[Obesity and diabetes mellitus].

New literature data and the results of own researches concerning the role of excessive body weight and the development of type 2 diabetes mellitus in humans are presented in the analytical review. Inaccordance with current insights, obesity and type 2 diabetes are considered diseases of inflammatory nature, characterized by systemic chronic low-grade inflammation, where different kinds of cytokines are cardinally involved. Unfavourable life style, i.e. excessive, high-energy, and irrational nutrition--an excessive consumption of animal fats and foods containing the high amount of glucose and starch with an insufficient use of high fiber vegetables, fish and vitamin D, and also sedentary, inactive life style leads to adipocyte hypertrophy and migration of M1 macrophages into the adipose tissue (AT). As a result, there is a low-grade inflammation accompanied by an increased production of proinflammatory cytokines (IL-1, IL-6, TNF-α, etc.), adipokines (leptin, resistin, visfatin etc.) and chemokines (CCL2, CCL5, CCL26 and CX3C). Under the influence of these cytokines, on the one hand, IR "is emerged", and on the other--there is apoptosis of the ß-cells, that should be followed by the occurrence of clinically diagnosed type 2 diabetes. However, there is also the opposite system in humans, protecting the organism from the development of type 2 diabetes, and including an increase in the formation of M2 macrophages and the increased formation of secretion of antidiabetic cytokines (IL-4, IL-10, IL-13, etc.) and adiponectin.

[Hormones of adipose tissue in diabetes mellitus and its complications (review of literature and the authors'own data)].

The contemporary ideas on endocrine function of the adipose tissue and its role in pathogenesis of diabetes mellitus and insulin resistance associated with it and the metabolic syndrome are shown in the review. A change in the life style (excessive and irrational nutrition, insufficient physical loading, psychological disorders) and also the reduction of genetic and immunologic controlling mechanisms contribute to the development of obesity, that is now considered as low-grade inflammation. An increased number of small size adipocytes and macrophages of the adipose tissue begin to secrete an increase number of proinflammatory adipocytokines and chemokines that result in the inflammatory and metabolic stress accompanied by the stimulation of signal pathways, leading to increased insulin requirement, on the one hand, and promoting to the beta-cell death, on the other hand. The role of some adipocytokines such as IL-6, TNF-alpha, leptin, adiponectin, visfatin and resistin was demonstrated in these processes.

[Task-orientated therapy (target-therapy) directed to patients with renal cell carcinoma].

Two main ways playing a cardinal role in the pathogenesis of metastatic renal cell carcinoma (mRCC) have been identified in recent years, they are following: 1) a way of the mutation of a gene suppressor VHL (Van-Hippel-Lindau), stimulating various types of tyrosine-kinases participating in the development of tumors; 2) mTOR way, where ramapycyn plays a leading role, which effect proliferation and angiogenesis of mRCC. This discovery enabled the development of a new generation of highly effective medications for target-therapy of mRCCC--tyrosine-kinases inhibitors (VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha/PDGFR-beta, Raf-kinases, etc.) sunitimab, sorafenib, pazopanib, axitinib, etc. and mTOR inhibitors--everolimus and temsirolimus as well as monoclonal neutralising antibody VEGF (bevasizumab). The review is devoted to the analysis of antitumor activity, patient tolerance and side effect of these preparations in the system therapy of patients with mRCC.

[The level of circulating cytokines and chemokines in the preclinical and early clinical stages of type IA diabetes mellitus development].

