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Sulfonylureas are widely prescribed all over the world, mainly because of their high effectiveness. At the same time, the heterogeneity of the group is obvious, primarily in relation to the effect of drugs on the risk of developing hypoglycemic events. The review presents the results of new studies, including «Comparative effectiveness of gliclazide modified release versus sitagliptin as second-line treatment after metformin monotherapy in patients with uncontrolled type 2 diabetes» and results of a model-based meta-analysis of 24 antihyperglycemic drugs for type 2 diabetes, confirming the higher efficacy of modified release gliclazide (gliclazide MB) compared to DPP-4, as well as a low risk of hypoglycemic conditions. The results of recent studies, as well as the results of the ADVANCE and ADVANCE-ON studies, suggest that gliclazide MB is safe to use as a second-line drug, especially in patients with chronic kidney disease.

Aim. To study the content of cytokines in the blood serum of patients with obstructive jaundice of gallstone origin before and after surgical treatment, depending on the development of postoperative complications.Materials and methods. The treatment group consisted of 70 patients with the diagnosis of obstructive jaundice of gallstone origin, verified following a comprehensive clinical and instrumental examination. In 54 patients, the postoperative period was uncomplicated, and in 16 patients, various infectious complications in the postoperative period were revealed. The control group consisted of 125 healthy volunteers. The concentration of six cytokines (interleukin (IL)-2, IL-4, IL-18, IL-10, tumor necrosis factor alpha (TNFα), and interferon gamma (INF γ)) was determined using reagent kits manufactured by Vector-Best LLC (Novosibirsk, Russian Federation) by enzyme-linked immunosorbent assay on the Thermo Scientific analyzer (BioMerieux, France).Results. We identified significantly high concentrations of proinflammatory cytokines in the blood serum of patients with obstructive jaundice of gallstone origin upon admission, compared with the data obtained in the study of blood serum in the control group and in patients with obstructive jaundice after surgery. In the postoperative period in patients with obstructive jaundice without complications, the proinflammatory cytokines are significantly reduced and IL-4 is increased, whereas with the development of infectious complications, the level of proinflammatory cytokines is significantly elevated.Conclusion. In the pathogenesis of obstructive jaundice, a local inflammatory process plays an essential role. This is confirmed by statistically significant changes in the studied cytokines. The established increase in the concentration of IL-4, which has anti-inflammatory activity, indicates its importance in the mechanisms underlying the absence of infectious complications in the postoperative period of obstructive jaundice of gallstone origin. The revealed increase in the levels of IL-18, TNFα, and INFγ in the blood serum of patients suggests their role in the pathogenesis of infectious complications in the postoperative period of obstructive jaundice of gallstone origin.

Aim. A study of monocyte chemiluminescent activity at variant stages of gastric cancer.Materials and methods. The study enrolled 90 gastric cancer patients and 70 healthy donors. Spontaneous and induced chemiluminescence in monocytes was assessed for 90 min with a “BLM 3607” 36-channel chemiluminescence analyser (Russia). Opsonized zymosan-induced chemiluminescence enhancement was measured as a ratio of the areas under the induced vs. spontaneous chemiluminescence curves, the activation index. Statistical significance was estimated with the Mann—Whitney criterion (p < 0.05).Results. The maximal spontaneous monocyte chemiluminescence intensity significantly decreased in stage IV gastric cancer patients compared to the control cohort (p = 0.035). Time to maximum in spontaneous chemiluminescence increased in all gastric cancer patients vs. control (p = 0.001), and in stage IV gastric cancer vs. stage I patients (p = 0.043). The areas under a curve in spontaneous and induced monocyte chemiluminescence increased in all gastric cancer patients vs. control (p = 0.001), and in stage IV gastric cancer vs. stage I patients (p = 0.037). The activation index was higher in all gastric cancer cases compared to control (p = 0.001).Conclusion. All patients with gastric adenocarcinoma, irrespective of the stage, revealed changes in the monocyte chemiluminescence activity, i.e. a longer time to maximum in spontaneous chemiluminescence and larger area under the curve of spontaneous and induced chemiluminescence, the activation index. Maximal monocyte spontaneous chemiluminescence intensity diminished in stage IV gastric cancer compared to the control cohort. Immune activity reflected in monocyte chemiluminescence correlates with the stage of gastric adenocarcinoma.

