Vol 6, No 1 (2006)

Molecular-genetic technologies play the significant role in solving problems of human infections pathology. Genetic engineering is used for development of vaccines. Recombinant interferons are applied for treatment of chronic virus hepatitis. Genetic diagnostic skill provides the possibility of operative and highly sensitive indication of any infections agent in biological tests and in outdoor environment as well as therapy monitoring. It is advisable to intensify the introduction of genetic diagnostic skill in the practice of RF health care service.

The review concerns recent studies in the problem of avian flu origin and evolution. Epidemic of avian influenza in Siberia led to actuation of the problem of influenza pandemic not only in Russia but in all the world In this connection clear understanding of this problem is in a great demand. It is obviously that now we have not any approaches in prognosis of appearance of influenza viruses in human population. Humanity and medicine remain hostages of this pandemic processes. This article is the attempt of genetic analysis of e mechanisms of fast evolution of pandemic influenza virus strains.

Present work summarizes experiences in our collaboration with various clinics of the Medical University, concerning, mainly, gene diagnostics of infectious pathogens (viruses and poorly cultivable bacteria). Special attention is paid to development and applications of DNA diagnostics of periodontal anaerobic microflora (B. Forsythi, P. Gingivalis, A. Actinomycetemcomitans) that have been tested in a study involving 2000 persons. Percentage of the samples positive for these microbes did sufficiently increase with age, beginning from 6-7 years, and, especially, between 15 and 35 лет, reaching it’s maximum by the age of 65 years.

Studies of common gene variants predisposing for malignant diseases represent an important issue. When studying the frequencies of MMP-1 and MMP-3 promoter variants in the patients with uterine leiomyoma, we have found significant correlations between the 1G allele of MMP-1, rates of myoma growth and presence of adenomyosis. Hence, it was shown that MMP-1 genotype should be taken into account as a prognostic factor for the clinical course of this disease.

Moreover, we have studied some interactions between unfavorable genotype of hepatitis C virus and mRNA expression for chemokines IL-8, MIP-1β и RANTES in the patients with chronic hepatitis. Sufficiently increased amounts of RANTES mRNA were found in plasma of the patients with unfavorable HCV 1b genotype. The article deals with perspectives for studies of gene polymorphisms of cytokines, chemokines and their receptors as prognostic markers of immune response in sepsis, hepatitis C, papillomavirus infections Further validation and development of standardized test systems are necessary for multiple genotyping.

The long-term study had allowed to create new approaches to the diagnostics of occupational lung disorders according to occupational factors; to knew some new pathogenesis mechanisms of the their development, to put complex of the therapy, screening programs, taking to the account type of dust, Concentration of dust and genetic factors. That facts gave opportunity to come to decision of the problem of making the prognosis and prevention of occupational lung diseases, and also treatment and rehabilitation measures had been done.

Goal: Development of consistent organizational system of medical care for women of childbearing age with diagnosed bronchial asthma and approaches for allergic pathology primary prophylactics in their kids

Materials and Methods: Examination and treatment of 250 pregnants with diagnosed BA by pulmonologist and obstetrician. Examination and treatment of 185 kids by neonatologist and pediatrician with conduct of all the procedures on primary prophylactics of allergic diseases. All the mothers passed spirometry and body plethysmography and genetic study GSTT1, GSTM1 with the use of PCR. Obstetrician performed clinical observation, dynamic ultrasound assessment, Doppler scan and haemostasis laboratory assessment. Genetics study had been enrolled for all kids.

Results: All BA pregnants were referred to pulmonologist. Individual curation plan and the system or preventive actions were developed according to the results of comprehensive examination. Complex examination and treatment allow to decrease the frequency of gestosis development, chronic placental insufficiency, potential miscarriage, threatened preterm labor, premature delivery. System of primary prophylaxis of allergic diseases in children, provided during their mother’s pregnancy, led to the elimination of different types of allergens. Estimation of genetic susceptibility to allergic diseases is performed for newborns are undergo, mothers are receiving recommendations on tolerance development and allergens dissociation. Kids are registered with neonatologist and from the age of 1 are switched to pediatrician. Genotypes GSTM1 0/0 and GSTT1 0/0 are risk factors of development of BA.