AIM: to study the level of circulating proinflammatory (IL-1alpha, IL-1beta, IL-6, alpha-TNF, IFN-gamma) and anti-inflammatory (IL-4, IL-10) cytokines and chemokines (IL-8, IL-16) in preclinical development of type 1A diabetes mellitus (T1DM) in children. SUBJECTS AND METHODS: An examination was made in 450 children who had normal blood glucose levels and a burdened history of positive or negative Langerhans islet autoantibodies (LIAA): IAA, GADA, and 1A-2A over time until the clinical manifestations of DM1 emerged. The levels of the cytokines and chemokines were determined by ELISA and the titer of LIAA was by radioimmunoassay. RESULTS: Long before T1DM was clinically diagnosed, most children with normal blood glucose levels and LIAA had elevated levels of the cytokines IL-1alpha, IL-6, and alpha-TNF and the chemoattractants IL-8 and IL-16 with lower IL-4 concentrations as compared with the similar indices in children without LIAA and controls. After the disease manifested, the magnitude of changes in the indices under study reduced in the majority of children with LIAA, which may suggest that the autoimmune process subsides after destruction of most beta-cells. CONCLUSION: The elevated levels of IL-6, IL-16, alpha-TNF, and the chemokine IL-8 with the lower blood content of the cytokine IL-4 were long before the development of DM1 in children with normal blood glucose level in the presence of LIAA, which should be borne in mind while developing the immune mechanisms specifically directed against block, which participate by means of cytokines in beta-cell destruction, as well as methods for preventing the development of T1DM in subjects with LIAA.

[Circulating interleukin-16 in blood of patients with metabolic syndrome and type 2 diabetes mellitus].

The authors determined interleukin-16 (IL-16) content in blood serum of patients distributed into three groups using an immunoenzymic method (ELISA). The first group consisted of patients with type 2 DM and metabolic syndrome (MS); the second group with type 2 DM and without MS, the third group - with MS and without T2DM. The control group consisted of normoglycemic subjects without MS signs who were distributed into two subgroups: 1) with excessive weight; 2) with normal weight. A significant increase in IL-16 concentration in blood serum was noted in patients with T2DM associated with MS (249,5+/-75,3 pg/ml) versus patients with MS without T2DM (130,5+/-41,2 pg/ml), and versus patients with T2DM without MS (69,5+/-35,6 pg/ml, P<0,05) and without obesity (77,4+/-11,6 pg/ml, P<0,05). This increase correlated with abdomen volume (r=0,4, P<0,05) and triglyceride level (r=0,4, P<0,05).

[The immunity during the pre-clinical period of type I diabetes mellitus].

The purpose of the study was to investigate the condition of immunity (blood lymphocyte immune phenotype and ultrastructure) in healthy children with a family background of type 1 diabetes mellitus (DM 1) having or not having diabetes-associated autoantibodies (DAAB). The subjects of the study were divided into three groups. Group 1 consisted of 90 children with a family background of DM 1 (first line relatives had DM 1), DAAB- (GADA, IA-2A, and IAA) positive or negative; group 2 consisted of 51 children with newly revealed DM 1; group 3 included 45 healthy controls, normoglycemic DAAB-negative children with no family background of DM 1. GADA, IA-2A, and IAA titers were measured using radioimmunoassay. The immune phenotype of lymphocytes (CD3+, CD4+, CDr8, CD20+, and CD56+ cells) were studied using flow cytometry (FACS-analysis); their ultrastructure was studied by means of electron microscopy. The study found a significantly lower total number of T-lymphocytes (CD3+ cells), T-helpers/inductors (CD4+ cells), and natural killer cells (CD56+ cells and large granule-containing lymphocytes) in the DAAB-positive children vs. the DAAB-negative ones and especially the controls. In the DAAB-positive children, electron microscopy found distinct changes in the ultrastructure of CD4+ lymphocytes and large granule-containing lymphocytes (CD56+ cells), which evidences changes in the secretory and cytostatic function. Such changes in the number and ultrastructure of these lymphocyte subpopulations are found in patients with newly revealed DM 1. Thus, immune changes happen in the organism of a healthy person a long time before clinical manifestations of DM 1 develop; these changes reflect a concealed autoimmune process in Langerhans islets. Detection of DAAB plays a significant role not only in studying poorly understood pre-diabetes nature, but also in the development of new, scientifically based methods of its prevention and treatment.

[Discovery of autoantibodies to Langergan's islands of the pancreas is a prominent achievement in the field of forecasting the development and diagnostics of diabetes mellitus in clinics].