Chronic atrophic gastritis and gastric cancer represent distinct steps of one pathogenic process. The risk of developing cancer of the stomach is directly proportional to the degree of atrophic changes simultaneously detected in antral segment and in the body of the stomach. The role of immune system in transformation of precancerous diseases into cancer is beyond doubt. During development of the malignant disease, the changes in lipid peroxidation systems – antioxidant defense become significant and contribute to the progression of the tumor and the development of metastases. A simultaneous study of lipid peroxidation and antioxidant defense indices along with phagocytic activity will allow us to evaluate relative contribution of these processes to development of chronic atrophic gastritis and gastric cancer. Purpose of the present study was to assess correlations between the lipid peroxidation indices, i.e. antioxidant protection, and chemiluminescent activity of neutrophilic granulocytes and monocytes in chronic atrophic gastritis and gastric cancer. Forty patients with chronic gastritis, 22 patients with chronic atrophic gastritis and 40 patients with gastric cancer were examined. The control group consisted of 50 practically healthy age-matched volunteers. Evaluation of spontaneous and induced production of reactive oxygen species by neutrophils and monocytes was carried out by chemiluminescent analysis. The parameters of lipid peroxidation/ antioxidant protection were determined by spectrophotometric methods. Statistical data processing was carried out using the Statistica v. 8.0 program (StatSoft Inc., USA). The normal distribution of indices was tested using the Kolmogorov–Smirnov method (adjusted by Lillefors). Quantitative indicators, given the normal distribution, were described using the median (Me) and interquartile scatter (Q0.25-Q0.75). To study statistical significance of differences between quantitative characteristics, the Mann–Whitney test was used. To study strength of relationships of these indicators, the Pearson rank correlation coefficient (r) was calculated. The critical significance level (p) when testing statistical hypotheses was taken equal to 0.05. Correlation analysis showed that the weight of positive correlations increases in patients with chronic atrophic gastritis, and it decreases in patients with gastric cancer, the strength of the correlation dependence and new relationships appear between chemiluminescent activity of neutrophils and monocytes in a spontaneous and induced state, and the amounts of malonic dialdehyde, enzyme activities of superoxide dismutase and catalase. In chronic atrophic gastritis and gastric cancer we have established the features of correlation patterns between lipid peroxidation/antioxidant protection indices, and activity of neutrophils and monocytes.

We analyzed the expression of molecular targets of natriuretic action of prolactin in different layers of the kidney in the rat model of cholestasis of pregnancy. Sodium bicarbonate cotransporter NBCe1 was most sensitive to the conditions of cholestasis and cholestasis of pregnancy: the expression NBCe1 mRNA and protein in the renal outer medulla decreased in comparison with the normal. All forms of cholestasis affected the mRNA expression of sodium-potassium chloride co-transporter NCC, α-subunit of the ENaCα epithelial sodium channel, and Nedd4-2 ubiquitin ligase in different layers of the kidney. The obtained data suggest that prolactin provides fine tuning of various sodium transporters in different parts of the nephron under pathological conditions.

Objective: comparative evaluation of treatment methods for neoadjuvant intra-arterial chemotherapy and chemoembolization by drug-saturated microspheres followed by surgical treatment in II–IVa stages cervical cancer.Materials and methods. This study presents the results of complex treatment in 209 patients (average age – 40.57 ± 8 years) with II– IVa stages cervical cancer and 384 endovascular interventions as the first stage of complex treatment in the period from 2010 to 2016. The scheme neoadjuvant intra-arterial chemotherapy was carboplatin (AUC6 intra-arterial) + irinotecan (200 mg/m2 intravenously on day 1) every 21 days. Radical surgical treatment was performed basically after 2 cycles of chemotherapy. Patients who did not respond sufficiently to neoadjuvant intra-arterial chemotherapy underwent a radical course of chemoradiation therapy according to the standard scheme.Results. The overall response to neoadjuvant intra-arterial chemotherapy was 84.8 % and 79 % of patients in groups of chemoinfusion and trans-arterial chemoembolization, respectively (p >0.05). Operability was higher in group of chemoinfusion (69 % versus 46.4 %) (p Conclusions. Neoadjuvant intra-arterial chemoinfusion and chemoembolization using irinotecan + carboplatin scheme are relatively safe treatment methods with acceptable toxicity and have a high cytotoxic effect. Patients in chemoinfusion group have a better prognosis compared with patients in chemoembolization group. Selective chemoembolization with subsequent surgical treatment or radiation therapy may be the treatment of choice for stage II cervical cancer complicated by bleeding.

Objective:to assess the efficacy of dose-intensive platinum-containing neoadjuvant chemotherapy in patients with FIGO stage IB2–IIB locally advanced cervical cancer.Materials and methods.We evaluated the efficacy and toxicity of 3 cycles of intravenous dose-intensive neoadjuvant chemotherapy with either AP regimen (cisplatin 75 mg/m2 and doxorubicin 35 mg/m2) or TP regimen (cisplatin 60 mg/m2 and paclitaxel 60 mg/m2).Results.The study included 105 patients (75 in the AP group and 30 in the TP group) aged between 27 and 63 years (mean age 44 years) with primary verified cervical cancer (T1–2B0–2Nx–0M0). Surgery was performed in 66 patients (88 %) from the AP group and 24 patients (80 %) from the TP group. Six patients (8 %) receiving AP regimen and 1 patient (3.3 %) receiving TP regimen developed disease progression. Four women (2.8 %) from the AP group developed relapses, whereas none of the patients from the TP group had relapses. Dose-intensive chemotherapy did not cause any significant complications at both chemotherapeutic and surgical stages. Our findings suggest that dose-intensive neoadjuvant chemotherapy is an effective method with an objective response rate of 84 % (63 cases) and 56.7 % (17 cases) in groups AP and TP respectively. Fifty-nine patients (78.7 %) receiving AP regimen had pathological response; of them, 7 participants (9.4 %) demonstrated pathological complete response (ypCR). In the TP group, 19 patients (63.3 %) had pathological response and 4 patients (13.4 %) had pathological complete response. Median follow-up time was 16.7 months (range: 3–29 months) in the AP group and 9.1 months (range: 2.8–12.7 months) in the TP group.Conclusion.Dose-intensive neoadjuvant chemotherapy can be considered as an alternative to standard treatment of locally advanced cervical cancer; however, further studies are needed due to the small sample size in this study.