The data are presented about immunogenetic associations of type 1 Diabetes Mellitus (DM type 1), Graves’ disease (GD) and Hashimoto thyroiditis (HT) with HLA II class genes. Molecular HLA II class typing was performed using polymerase chain reaction method in 65 patients with DM type 1,67 - with GD and 74 -with HT. We have shown the common immunogenetic basis for these organospecific autoimmune endocrine diseases, a predisposing specificity is HLA-DRB1*03 and its interlocus association with DQB1*0201, DQA1*0501. Also, in patients with DM type 1 the following specificities occur more frequently than in healthy population control: DRB1*04, DQB1*0201, DQB1*0302, DQA1*0301. In the group of patients with GD with endocrine ophthalmopathy HLA-DRB1*03 frequency was even higher than in the whole GD group (with and without endocrine ophthalmopathy). Also we have established a range of protective HLA-specificities. The obtained data are of importance for early diagnostics, prognosis of course and development of such widely spread autoimmune endocrine diseases, as GD and HT and, especially DM type 1.

BRCA1 defects are known to be associated with hereditary breast cancer (BC). Here we screened the occurrence of BRCA1 5382insC mutation in 1001 BC patients and 822 non-affected females. BRCA1 5382insC carriership was detected by real-time allele-specific PCR. The utmost frequency of the 5382insC allele was observed in patients with 3 clinical features of hereditary BC (bilaterality, young onset (≤40 years), BC in mother). Unselected monolateral BC contained 3.7% BRCA1 5382insC carriers. The obtained data point at clinical utility of the BRCA1 5382insC genetic testing.

Neural amyotrophies belong to the heterogenous group of genetically determinated diseases of the nervous system. They are manifested by multiple lesions of peripheral nerves and distinguished by a heritability type, distinct clinical polymorphism, rate of symptom augmenting, peculiarities of electromyographic and morphologic changes. In accordance with Dick suggestion (1975), hereditary motosensory neuropathies were subdivided into seven types. Clinical practice shows a great variety of neural amyotrophy forms, and their quantity is likely to be well in excess of seven.

Phenotypic variability of organisms is not solely conditioned by the nucleotide sequence of nuclear genome, but also by traits encoded in mitochondrial DNA and by epigenetic factors. An example of nuclear genome-independent phenotypic variations among close relatives are alterations of energy metabolism transmitted along maternal lineage. Manifestations of epigenetic regulation of nuclear genes' activity are parental imprinting and X chromosome inactivation. Such regulation includes variations in DNA methylation and/or introduction satellite DNA into the regions of nuclear genome under regulation.

Many genes and signaling pathways are known to be involved in cancer initiation and progression. The molecular understanding of these processes is important for effective diagnostic and successful treatment of tumor diseases. The multiple parallel analysis of gene expression (cDNA array) is a powerful tool for simultaneous monitoring of the expression of thousand genes and identifying among them the ones with relevance to tumor. To discover the potential diagnostic and prognostic markers we have performed the expression profiling of more than 200 genes (protein-kinases and phosphatases) for tumor and normal tissues of patients with prostate cancer and renal cell carcinoma. The DUSP9 gene has showen the differential pattern of expression in normal and cancer renal tissues. We have used the semiquantitative RT-PCR to verify date obtained by cDNA array. We analyzed the expression of DUSP9 in 26 paired samples (cancer and adjacent normal kidney tissue). The analysis has confirmed the down-regulation of DUSP9 in tumor tissues The gene inactivation was revealed early in cancer development. DUSP9 codes the dual specificity protein kinase phosphatase 4 (MKP-4). The biological role of MKP-4 and loss of its expression in renal cancer could indicate a tumor suppressor function of this protein. Semiquantitative RT-PCR of other gene, ADFP also has confirmed cDNA array analysis date. The up-regulation was seen in 68% of renal cell carcinomas Thus the genes DUSP9 and ADFP, identified through the cDNA array may be potential candidates for renal cell cancer diagnostic and therapy.

