in vitro. The dose-dependent increase of cytogenetic effects rate appeared to be of linear and exponential dependence for SCE and CA, respectively, both in vivo and in vitro. The regression equation coefficients coincided in in vivo and in vitro experiments.

Sensitivity to immunodepressant action of cyclophosphamide: analysis of interstrain differences in mice.

In one of our previous studies (Pevnitsky et al., Bull. exp. Biol. Med., 83, 438-440, 1977), we have found significant differences between various strains of mice in the sensitivity to immunodepressant action of cyclophosphamide (CP). The degree of these differences was not determined by the level of their immune response which indicates that the cause of the interstrain differences lies in a specific reaction of mice to the immunodepressant. The main parameters of CP effect which may be responsible for variable sensitivity to the immunodepressant action in vivo were studied in several murine strains (Balb/cJLacSto, CBA/CaLacSto, and DBA/2JSto): (1) rate of the preparation activation in liver microsomes; (2) pharmacokinetics of NBP-metabolites in the blood serum; (3) immunodepressant action of the in vivo activated CP; (4) sensitivity of immunocompetent target cells to activated CP effect. It was found that DBA/2 mice are the most sensitive to CP in vivo. The level of "active" CP in their blood serum is higher than in BALB/c mice. Besides, they are characterized by a higher sensitivity of immunocompetent cells compared to BALB/c and CBA mice.