The authors have summarized literature data and results of own studies on autoantibodies and beta-cells of Langergan's islands of the pancreas (ICA, GADA, IA-2A and IAA). It may help predicting the development of I type diabetes mellitus even in practically healthy individuals before they present clinically evident disease. The history of the discovery of these autoantibodies, their immunological properties, comparative characteristics, sensibility and specificity and their application in clinical practice to forecast the development of I type diabetes mellitus in different populations of children and adolescents as well as to more exactly carry out differential diagnostics of DM type I and DM type II in difficult cases in adults is presented in the article. Having diabetes-associated autoantibodies as a diagnostic tool allows to diagnose a separate subtype of diabetes mellitus--autoimmune diabetes mellitus of adults (LADA) and it is very important to choose a right way of the treatment.

[The ultrastructure and function of lymphocytes in children with first detected untreated type 1 diabetes mellitus].

Flow cytometry (FACS-analysis), light and electron microscopy, and cytotoxic test were used to study the leukocytic composition, content, ultrastructure, and function of different lymphocytic populations (CD3+, CD4+, CD8+, CD20+, and CD56+ cells) in the blood of 90 children aged 8 to 15 years who had untreated new-onset type 1 diabetes mellitus. A control group consisted of 45 apparently healthy normoglycemic children. The sick children were observed to have a slight, but statistically significant reduction in the relative and absolute blood content of CD3+, CD4+, and CD56+ cells, CD4/CD8 index and particularly large granule-containing lymphocytes (the morpho-logical homologue of natural Idller (NK) cells). Ultrastructurally, CD20+4 cells (lymphocytes containing Gall's bodies) showed the signs of a high functional activity while NK cells (large granule-containing lymphocytes) exhibited a low one, which was confirmed by the decreased cytotoxic activity of these cells determined in vitro. Three-month insulin therapy leading to the restoration of the blood content of glucose and glycosylated hemoglobin fails to normalize the detected changes in the parameters of T- and NK-cell immunity.

[Electron microscopy and ultracytochemistry of lymphocytes containing Gall bodies in the blood of patients with diabetes mellitus, Hodgkin disease and clean-up workers of the Chernobyl Atomic Electric Plant accident]. / Elektronnaia mikroskopiia i ul'tratsitokhimiia limfotsitov, soderzhashchikh tel'tsa Golla, v krovi bol'nykh, stradaiushchikh diabetom, bolezn'iu Khodzhkina, i likvidatorov avarii na ChAES.

Submicroscopic and ultracytochemical changes in lymphocytes containing Gall body complex in the cytoplasm, have been studied in the blood of patients with type 1 and 2 diabetes mellitus, Hodgkin disease, and clean-up workers of the Chernobyl accident. It has been shown that each pathological state was characterized by specific changes in the ultrastructure of Gall body complex, that pointed out its important role in the function of this type of lymphocytes and may be used as an additional cytological criterion in the estimation of T-immunity status.

[Considerable decrease in chemokine interleukin-16 level in blood of children with diabetes mellitus type I diagnosed for the first time]. / O znachitel'nom snizhenii urovnia khemokina interleikina-16 v krovi detei s vpervye vyiavlennym sakharnym diabetom tipa 1.

Considerable decrease in chemokine interleukin-16 level has been detected in blood serum of children with the first diagnosed in life diabetes mellitus type I.

[Effect erythropoietin-beta on parameters of erythropoiesis and immunity in patients with diabetes mellitus complicated with diabetic neuropathy and anemia]. / Vliianie éritropoétina-beta na pokazateli éritropoéza i immuniteta u bol'nykh sakharnym diabetom, oslozhnennym diabeticheskoi nefropatiei i anemiei.

Erythropoiesis indices, number of leucocytes in 1 ml of blood, leukocytic formula, lymphocytes immunophenotype in the patients' blood with diabetes mellitus complicated with diabetic neuropathy and marked normochromal anemia after the treatment with Erythropoietin b have been analyzed in the study. Significant increase in haemoglobin, erythrocytes content, hematocrit indices of peripheral blood has been observed during the treatment. The patients felt better, their quality of life improved, CD3+, CD4+, CD5+ cells and granule-contained lymphocytes content normalized. Serious adverse affects of the medication haven't been observed in the study.

