Topicality and demand of the subject of dissertation. Bronchial asthma (BA) is one of the most common and serious diseases, which in the world suffer from 3 to 12% of the child population of the globe. Proportion of adolescents with asthma, is one third of all children with this disease. High prevalence of asthma in the numbers of teenagers, characteristics of the disease, age-related aspects of the functioning of the endocrine and immune systems of teenagers that cause difficulties which arise in the course of the diagnostic process, highlight the need to find innovative approaches to diagnosis and treatment of this disease.
It is known that the key immune mechanisms in the pathogenesis of the vast majority of AD cases is real and indisputable fact. Currently, considerable interest to researchers involved in the pathogenesis of positions of allergic diseases, especially asthma, along with IL-4 and IL-13 causes a number of other (IL-6, IL-8, IL-10, IL-5, INF-a and INF-y) immunoregulatory cytokines.
Genetic predisposition plays an important role in the development of allergic diseases. Currently available data on the relationship with asthma and associated with disease symptoms polymorphism approximately 150 genes. Important role as the main contender for the predisposition to asthma gene is a gene encoding flchain of high affinity receptor IgE. Interaction elevated levels of antigen-specific IgE with FceRip plays a central role in the pathogenesis of allergic asthma. Particularly attractive candidate gene asthma is also one of the enzyme genes biotransformation - GSTirl, encoding glutathione S-transferase and л1 express almost exclusively in the pulmonary tissue. This gene is located at the locus 11 ql 3, for which repeatedly shown clutch with atopic symptoms. Accumulated in the literature say about the relationship of gene polymorphism FceRI, GSTnl with different allergic diseases.
From this perspective, the study of immunological and genetic mechanisms of the pathogenesis of this disease for the construction of rational treatment and prevention emphasizes the relevance of this thesis research.
From the earliest days of independence, the country has successfully implemented state programs aimed at reforming the health care system. As a result, the targeted implementation of organizational health and research activities aimed at effective diagnosis, prevention and treatment of asthma among adolescents, with some success in the treatment of this disease in the country. However, now the problem of early diagnosis and the development of effective programs for treatment and prevention among adolescents with asthma remain one of the most important issues of modern health care. This research work was carried out in the framework of the tasks set by the Resolution of the Cabinet of Ministers of the Republic of Uzbekistan "On additional measures to improve the health of women and the younger generation," dated 25.01.2002 for the №32. In this regard, the need to deepen the information received about the state of cellular and humoral immunity among adolescents, asking pathogenetic informative immunogcnctic studies in asthma arc one of the important criteria demand the dissertation topic.
Purpose of research is study the immunological and genetic mechanisms of the pathogenesis of asthma in adolescents and form the basis of this plan rational diagnostic and therapeutic measures in this pathology.
In To achieve this goal the following tasks of research is solved:
to establish the clinical course of asthma in the population of adolescents living in the Samarkand region, in the early stages of the pathological process in the bronchopulmonary system.
explore the features of the state of cellular and humoral immunity, as well as activation markers in asthma in adolescence by determining the immunophenotype of lymphocytes in the peripheral blood.
to examine the level of production of immunorcgulatory cytokine interleukin-6 and interfcron-y and install them pathogenetic informative in asthma among adolescents.
to determine the features of distribution of allele and genotype frequencies of polymorphic variants of genes and FceRip GSTnl population Uzbek people with asthma, compared with the healthy part of the population.
examine the clinical and immunological aspects effectiveness of therapies using drugs and polioksidony tsikloferon in patients with asthma in adolescence.
on the basis of studies to develop a multivariate model of formation of bronchial asthma and develop an optimal algorithm for the diagnosis, treatment, prevention in adolescents with this pathological condition.