Colorectal cancer is one of the most common malignant diseases in Russia worldwide making up 5-6% of all human malignant tumors. Neutrophilic granulocytes are actively involved in development of antitumor response. A key role in tumor regression is assigned to active forms of oxygen produced by neutrophils. In connection with these pre-requisites, our goal was to study functional characteristics of spontaneous and induced chemiluminescent activity of neutrophil granulocytes in patients with rectal cancer before starting pathogenetic therapy and in subsequent dynamics. The paper presents some laboratory results, i.e., functional indices of neutrophilic granulocytes’ activity in 36 patients with rectal cancer being at different stages of oncological process. The control group consisted of 112 practically healthy volunteers, comparable in sex and age to the group of patients under study. To perform the study venous blood was taken from patients to vacuum test tubes with lithium heparin in the morning time before surgical treatment, and on day 7 after the surgical intervention. Evaluation of spontaneous and induced chemiluminescence was performed for 90 minutes in a 36-channel “CL 3606” chemiluminescence analyzer (Russia). The following characteristics were determined: time of the curve transition to maximal chemiluminescence intensity (Tmax), maximal value of chemiluminescence intensity (Imax), integral area under the chemiluminescence curve (S). Luminol was used as the chemiluminescence enhancer. Opsonized zymosan was used to induce the respiratory explosion. Chemiluminescence amplification induced by opsonized zymosan was evaluated by the ratio of induced-tospontaneous chemiluminescence (Sind/spont) designated as an activation index.Analysis of chemiluminescence activity in neutrophilic granulocytes showed a significant increase in spontaneous chemiluminescence activity at the stages III and IV of the disease. The production of active oxygen forms induced in neutrophilic granulocytes by opsonized zymosan increased in all the study groups, relative to control parameters. The area under the curves of spontaneous and induced chemiluminescence in patients with colorectal cancer at all stages of the oncological process is less, as compared to the control group, which, despite high indices of maximal chemiluminescence activity, may indicate insufficient total production of reactive oxygen species. The time-to-peak values of the chemiluminescence curves in patients with rectal cancer at all stages of the disease did not show statistically significant differences from the control group.

Mechanical jaundice (MJ) of malignant genesis is a clinical syndrome caused by obturation of bile ducts due to malignant tumor growth. It is characterized by specific pigmentation of skin, mucous membranes and sclerae due to increased accumulation of bilirubin in blood serum and other fluids and tissues of the organism. Various immune disorders are detected in patients with mechanical jaundice. Immune reactivity in mechanical jaundice is affected by toxic, infectious, or tumor factors. In connection with these findings, the aim of our study was to measure levels of some pro-inflammatory (IL-2, IL-18, TNFα, IFNγ) and antiinflammatory (IL-4 IL-10) cytokines in patients with malignant disease, depending on serum bilirubin levels. The study included 50 patients with MJ by malignant origin. A control group consisted of 125 practically healthy volunteers comparable with the study group by sex and age. Blood serum cytokine contents in patients and controls was determined by enzyme immunoassay using reagent kits produced by ZAO Vector-Best. Statistical evaluation of data was carried out by means of Statistica for Windows 8.0 and Microsoft Excel software. The levels of IL-2, TNFα, IFNγ and IL-18 were increased before surgery in the patients with mechanical jaundice of malignant genesis, while IL-4 and IL-10 values were reduced in comparison with healthy controls. Altered cytokine regulation in the MJ group manifests as increase in proinflammatory and immunostimulatory cytokine levels, along with decrease in anti-inflammatory cytokine amounts. Predominant feature of immune response may be regarded as prevalence of Th1-immune response when taking into account cytokine levels in blood serum of patients with MJ of malignant genesis. The features of cytokine regulation of patients with malignant MJ depend on the bilirubin content in blood serum. These changes were most frequent in patients with bilirubin level exceeding 60 μmol/L. In general, the quantitative indices of cytokines exhibited unidirectional changes in the groups of MJ patients with different bilirubin levels, except of IL-10. This parameter showed almost 6-fold increase in MJ patients with bilirubin level < 60 μmol/L against control group, and approximately 40 times with respect to the remaining 2 groups. This biological effect may occur due to malignant etiology of the MJ.

In recent years, there has been an increasing interest in myostatin, a hormone that inhibits the growth and differentiation of muscle tissue. This interest is associated with an increase in the amount of data on the spectrum of the myostatin functioning. Myostatin, which has been known since 1997, belongs to the family of transforming growth factor β (TGF-β) and is a paracrine factor of skeletal muscle myocytes. It turned out that myostatin also affects the satellite cells and muscle fibroblasts, and its functions are not only to limit growth, but also to remodel skeletal muscles, which is necessary for muscle adaptation to physical training. Recent studies show that myostatin can play a significant role in musculoskeletal and cardiac cachexias in various pathologies, including cancer. It has been found that myostatin can be produced not only by skeletal muscle cells, but also by adipocytes and cardiomyocytes. It has been shown that, in cardiac pathology, the level of myostatin production increases in cardiac tissue. It is suggested that an increase in the myostatin production in the heart is necessary to prevent myocardial hypertrophy, which develops in some cardiac diseases. In this review, we examined the myostatin functions, as well as aspects of myostatin gene expression, mechanisms of its biosynthesis, its effect on various intracellular targets and transcription factors, and the regulation of its production. The importance of myostatin functions, as well as its involvement in pathological processes, allows us to consider this hormone as a promising target in therapeutic studies.