[Electron microscopy and ultracytochemistry of blood lymphocytes containing Gall bodies in healthy individuals]. / Elektronnaia mikroskopiia i ul'tratsitokhimiia limfotsitov, soderzhashchikh tel'tsa Golla, krovi zdorovykh liudei.

The authors have conducted electron microscopic and ultracytochemical studies of blood lymphocytes of healthy individuals containing Gall bodies (GB) which are typical for CD4+ cell subpopulation. It has been established that GB have quite a complex submicroscopic structure and together with its derivates, granules-satellites, as well as mitochondria, microfilaments, rough endoplasmic reticulum canaliculi, and Golgi complex it forms a unique active functional complex. GB show a high activity of acid phosphatase and positive reaction to glycogen. The data obtained suggest the leading role of GB in the production of cytokins and other biologically active substances.

[Content of different cytokines in the blood of healthy children and their siblings who are either.positive or negative for diabetes-associated autoantibodies (GADA, 1A-2A, IAA)]. / Soderzhanie razlichnykh tsitokinov v krovi zdorvykh detei-sibsov, pozitivnykh i negativnykh po nalichiiu diabetassotsirovannykh autoantitel (GADA, 1A-2A, IAA).

Content of different cytokines (IF alpha, TNF alpha, IL-1 alpha, IL-4, IL-6 and IL-10) was examined in the blood serum in two groups of healthy children-siblings with type 1 diabetes mellitus with and without revealed insulin autoantibodies against pancreatic islets (GADA, IA-2A and IAA) by enzyme-like immunosorbent assay (ELISA). In the group of patients with two and more revealed autoantibodies the higher indices in the number of IF alpha, TNF alpha and IL-6, and the decrease in the level of IL-4 comparing with the group of children with negative reaction to diabetes associated autoantibodies were more often observed.

[Biological and therapeutic properties of erythropoietin]. / Biologicheskie i lechebnye svoistva éritropoétina.

In this review the authors present data on biological and medical properties and high therapeutic efficacy of recently produced recombinant drugs of alfa and beta erythropoietin in the treatment of erythropoietin-deficient anaemia in patients with malignancies, diabetes mellitus, and nephropathies of other genesis. The article contains materials of international congresses held in 2001 addressing the above issues besides the newest publications.

[Clinical and immunological studies of the therapeutical effect of cytokines combined with 5-fluorouracil in metastatic kidney cancer]. / Kliniko-immunologicheskoe izuchenie lechebnogo vozdeistviia tsitokinov v sochetanii s 5-ftoruratsilom pri metastaziruiushchem rake pochki.

The authors present the results of a six-year clinicoimmunological study of a therapeutic effect of cytkins combined with 5-fluoruracyl in metastatic renal-cell carcinoma. Two therapeutic regiments have been used: rhIFN-a + 5-FU and rhIL-2 + RHifn-A + 5-FU. In cytokin-sensitive patients, both therapy protocols vrs conventional therapeutic alternatives (cytostatics, hormones, irradiation) have been shown to increase the frequency of achievement of remission by objective scoring and life span of the patients. There was an improvement in patients on having received the complex with IL-2 but a higher therapeutic effect appeared to be accompanied by substantial side effects. Recommendatory measures well-targeted to those patients with metastatic renal-cell carcinoma who are to be placed on cytokinotherapy are presented together with immunological indices to monitor the treatments administered and prognosis.

[Lymphocyte immunophenotype in children with diabetes mellitus type I during long-term insulin therapy]. / Imunofenotyp limfotsytiv krovi ditei, khvorykh na tsukrovyi diabet I typu, v dynamitsi tryvaloï insulinoterapiï.