Scientific novelty of dissertational research consists in the following:
proposed introduction to the work of doctors teen clinics layered approach testing can significantly improve the detection rate of asthma in adolescence and optimize treatment and preventive measures in high-risk groups;
first defined the peculiar characteristics of the quantitative parameters of the immune status of patients with asthma in the cohort of adolescence and the corresponding proposed regulations and guidance documents for the healthy part of the adolescent population;
for the first time presents a comprehensive assessment of the cytokine profile of blood serum in bronchial asthma in adolescents. Specific features of products immunorcgulatory cytokines IL-6 and INF-y and their pathogenetic and regulatory information content in asthma among adolescents;
first analyzed the distribution of alleles and genotypes of polymorphic gene variants and gene FceRip GSTirl among patients with different phenotypic variants of AD and healthy individuals of Uzbek nationality, which resulted in the identified markers of increased risk or, conversely, resistance to the development of asthma in adolescents Uzbek ethnicity;
algorithms for phase diagnosis, treatment and prevention of asthma in adolescence in terms of disclosure of important moments of the pathogenesis of the disease, allowing to build a rational sequence of diagnostic search, aimed at verifying the diagnosis and expedient construction of preventive measures.
Conclusion
1. Set the frequency of occurrence of the disease and the structure of "asthma" in the arid zone among teens. Said pathology is recorded in 9,6% of the population surveyed adolescents, while the disease is more common among females. In the structure of the disease prevails periodical exposure and mild persistent form.
2. Identified by clinical features of asthma among adolescents living in the arid zone, indicate a high frequency of lesions of the bronchial tree association with allergic processes in other organs and tissues: in 73,9% of the AR, 53,7% with AK. 16,6% with BA and 14% with urticaria/angiocdcma.
3. Found that in the study population of patients with asthma adolescence occur expressed disturbances of the immune status, manifested deficit indicators as cell (CD3‘, CD4+, CD8 , CD16+), and humoral immunity (CD19 , IgA, IgG, IgM) and activation markers (CD23+, CD95). The immune status of patients with asthma in young people, adolescence has distinctive features, the depth of detected violations immunoreactivity was most pronounced in the younger age group.
4. In patients with bronchial asthma in adolescence revealed distinct changes in cell-cell interactions in the immune system: a significant increase in the content of Th2-cclls secreted IL-6 is a regulator of maturation of antibodies and immunoglobulin production itself, and vice versa reducing regulator activity of Th 1-cell cytokine INF-y.
5. It was found that the contents of cytokines IL-6, INF-y and in the peripheral blood is in communication with one pathogenic disease. It is shown that the lowest level of INF-y production in the scrum is characteristic of allergic clinical pathogenic variant asthma in adolescence. Adolescents suffering from predominantly infectious form of asthma, there is a sharp trend towards increased production of IL-6 in peripheral blood.
6. Revealed that markers of increased risk of allergic forms of asthma in adolescents Uzbek ethnicity arc genotype FceRip-109T/T allele FceRip-109T, low-risk markers - FcsRip-109C/C and allele Fc£Rip-109C. A high degree of cohesion genotype FcsRip-109T/T allele and FcsRip-109T with hereditary burden of asthma in the Uzbek population.
7. Among females ethnic Uzbek Association revealed lie-105 allele and genotype Ilc-105/Ilc-105 polymorphic gene locus GSTkI at high risk for asthma. Revealed that the genotype associated with the development Ilc-105/Ilc-105 allergic form of asthma in adolescents Uzbek population.
8. Complex therapy with adolescents’ patients with asthma ciklofcron and polyoxidonium, providing immunocorrective effect, enhances the clinical efficacy of basic therapy. In the study of prophylactic efficacy of immunomodulators positive indicators prevailed in the group of patients receiving polioksidony, necessitating its inclusion in the priority scheme of integrated treatment and prevention of asthma in adolescents.
Topicality and demand of the subject of dissertation. Researches of human population genomic variety and scenarios of its genetic pool formation arc one of perspective directions of modem genetics. Prompt progress in this field has allowed defining the basic routes of continents settlement. However the information about Central Asian (CA) populations even on «classical» genetic markers has accidental, fragmentary character, and requires additional large-scale investigations. Besides, according to historical, archeological, paleontological and some anthropogenetic studies, given region was playing certain role in ancient moving of modem human ancestors throughout Eurasian continent. Therefore it is extremely important to summarize and perform complex assessment of new and collected data on Central Asian populations as practically there arc no multivariate analyses studies of given region as a complex population system.