Aim. To study the oxygen transport function in red blood cells and energy balance in patients suffering from epistaxis of various progress severities. In case of epistaxis a single blood loss is insignificant, yet in case of recurrent epistaxis there is a threat of a tissue hypoxia development. However no indicator blood values demanding transfusion therapy exist these days. This is a study of the blood oxygen transport function and energy balance in the red blood cells in those suffering from single epistaxis, recurrent moderate epistaxis and recurrent severe epistaxis. Materials and methods. In patients’ red blood cells a contents of 2.3-diphosphoglyceric acid (2.3-DFG) and hemoglobin oxygen affinity (Р50) were estimated; energy balance was assessed by the activity of glucose-6-phosphate-dehydrogenase (G-6-FDG), lactate-dehydrogenase (LDG), as well as by the lactate and pyruvate contents in the red blood cells and plasma. Tissue hypoxia severity was assessed by the lactate/pyruvate ratio in blood plasma. Results. It has been determined that in case of single epistaxis the studied parameters do not differ from normal ranges. In case of recurrent epistaxis the level of hemoglobin and P50 goes down, plasma LDG activity goes up, the pyruvate content goes down, while plasma lactate retains within the normal ranges. Conclusion. The stated changes in the carbohydrate metabolism in the red blood cells and blood plasma of patients suffering from severe recurrent epistaxis suggest a breakdown of compensatory mechanisms, which manifests itself in the reduced cell energy reserve and disturbed red blood cell membranes. The obtained data testify that the severity of the state of patients suffering from epistaxis is not only defined by a quantitative loss of red blood cells and hemoglobin, but also by the adaptive capacities of the body, which determine its resistance to hypoxia. The guide link in the pathogenesis of disturbed gas transport function of blood in patients suffering from epistaxis is metabolic acidosis developing as a consequence of tissue hypoxia.

Chronic gastritis is the most common disease of gastro-intestinal tract. Precancerous potential is among most important epidemiological features of chronic gastritis. Immune system plays a distinct role in transformation from precancerous state to malignancy. In this context, the aim of our work was a study of spontaneous and induced chemiluminescence activity of neutrophilic granulocytes in patients with chronic superficial gastritis, chronic atrophic gastritis and gastric cancer. The work presents results of comprehensive laboratory examination of patients with chronic gastritis (CG) (a total of 85 persons. 25 patients with chronic atrophic gastritis (CAG), and 50 patients with gastric cancer (GC) at the age of 19 to 70 years were enrolled. Control group included 115 healthy donors without gastrointestinal complaints at the age of 19 to 67 years. The study was performed with venous blood samples taken from cubital vein into Vacutainer tubes with sodium heparin (5 U/mL) prior to starting any pathogenic treatment. Evaluation of spontaneous and induced chemiluminescence was performed for 90 minutes at a 36-channel “CL 3606” chemiluminescence analyzer (Russia). In our study, patients with gastric cancer showed clear unidirectional changes in chemiluminescent activity of neutrophilic granulocytes (NG). When measuring spontaneous and induced NG chemiluminescence, we diagnosed a decreased phagocytic activity characterized by prolonged time-to-peak and area under the curve for spontaneous and induced CL, thus presuming longer activation time required in cases of reduced phagocytic function. The NG activity in patients with chronic gastritis is not impaired, but, similar changes of time-to-peak and area under were detected. Chemiluminescent activity of NG is increased in the group of CAG patients, and, considering similar changes in activation time and area under the curve, NG also produce greater amount of reactive oxygen species. Thus, for all H.pylori-associated diseases, the blood NG take longer time to activate, whereas their functional activity is not disturbed in CG, enhanced in CAG patients, and reduced in gastric cancer.

Participation of Na+/K+-ATPase in the natriuretic effect of prolactin in a cholestasis of pregnancy model was investigated. The Na+/K+-ATPase activity in rat kidney medulla, where active sodium reabsorption occurs, decreased in the model of cholestasis of pregnancy and other hyperprolactinemia types compared with intact animals. This effect was not connected with the protein level of α1- and β-subunits of Na+/K+-ATPase measured by Western blotting in the kidney medulla. Decrease in Na+/K+-ATPase activity in the kidney cortex was not significant, as well as decrease in the quantity of mRNA and proteins of the α1- and β-subunits of Na+/K+-ATPase. There were no correlations between the Na+/K+-ATPase activity and sodium clearance, although sodium clearance increased significantly in the model of cholestasis of pregnancy and other hyperprolactinemia groups under conditions of stable glomerular filtration rate measured by creatinine clearance. We conclude that the Na+/K+-ATPase is not the only mediator of the natriuretic effect of prolactin in the model of cholestasis of pregnancy.