Indices have been studied for cell-bound immunity in those children with freshly detected type 1 diabetes mellitus (Type 1 DM) who ranged from 8 to 15 years old prior to the onset of insulinization and during its time-related course at month 3, 6, 12, 18 and 24. The control group was 25 essentially healthy children the same age as diabetic children. Prior to insulinization the children demonstrated a significant decrease in the content of T-lymphocytes (CD 3+ cells), with the T-supressors/killers (CD 8+ cells) counts being not different from values in the control group. Relative and absolute number of natural cells-killers (CD 56+ cells) in the blood of children with Type I DM first diagnosed was lower than in healthy subjects. In the time-related course of insulin therapy the CD 3+ cells count had come to be lower than prior to the onset of insulinization. Similar changes were recordable in CD 4+ cells. The content of CD 8+, CD 20+ cells over the period of examination was within the normal range.

Leukemia-associated gene rearrangements in blood mononuclears of subjects in long terms after radiation exposure.

The results of electron microscopy and molecular genetic study of blood mononuclears of 220 clean-up workers after 7-10 years since Chernobyl accident are presented. An increase of lymphocytes with altered ultrastructure of nuclei and membrane has been observed. Structural polymorphism of leukemia associated bcr and rRNA genes has been analyzed using Southern blot hybridization. Allelic polymorphism of bcr gene with allele distribution characteristic of myeloid leukemia and rearrangements of rRNA genes have been revealed in 11,5% of clean-up workers under study.

[Genomic disorders in the mononuclear blood cells of those who worked in the cleanup of the accident at the Chernobyl Atomic Electric Power Station]. / Issledovanie genomnykh narushenii v mononuklearakh krovi likvidatorov avarii na ChAES.

The results of molecular investigations of blood mononuclears from 120 clean-up workers after 7-9 years of Chernobyl accident with the total exposure radiation doses ranging from 5 to 76 cGr are presented. Structural polymorphism of the leukemia associated bcr and ribosomal RNA (rRNA) genes were studied using Southern blot hybridization. Allelic polymorphism of bcr gene with characteristic for leukemia allele distribution was detected in 16.6%. Rearrangements of rRNA genes were observed in 13% of Chernobyl accident clean-up workers.

[Quantitative and cytologic changes in various types of blood leukocytes in liquidators 5-6 years after the accident at the Chernobyl power plant]. / Kolichestvennye i tsitologicheskie izmeneniia razlichnykh vidov leikotsitov krovi u likvidatorov cherez 5-6 let posle avarii na Chernobyl'skoi AES.

Radiation-induced effects were studied in leukocytes from 300 males 5-6 years after the Chernobyl accident. Radiation dose received ranged from 5 to 100 sGy. Leukocyte composition of blood was determined in blood smears stained according to Pappenheim and at flow cytometry on Facs tar laser cell sorter. Compared to controls, the majority of the patients had moderate relative and absolute lymphocytosis, eosinophilia and neutrophilopenia. Nuclear structure was changed more frequently in lymphocytes and neutrophils from the exposed subjects, especially in those who had received large dose. The findings evidence that 5-6 years after radiation accident the exposed subjects develop quantitative and qualitative shifts in leukocytes suggesting probable radiation effects on genetic system of the baseline hemopoietic cells.

[The effect of insulin therapy on the level of natural killer cells of different immunological phenotypes (CD16+, CD56+ and CD57+) in the blood of patients with diabetes mellitus type I]. / Vliianie insulinoterapii na soderzhanie estestvennykh kletok-killerov razlichnogo immunologicheskogo fenotipa (CD16+, CD56+ i CD57+) v krovi bol'nykh sakharnym diabetom I tipa.

Flow cytometry with monoclonal antibody Leu-7 (CD57), Leu-11 (CD56) and Leu-19 (CD56) were used to study the content of different subpopulations of natural killer cells (NK-cells) in the blood of type I diabetes mellitus patients before and after insulin treatment and in healthy people. After a course of insulin therapy most patients showed restoration of the total cell number with antigens on their surface characteristic of NK-cells, especially CD56, that indicates the essential role of hypoinsulin in the depression of the NK-system. At the same time a small group of patients was distinguished who did not show such normalization. This may indicate participation of other mechanisms in the formation of natural immunity failure, in particular, the genetic.