In studies of human population genetic structure arc usually used various approaches allowing understanding concept of populations subdivision and character of genetic relationships between them. Among these techniques the prominent place belongs to approaches based on an assessment of genetic distances between populations with their subsequent analysis by multivariate statistics methods. For even more compelling picture of the relationships between the populations on tree diagram we composed «the genetic landscape» of area, where the description of population genetic structure is presented by equally spaced figures consistently consolidating populations according to their genetic distances from each other and thus creating a genetic landscape. This approach is not only a tool for elementary population boundary detection, but also can be effectively used for identification of borders and sizes of population as naturalistic unit.
Multigcnctic landscape is a collection of different genetic systems which arc specific to the region and ethnic groups, which have their geographical areas, their geographical, historical and cultural boundaries. Gene flows arc run through these conventional boundaries, but they arc less intense than in the limits of area. These limits arc ambiguous and fluid, but it is real. You can identify them by studying, for example, the structure of marriage migration. Therefore anthropogenesis of different populations will inevitably differ from each other. Ethnogenetic composition tends to change over time, from generation to generation, and hence there is a need to understand the structure of the genepool, not only at a given time, but also in the study of genetic processes that form and reform the gcncpooL In this regard, the studying of multigcnctic landscapes is in close contact with the demographics, medical and genetic ecology, anthropology, ethnology, archeology and history of the peoples, that is, with a range of areas, not only natural, but also the humanities knowleges.
Study of genomic diversity is important not only to address questions of origin and genetic history of different ethnic groups, but is also the basis for molecular epidemiology of hereditary and multifactor diseases. Each region is characterized by a specific set of common genetically determined diseases. To understand the causes of the prevalence of disease in different regions, and to develop approaches to their early DNA diagnosis and effective prevention, initially it is necessary to conduct population-based studies, which determine the development of the disease.
Purpose of research is to implement a comprehensive description of the structure of indigenous Central Asian populations genetic pool, examine demographic, phylogenetic and evolutionary features of Central Asian populations through the analysis of genetic variety of mtDNA, Y-chromosomal (NRY), autosomal, X-chromosomal microsatcllites and immunogcnetic variants of Helicobacter pylori (H.pylori) and hepatitis В virus (HB V).
To achieve this goal the following tasks of research is solved:
specification of immunogcnetic variants of H.pylori and HBV, allocated at the patients in Central Asian region, with the subsequent comparative phylogenetic analysis of H.pylori and HBV regional versions with those in other regions of the world;
examination of genetic variety and degree of genetic differentiation of Central Asian populations according to classical population-genetic objects -polymorphisms of mtDNA, Y-chromosomal, autosomal and X- chromosomal STRs;
assessment of the Western and East-Eurasian lines of population inheritance contribution to Central Asian populations’ genetic pool at regional, ethnic, sub-cthnic levels and in a level of elementary populations;
reviewing of character of regional populations relationships by genetic variety of mtDNA, autosomal, X-chromosomal, Y-chromosomal STRs markers in view of ethnographic, social and linguistic data;
evaluation of sex-specific genetic structure and the social organization according to polymorphisms of mtDNA, autosomal, X-chromosomal, Y-chromosomal markers in the region;
determination of ancient ways of migrations and scripts of formation of Central Asian populations according to mtDNA, autosomal, X-chromosomal, Y-chromosomal STRs markers and immunogcnetic variants of H.pylori and HBV',
evaluation of ethnogenetic position of studied Central Asian populations in the system of genetic pools of Eurasia and the world in general through comparative analysis of all studied population-genetic parameters.