We studied possible involvement of prolactin in the regulation of bicarbonate biodynamics using female rat model of cholestasis of pregnancy induced by transplantation of the donor pituitary under the renal capsule of a recipient (hyperprolactinemia) and bile duct ligation (cholestasis). The concentration of bicarbonates in the bile and blood, their excretion, clearance, and reabsorption, as well as glomerular filtration rate and excretion of sodium ions were assessed. It was found that the main effect of prolactin was directed to the kidney-regulated pool of bicarbonates and consisted in stimulation of their clearance and inhibition of reabsorption, which led to a decrease in bicarbonate blood concentration. Parallel influence of prolactin on the clearance of bicarbonates and sodium ions was observed.

Cholestasis of pregnancy is a pathology associated with disruptions in the bile flow and dysregulation of salt and water homeostasis. Prolactin is one of the most important regulators of salt and water balance. Changes in the expression of long and short isoforms of the prolactin receptor (PrlR) and mediators of prolactin signaling were studied by immunoblotting and RT-qPCR in the rat kidney cortex and outer medulla in the model of cholestasis of pregnancy. Both PrlR isoforms were shown to participate in the effects of prolactin in cholestasis of pregnancy. Direct impact of prolactin on the kidney has been demonstrated: (i) mRNA expression of both PrlR isoforms in the kidney depended on the physiological conditions and prolactin levels; (ii) expression of pSTAT5, a key mediator of the long PrlR isoform signaling, was increased in animals with cholestasis of pregnancy; (iii) in the case of long PrlR isoform predomination, expression of mRNAs for the prolactin signaling inhibitors SOCS3 and PIAS3 was upregulated (the genes of these regulators contain STAT-responsive elements in their promoters); (iv) expression of the mRNA for galactose-1-phosphate uridyltransferase (GALT), a molecular target of the PrlR short isoform, was decreased in the kidney outer medulla.

The last two decade discoveries shift the accent from consideration of human chorionic gonadotripin (hCG) as a hormone, that controls progesterone production by corpus luteum cells, to a powerful paracrine regulator which'in the tandem with its hyperglycozilated analog (hCG-H) induces successful implantation and coordinated dialog between blastocyst and uterus tissues. Ability of hCG to interact with TSH receptor and hCG-H with TGF-beta-RII extend significantly the spectrum of processes controlled by these molecules. Differences between intracellular pathways of signal transduction between hCG and LH mediated by the same receptor (LH/hCG-R) impugn unity of their effector mechanisms previously considered as obvious. Paracine properties-of hCG comprise control of fusing of trophoblasts into syncytiotrophoblasts, angiogenesis, immunity regulation and endometrium predisposition to implantation. Angiogenesis is associated with LH/hCG-R expressed on mural cells of uterine spiral arteries as well as induced secretion of soluble VEGF type by endometrial cells. hCG.regulates ratio between different forms of T-helper cells in maternal organism on the initial gestation stage determining high level of Th2 cells. hCG supports local immunotolerance acting as chemoattractant for T-suppressors (T-Treg) and apoptotic factor for T-lymphocytes. Endometrial susceptibility arises from activation of osteopantin secretion and decline of mucin secretion by epithelial cells. hCG-H acts on the same tissues as hCG as a paracrine agent regulating multiple cascades of cytokines. hCG-H plays the key role in trophoblast invasion into,uterine decidua as a result of gelatinase secretion by these cells.The degree of angiogenic effect of hCG-H is compatiblewith hCG but its signal transduction is mediated by TGF-beta signal transduction pathway that stimulates mural cell proliferation. hCG-H acts as mitogen on NK-cells and is able to activate them and direct to angiogenesis maintenance. In this article the attempt was made to elucidate the most important discoveries about the role of hCG and its hyperglycosylated analog yet accomplished and still upcoming.

The status of patients with nose bleedings (NB) depends not only on the volume of blood loss, but also on the degree of compensation for hypoxia accompanying hemorrhage. Aim . The main aim of our research was to study the antioxidant properties of blood serum and the intensity of LPO processes in erythrocyte membranes of patients with epistaxis of varying severity. Materials and methods . 82 patients with nose bleeding of varying severity were examined. The antioxidant activity of the blood serum of patients was studied by the chemiluminescence method induced by divalent iron ions. The processes of lipid peroxidation were studied by evaluating the activity of antioxidant defense enzymes – superoxide dismutase (SOD) and total peroxidase activity in blood erythrocytes, as well as the content of the final product of LPO-malonic dialdehyde (MDA) in erythrocytes. Results. It has been established that the potential of antioxidantprotection of serum and formed elements of blood is one of the most important links in the pathogenesis of NB. Conclusion. High capacity of antioxidant protection can significantly reduce the risk of irreversible changes in erythrocytes and the development of clinical signs of deep tissue hypoxia in patients with epistaxis.