During last years a lot of data have been accumulated concerning the role of single nucleotide polymorphisms (SNP), forming specific alleles of certain genes, in the individual variations of immune reactivity. Genetic functional polymorphisms of the early inflammatory genes, especially that of cytokine genes are responsible for the mode of defense reactions and predisposition to some illness. The aim of this study was to investigate the associations of IL-1 beta gene (IL1B) and IL-1 receptor antagonist gene (IL1RA) polymorphism and compare it to the cytokine production levels in healthy donors and in patients with chronic rhinosinusitis. Genomic DNA was extracted from the peripheral blood of 53 patients and 54 healthy volunteers, IL-1beta and IL-1Ra gene polymorphism was analyzed by polymerase chain reaction (PCR) amplification оf the polymorphic site, followed by site-specific restriction digestion. Two sites were examined: IL-1B (+3953 C>T, intron 5). IL-1RA (86 bp variable tandem repeat, intron 2). IL-1B. IL-1RA and IL-8 levels in supernatants of LPS-stimulated peripheral blood leukocytes were measured using cytokine-specific ELISA. The results showed that there were significant differences in the frequencies of alleles or genotypes of IL-1В and IL-1RA between patients with chronic rhinosinusitis and controls. Combination of normal 1/1 variants of IL-1B and IL-1RA genes was 10 times higher in donors compared to patients with chronic rhinosinusitis (20,2% versus 2,1%. respectively) and combination of IL-1B 1/2 with IL-1RA 2/2 genotypes was nearly 15 times higher in patients (30,1%) than in donors (2,1%). Different combinations of cytokine alleles correlated with the clinical manifestations of rhinosinusitis. Our findings suggest that the IL-1 family gene cluster polymorphism may play a significant role in the pathogenesis of chronic rhinosinusitis probably due to the disregulation in the IL-1 family cytokines production. Nowadays SNP studies are very actual because it can make prognosis for the risk of severe illness development, and from the other hand in advance propose specific individual therapy, including modern immunotherapy.

The paper reviews publications and summarizes results of the self-made researches on the ecogenetic aspects of the long-term human health consequences of the acute and/or persistent exposure with dioxins, and so called individual «Dioxin Pathology». Such consequences and the dioxin pathology were revealed in the South Vietnam among the exposed subpopulations - those, affected by the war defoliants, containing dioxins, during their massive application, or living on the sprayed territory. The mostly studied ecogenetic manifestations and characteristics of the dioxin pathology are presented, as well as some mechanisms of their development.

According to clinical, clinicogenealogical and molecular genetic studies, the conception of two general pathogenic lung cancer types - hereditary and ecological - was proposed and theoretically proved. Malignant lung tumors of hereditary type tend to be more aggressive in comparison with ecological type. They are characterized by high level of invasion to adjacent organs and high metastatic potential, both to lymph nodes and distant organs, mostly owing to multiple metastases. Biological features of hereditary pathological lung cancer type have a great effect on surgical treatment. Patients with disease burdened with hereditary factors have at least 10% less chance to undergo a radical operation. Extended operations are performed more common for this patients than wedge resection. 5 year survival for patients with hereditary type lung cancer is 1,8 times lower than for those with ecological type.

Genesis of surgical sepsis is determined by the whole complex of effects of genetic factors of both pathogenic microorganisms and the host being in a critical state.

As a result of infectious process induction, pathogen-associated molecular pattern (PAMP) forms, which is capable of influencing Toll-like receptors (TLR-4 for Gram-negative bacteria and TLR-2 for Gram-positive bacteria) causing alarm signal in deep intracellular structures. Phagocytic cellular activity of monocytic macrophage link leads to the discharge of inductor molecules of immunogenesis (interleukins) and the systemic inflammatory response (SIRS) into internal environment of the host. Among these the most important are kВ factors (NF kВ), Toll/IL-1 resistance (TIR) etc.

In case of unfavorable tendencies for the host of SIRS development certain factors leading to the lethal outcome become activated in the cytokine cascade, namely TRADD or FADD.

SIRS phenotype depends not only on the relationship between proinflammatory and anti-inflammatory cytokines, but on exogenous or ‘ spontaneous ‘ mutations of host DNA as well. The tendency to SIRS development determines sepsis outcome.