Scientific novelty of dissertational research consists in the following:
for the first time was performed a study of genetic pool structure of 26 Central Asian populations from 6 ethnic groups as complete population systems using a wide range of genetic objects;
for the first time was made an assessment of informativeness of each type of genetic subjects. For the first time was received detailed characteristic of genetic pool structure of indigenous Central Asian population on the basis of variability lines of the spectrum of genetical objects;
for the first time was defined the ratio of Westem-and the East-Eurasian lines in a genepool of Central Asian population and were made an assessments of genetic variety level and genetic differentiation degree of regional populations as a whole;
for the first time phylogenetic analysis of major haplogroups of investigated genetic subjects was conducted;
for the first time the position of Central Asian population in population genetic pool system of surrounding regions and Eurasia in the whole was studied;
for the first time the evolutionary-adaptable mechanisms, necessary in the forecast of formations of multigenic pathologies in region were studied at 6 ethnoses of Central Asian.
CONCLUSION
1. H.pylori from Central Asian territory is similar to Western Europe isolates, and shaped by two ancestral populations genotype Ancestral Europe 1 (dominant) and Ancestral Europe2 and for AE1-genotype Central Asian region probably is the source. H.pylori from the territory of Central Asia form a separate cluster group: close relationship of Tadjik, Uzbek strains and Iranian isolates from the north of Iran is established. Kirghiz isolates were found to be closer to populations from territory of Siberia.
2. High diversity of HBV genotypes in Central Asia was found -4 genotypes (A, C, D, and G). Phylogenetic analysis of Central Asian genotype HBV-with options for other regions of the world showed a close relationship between the dominant genotype D (0,78), the D1-subtype with variants of the virus in Europe, the Middle East and Africa.
3. The rates of genetic affinity for STR-NRY in Kazakhs, Turkmens, Karakalpaks Turtkul at the level of the same lineage were high: 0,58 (p<0,001); 0,34 (p<0,01) and 0,77 (p<0,001), respectively. The coefficients of relationship at the level of clan for Kazakhs, Turkmens, Uzbeks and Karakalpaks from Kungrad and Turtkul were lower: 0,30 (r<0,01); 0,21 (p<0,001) and 0,40 (r<0,001); 0,07 (p<0,05) and 0,09 (p<0,05), respectively. At the level of the tribe, the indicators were negative for all Turkic populations: -0,02 (r<0,05);-0,04 (r<0,001);-0,07 (p<0,01); -0,0011 (r<0,1) and -0,10 (r<0,01), respectively.
4. The analysis of mtDNA HVS-1 showed that total rate of differentiation level for all populations was low: FST=0,013; p<0,0001. Level of diversity between groups was 0,6% (p<0,001) of the total variability. Parameter of genetic differences between Turkic and Indo-Iranian populations made 0,55% (p<0,0283) of the total genetic variability. The rate of genetic differentiation on a sub-ethnic level was significantly expressed in Indo-Iranian group (FST=0,0197;r<0,001) than among the Turkic-speaking (0,3%; p=0,10). In all populations, in general, wasn‟t detected the correlation between genetic and geographic distances at the global level on mtDNA HVS-1: r=0,00682; p=0,502.
5. Analysis of STR-NRY showed that the level of the genetic differentiation between ethnic groups was 5,6% (p<0,02); general differentiation between populations made RST=0,186 (p<0,001). Combined analysis, taking into account the language and way of life of Turkic and Indo Iranian populations, showed the general differences between the two groups – 9,1% Value of genetic differentiation when comparing the ethnos-ethnos was slightly lower than the level within ethnos: 5,6% among ethnic groups, 18,6%, and 13,7%-between populations within the ethnic group.
6. Analysis of heterozygosity (H) and the average number of pairwise differences (p) of mtDNA, were high in nomadic populations (av.H=0,99; av.p=5,29) and farmer populations (av.H=0,99; av.p=5,32). Heterozygosity (H) on Y- chromosome was lower in nomadic groups than in the agrarian – 0,86 and 0,99,respectively (p<0,01). Nomadic populations exhibit a higher level of population differentiation (RST) in comparison with farmers - 0,19 and 0,06, respectively (p<0,01). Indicators of population growth (r) were lower in nomadic populations compared with farmers - 1,004 and 1,008, respectively (p=0,056).