Aim. To study changes in the indices of prooxidant and antioxidant systems in plasma in men with atrophic gastritis and gastric cancer. Materials and methods. The study included 60 healthy men, 42 patients with atrophic gastritis and 50 men, nicardipine patients with gastric cancer stage II according to TNM. All patients underwent serological diagnosis of diffuse atrophic gastritis (definition of pepsinogens and gastrin-17) and Helicobacter pylori infection. The diagnosis of "atrophic gastritis" was verified by morphological examination of biopsy specimens obtained during fibroesophagogastroduodenoscopy. Diagnosis of gastric cancer was carried out in the Krasnoyarsk regional oncologic dispensary on the basis of a comprehensive instrumental and morphological examination. All patients spectrophotometric methods in plasma was determined the content of diene conjugates (DC), malonic dialdehyde (MDA), glutathione-S-transferase (GST), glutathione peroxidase (GPO), superoxide dismutase (SOD) and catalase. Results. The concentration of SOD, GST, GPO and catalase had no significant differences in patients with atrophic gastritis and gastric cancer and prevailed in comparison with healthy persons. Patients with cancer of the stomach content in the blood plasma DK 2.7 times and MDA at 35.2 times higher than healthy individuals, indicating severe oxidative stress in patients with cancer. In patients with atrophic gastritis was observed similar but less pronounced pattern. Conclusion. The results indicate the presence of oxidative stress in men with atrophic gastritis and gastric cancer.

Using immunohistochemical method with semiquantitative analysis of images, we showed that mrp2 expression in response to cholestasis decreased in hepatocytes and cholangiocytes, and remained unchanged in the kidney structures. A decrease of mrp2 expression in renal tubules leading to a decrease of metabolic intoxication of the kidney was demonstrated in cholestasis of pregnancy model. In bile ducts cells, negative correlations of mrp2 with previously measured levels of prolactin receptors, CFTR, and mrp3 were revealed. In renal structures and in hepatocytes, no correlations were found between the expression of these proteins. We hypothesize that prolactin produces a direct effect on mrp2 expression in bile ducts cells mediated by prolactin receptors in cholangiocytes. The absence of correlations between mrp2 and the above-mentioned proteins in hepatocytes and renal structures is most likely related to prolactin effects on other systemic regulators.

We showed the data on clinical efficiency of low doses of antibodies to brain-specific protein S100 in the complex therapy of schoolchildren with painful variant of functional dyspepsia syndrome. Significant positive effects of the substance on the dynamics of epigastric pain, in particular, its duration, were found. The maximum clinical effect was observed in children with emotional disorders ( $$ \sim \raisebox{1ex}{$1$}\!\left/ \!\raisebox{-1ex}{$3$}\right. $$ of all examined children). Along with significant decrease in frequency appearance and duration of pain syndrome, the substance also normalized emotional state and improved attention concentration in children.

The safety of therapy of diabetes mellitus with hyperglycemic agents is a challenging problem in modern diabetology extensively discussed in the last years, with the special emphasis being laid on the associated risk of formation and development of various neoplasms. The main forms of cancer known to occur in association with type 2 diabetes mellitus are related to obesity and insulin resistance. It suggests the important role of various factors, besides hyperinsulinism and hyperglycemia, in cancer pathogenesis. The present review is designed to analyse the influence of insulin analogs, sulphonylurea derivatives, metformin, and thiazolidindiones on the risk of malignization in the patients with diabetes mellitus.

Results of comparative study of cryoplasmic therapy applied at complex treatment of 168 patients with disseminated intravascular coagulation syndrome were presented. In 56 patients complex therapy included cryosupernatant plasma (CSNP) and 112 patients received fresh frozen plasma (FFP). Study of coagulation and fibrinolysis system showed that restoration of fibrinolysis activity, physiologic anticoagulants and normalization of plasma fibrinogen levels occurred sooner when CSNP was used. Application of CSNP promoted the relaxation of disease severity, prevention of thrombotic complications and decrease of lethality (by 14.2%) to a greater extent as compared to FFP use.

The contribution of intensive control of glycemia to the reduction of the risk of microvascular complications of type 2 diabetes mellitus is known perfectly well whereas its influence on the development of macrovascular complications remains to be clarified and remains a subject of debates. Bearing in mind that hyperglycemia is a key pathogenetic factor triggering formation of diabetic complications, it is necessary to identify characteristics of carbohydrate metabolism to be taken into account when choosing therapeutic strategies and to determine their target values. Control of the HbA1c level remains the most accessible and informative tool for the assessment of the efficiency of long-term compensation of type 2 diabetes mellitus. However, this method is not altogether free from limitations that can hamper its clinical application. The fasting glycemia level does not completely reflect the quality of DM2 treatment. There is potential relationship between high postprandial plasma glucose levels and the development of vascular complications. Also, it has been shown that variability of glucose concentration may be an important risk factor of diabetic complications. Measurement of the full range of glycemic parameters including fasting plasma glucose level, HbA1c and postprandial glycemia gives an idea of the general picture of the course of the disease necessary for the choice of the treatment strategy.

We measured blood concentration of active and non-active sex steroids, metabolites, and precursors and compared to changes in protein and peptide hormones controlling the reproductive axis (total 14 hormones and hormone-like substances) in male subjects aged 18 to 72 y.o. We found a significant decrease in serum concentration of precursors for active sex steroids (pregnenolone, progesterone, dehydroepiandrosterone, and DHEA-sulfate), free testosterone, androstenedione (non-active metabolite of testosterone) as well as 5α-dihydrotestone after the age of 35. However, the level of total testosterone and estradiol (another active testosterone metabolite) remained steady. The systems regulated production of active sex steroids resisted a higher load associated with age and caused the increase in luteinizing and follicle-stimulating hormones in hypophysis and activin in steroidogenic glands directly correlating with age; negative correlation for these hormones was confirmed with certain sex steroids explaining the negative feedback. Decrease in level of hypopheseal adrenocorticotropic hormone with age demonstrated a more substantial role for adrenal glands compared to that of testicles in reduction of blood concentration of active sex steroids. In general, despite the reduced activity of steroidogenic glands in 60-to 70-year old male subjects the level of testosterone and estradiol remained unchanged due to associated growth of level of luteinizing and follicle-stimulating hypopheseal hormones as well as activin in steroidogenic glands that stimulated biosynthesis of sex steroids. Also androgen effects were inhibited due to the reduced level of free (unbound) testosterone and 5α-dihydrotestone.

The effect of hyperprolactinemia on bile excretion from the liver of female rats was shown to increase significantly during obstructive cholestasis. The observed changes were biphasic: initial increase in bilirubin release of into the bile was followed by its reduction. Under conditions of obstructive cholestasis, hyperprolactinemia had a negative effect on the recovery of bile flow rate during decompression of the duct (up to complete cessation of bile flow).

Experiments on rats revealed sex-related differences in bilirubin concentration in the bile and bile flow rate against the background of obstructive cholestasis. These differences disappeared after gonadectomy. There were no sex-related differences in the rate of bilirubin excretion with the bile after removal of cholestasis, which was attained through different mechanisms in males and females.

Immunohistochemical study revealed overexpression of prolactin receptors in central and peripheral cells of intrahepatic grafts from H27 rat hepatoma without changes in compartmentalization compared to hepatocytes of intact animals. Experiments with gonadectomized animals showed that the hormonal regulation of prolactin receptors in both types of tumor cells does not differ from that in normal liver cells (positive estrogen-dependent regulation and negative androgen-dependent regulation).

Recent studies suggest that progesterone may possess anti-tumorigenic properties. However, a growth-modulatory role of progestins in human cancer cells remains obscure. With the discovery of a new class of membrane progesterone receptors (mPRs) belonging to the progestin and adipoQ receptor gene family, it becomes important to study the effect of this hormone on proliferation of tumor cells that do not express classical nuclear progesterone receptors (nPRs). To identify a cell line expressing high levels of mPRs and lacking nPRs, we examined mRNA levels of nPRs and three forms of mPRs in sixteen human tumor cell lines of different origin. High expression of mPR mRNA has been found in pancreatic adenocarcinoma BxPC3 cells, while nPR mRNA has not been detected in these cells. Western blot analysis confirmed these findings at the protein level. We revealed specific binding of labeled progesterone in these cells with affinity constant similar to that of human mPR expressed in yeast cells. Progesterone at high concentration of 20 μM significantly reduced the mRNA levels of proliferation markers Ki67 and PCNA, as well as of cyclin D1, and increased the mRNA levels of cyclin dependent kinase inhibitors p21 and p27. Progesterone (1 μM and 20 μM) significantly inhibited proliferative activity of BxPC3 cells. These results point to anti-proliferative effects of the progesterone high concentrations on BxPC3 cells and suggest that activation of mPRs may mediate this action. Our data are a starting point for further investigations regarding the application of progesterone in pancreatic cancer.

The presence of prolactin receptor and peculiarities of its isoform expression in bile duct cells (cholangiocytes) differentially isolated from rat liver under different conditions were investigated in the present study. Normal cholangiocytes express prolactin receptor at relatively low level comparable to those of some prolactin-dependent tissues. Long receptor isoform is predominant in cholangiocytes but not in hepatocytes. The prolactin receptor level increases significantly under obstructive cholestasis due to evaluation of long and appearance of short isoforms. In rat cholangiocytes, unlike other tissues, the main positive regulators of prolactin receptor expression are cholestasis-induced factors instead of sex hormone and prolactin levels. Long isoform is predominant and induced primarily by cholestasis-induced factors.

The effects of obstructive cholestasis and sex hormones on the total content of prolactin receptor mRNA and ratio of mRNAs of its short and long isoforms have been studied in rat hepatocytes. Obstructive cholestasis caused insignificant changes in total content of prolactin receptor mRNA, but the proportion of mRNA of the long isoform increased. Comparison of prolactin receptor mRNA levels in gonadectomized and intact animals revealed opposite effects of male and female sex hormones on total mRNA, but both groups of these hormones increased the proportion of prolactin receptor short form mRNA. Changes in ratio of mRNA of receptor isoforms found in rat hepatocytes under obstructive cholestasis did not depend on levels of sex hormones. Obstructive cholestasis and sex hormones are suggested to regulate the content of long and short prolactin receptor isoforms in hepatocytes independently.

Indirect immunoperoxidase assay and computer analysis of photographic images revealed more intensive expression of prolactin receptors in hepatocytes of women compared to men. The intensity of expression was maximum in secondary liver cancer, high in obstructive jaundice of different etiology, and less pronounced in cholelithiasis. The expression of prolactin receptors in cholangiocytes was higher than in hepatocytes and was maximum during obstructive jaundice of different etiology. Cells of secondary tumors were characterized by low expression, while distant hepatocytes most intensively expressed prolactin receptors.