7. The level of genetic differentiation in all ethnic groups was higher on the Y chromosome in comparison with mtDNA. The farming populations showed no significant difference in the genetic differentiation FST (Y)=0,069 and FST (mtDNA)=0,034, while among patrilineal nomadic population the level of genetic diversity was higher in the male line of inheritance - FST(Y)=0,177 and FST (mtDNA)=0,010. Genetic diversity of population structure in patrilineal nomads on autosomal and X-linked markers were: FST (A)=0,008 (0,006-0,010) and FST (X)=0,011 (0,001-0,004) (H0: FST(A)=FST(X); H1: FST(A)>FST(X); p=0,02). In bilinear farmer populations the differences of autosomal and X-chromosomal markers were insignificant: FST (A)=0,014 (0,012-0,016) and FST (X)=0,013 (0,008-0,018 at p=0,36).
8. Analysis of mtDNA indicated that the age of expansion on the territory of Eurasia (τw) declined significantly from East to West (r=0,72; p<0,001). The age of expansion had a pronounced tendency to decrease from 30 thousand years in China to 17 thousand years in Western Europe. Age of expansion in Central Asia amounted to 26 thousand years. Results of expansion analysis on NRY also show a decrease in genetic diversity from the East to the West of Eurasia (r=0,49; p<0,001). In Central Asia this age was 16 thousand yrs. According STRs-NRYBatwing analysis of the minimal age of Uzbek population origin was 1232,71 yrs old (Ne=14088 (6765-23942); α=0,0108 (0,0065-0,0155)).
9. The apportionment of multilocus genetic variations among ethnic and linguistic groups of Central Asian populations showed that more than 98% of all variations were within the population (p<0,0001). Evaluation of the ethnic and linguistic affiliations in the observed variations showed reliable conformity - FST=0,007; p<0,0001 and FST=0,011; p<0,0001, respectively. We didn‟t find evidence of geographical isolation within each of the Turkic and Indo Iranian groups of populations (p=0,363 and p=0,772, respectively).
10. Analysis of multilocus allelic diversity (AR) and heterozygosity (He) showed differences among the Central Asian and other populations in allelic variety (χ2 =105,29; d.f.=25; p<0,0001) and heterozygosity (χ2=67,98; d.f.=25; p<0,0001). Population differentiation at multilocus analysis at populations of Central Asia is more pronounced than in the other regions of Eurasia: in European and Middle Eastern groups pairwise estimation of FST ranged from 0,011 to 0,015 and -0,008-0,021, respectively; in East-Asian groups from -0,011 to 0,046; and finally, in Central Asia these rates ranged from -0,004 to 0,056. Heterozygosity was significantly higher in the group of the Indo-Iranian populations than among Turkic-speaking (He=0,818 and He=0,787, respectively; Z=-4, 55; p<0,0001). According to multilocus analysis all 26 Central Asian populations slightly but significantly differed (FST=0,015; CI99%=0,011-0,018; p<0,01).
Our results confirm the hypothesis that the presence of an unfavorable genotypic variant of the IL4 gene can lead to a violation of the synthesis (expression) of anti-inflammatory cytokines-interleukins, a decrease in the body's resistance to infectious diseases, and an increase in the risk of developing CPRS. In addition, these data emphasize the prognostic significance of the C/C genotype of the IL4 gene polymorphism in the development of CPRS. The relative risk of developing CPRS in carriers of these genotypes is more than 3 times higher than in carriers of other genotypic variants of IL4 gene polymorphism.
Currently, the number of patients with gallstone disease (GD) and metabolic syndrome (MS) is growing every year, and there is a "rejuvenation" of these diseases. This is all the more important that convincing data are given that MS is not only the risk factor of the manifestation of the GD, but also its complicated flow. GD and MS remain contradictory, despite the well-studied mechanism.
Розацеа – это хроническое воспалительное заболевание кожи не установленной этиологии. Заболевание характеризуется рецидивирующей гиперемией, эритемой, папулами, телеангиэктазиями, отеком, пустулами или сочетанием этих симптомов. Патофизиология розацеа до конца не изучена, но наследственность, иммунная дисрегуляция, инвазия микроорганизмов, хроническое воспаление, сосудистая гиперреактивность и другие факторы окружающей среды играют важную роль в развитии заболевания. Все большую роль в возникновении и развитии розацеа в последние годы отводят генетическому фактору.
Early diagnosis of Myeloproliferative diseases (MPD) is one of the serious problems of oncohematological practice. MPD efers to multifactorial diseases, the development of which is influenced by both environmental factors and genetic predisposition. The study studied the association of the carriage of the genotype for the polymorphic marker encoding glycoprotein-P and the development of MPD. The homozygous T / T genotype of the rs1045642 polymorphism of the MDR1 gene is a significant determinant of the increased risk of developing MPD in Uzbekistan (P<0.05). Conclusion. Genotype association the rs1045642 polymorphism of the MDR1 gene is associated with the risk of developing MPD.
The new legislation in the field of environment law, relating to the issues protecting natural environment and using natural resources that will serve the further development in the next ten years o will be held in the following areas: Firstly, the legal circumstances of genetic engineering issues in the field of environment, secondly the energy efficiency (solar, wind, water, heat energy) and the environmental protection issues, thirdly development of ecological tourism activities in the priorities of attracting foreign and internal investment resources and technologies. Fourthly, the use of trans-boundary waters, along with transboundary waste issues.
Gormonlar hujayraning genetik apparatini stimullash, fermentlarni faollashtirish va fermentativ reaksiyalar tezligini oʻzgartirish yoʻli bilan moddalar almashinuviga taʼsir koʻrsatadi. Ular oqsilning tuzilishini belgilab beradigan informatsion ribonuklein kislotasining hosil boʻlishini kuchaytirib, oqsillar biosinteziga taʼsir etadi. Shunday xususiyatga ega somatotropin gormoni (STG)-191 ta aminokislotadan tashkil topgan peptid tabiatli gormon bo'lib, gipofizning oldingi bo'lagidan sekretsiya bo'ladi. Bu gormon yetishmasligi gipofizar past bo'ylikka olib keladi. Yаqin kelаjаkdа rekоmbinаnt somatotropingа bо’lgаn tаlаb оshish ehtimoli mavjud. Chunki, hоzirgi ishlаb chiqаrish texnоlоgiyаlаri ishlаb chiqаrish quvvаtlаrining cheklаngаnligi vа ishlаb chiqаrish nаrxining yuqоriligi sаbаbli аrzоn somatotropinga bо’lgаn tаlаbni qоndirа оlmаydi. Natijada, terаpevtik rekоmbinаnt оqsillаrni ishlаb chiqаrish mexаnizmlаrini о`rgаnishni tаlаb qilаdi. Rekоmbinаnt somatotropin аsоsаn E. cоlining lemo shtammi yоrdаmidа sintez qilingan bo’lib, terаpevtik bosqichlarni amalga oshirishda fоydаlаnish uchun qо’llаnilаdi.
Бронхиальная астма - это заболевание дыхательных путей, вызывающее их отек и сужение; что приводит к свистящему дыханию, одышке, стеснению в груди и кашлю. Воздействие бронхиальной астмы на детей зависит от сложного взаимодействия между тяжестью заболевания, реакцией детей на заболевание, эффективностью лечения, социальными ролями и социальным окружением. Наиболее распространенными триггерами бронхиальной астмы являются пыль, перхоть животных, погодные изменения, загрязнение окружающей среды, плесень, пыльца, респираторные инфекции, стресс и табачный дым. Основными патофизиологическими характеристиками астмы являются воспаление и ремоделирование дыхательных путей, которые включают гиперплазию бокаловидных клеток, субэпителиальный фиброз, отложение коллагена, слизистую железу, гиперплазию, гипертрофию гладких мышц и изменения во внеклеточном матриксе.