Immunohistochemistry with semi-quantitative analysis of computer images showed that prolactin receptor and cystic fi brosis transmembrane regulator (CFTR) in cholangiocytes of female rats elevated in cholestasis quickly respond to its relief. The effect of hyperprolactinemia on the extent of return of these proteins to baseline was different. Decompression of the bile duct abolishes the negative effect of hyperprolactinemia on CFTR expression and its positive effect on mrp3 expression in the proximal renal tubules. In renal medulla, mrp2 expression decreased when cholestasis was induced against the background of hyperprolactinemia and increases after its removal. Prolactin receptors and CFTR in cholangiocytes are most susceptible to the decrease in bile duct pressure. Changes in the expression of the studied proteins after cholestasis relief are apparently associated with attenuated toxicity of the products removed by the kidneys, which abolishes the effects of prolactin.

Using the technique of immunohistochemistry in combination with cytophotometry, we have studied the effect of periovulatory hyper- and hypoprolactinemia on the expression of prolactin receptors in various cell types of rat ovaries during early estrus. It has been shown that intense specific staining of oocytes is positively controlled by prolactin. The maximal intensity of specific staining was found in cells of the cumulus and the inner layer of granulosa cells in mature follicles; staining intensity gradually diminished towards the outer boundary cell layer. Postovulatory follicles are distinct from those mature follicles in which there was no ovulation in their more intense manifestation of prolactin receptors in cells of the inner layer and cumulus, as well as in increased positive staining (after prolactin administration) only in the granulosa layer cells closest to theca. In follicles which did not ovulate by the time of the early estrus, prolactin administration leads to a proportional growth of specific immunoreactivity in all cell layers of the granulosa. The administration of bromocryptin, an inhibitor of prolactin secretion, leading to a 10-fold decrease in the prolactin level in the blood, results in a twofold decrease in the intensity of specific staining of all cell layers of the granulosa in either type of follicle. Corpora lutea of the previous cycle have irregularly positioned luteocytes with weak and strong specific staining, the intensity of which is not changed in response to prolactin and diminishes slightly after the administration of bromocryptin. We conclude that the most intense changes in the content of prolactin receptors under the conditions of imbalance of this hormone during the periovulatory period are observed in those follicles where the oocyte did not ovulate by the time of early estrus.

Ligation of the common bile duct induced intense nuclear expression of prolactin receptors in hepatocytes of male and female rats. Bromocriptin abolished this effect in female, but not in male rats. In males with ectopic pituitary transplants, nuclear and cytoplasmic manifestations of prolactin receptors in hepatocytes decreased. It is concluded that prolactin exerted a sex-dependent effect on the content of prolactin receptors in hepatocyte nuclei in rats.

Intense expression of prolactin receptors in cholangiocyte nuclei, nuclear membranes, and cytoplasm was demonstrated by the indirect immunoperoxidase method in intact and gonadectomied male and female rats after ligation of the common bile duct. The intensity of staining increased during cholangiocyte proliferative response to the intervention and, in contrast to hepatocytes, did not depend on animal sex and the presence of the gonads.

Peculiarities of cell and tissue distribution of somatotropin receptors in liver cells of male rats and intact, pregnant, and estrogenized female rats is studied using an indirect immunohistochemical method. Experiments reveal equal and positively regulated by female hormones expression of somatotropin receptors in all hepatocytes.

Changes in the expression of prolactin receptors in the liver in response to partial hepatectomy are studied in gonadectomized male and female rats using the indirect immunoperoxidase method. Experiments reveal the rise of prolactin receptor expression only at the early stages of regeneration (15 and 30 min postoperation). Intense expression of prolactin receptors in vesicular hepatocyte membranes coincides with lipid infiltration and high mitotic activity of hepatocytes 35 h after initiation of regeneration.

Immunohistochemistry with semiquantitative image analysis showed that cholestasis induced an increase in the manifestation of mrp3 in cholangiocytes of female rats, but did not affect this parameter in the studied structures of kidney. Under conditions of normal liver function, mrp3 expression in cholangiocytes was also elevated during hyperprolactinemia. Expression of mrp3 in cholangiocytes directly correlated with prolactin receptor expression. In cholestasis, prolactin increased mrp3 manifestation of only in the distal renal tubules. Thus, mrp3 manifestation increases in liver cells, but remains unchanged in kidney cells. The hyperprolactinemia-induced changes in the mrp3 levels and their correlations with prolactin receptor expression were shown to differ in the kidney and liver cells. It was hypothesized that prolactin produced a direct effect on mrp3 expression in cholangiocytes.

Disturbances of the erythrocyte antioxidant system presented by LPO intensifi cation were detected in patients with multiple myeloma. Plasma concentrations of MDA in these patients were close to normal due to effective work of the nonenzymatic antioxidant system. Activities of antioxidant enzymes in the plasma were reduced, while catalase activity was high, and ceruloplasmin content did not differ from the control, this indicating suppression of the enzymatic component of the antioxidant system. In erythrocytes, the level of reduced glutathione was low, especially at stage III of the disease. Changes in SOD and catalase activities were similar to those in the plasma, while activities of glutathione-dependent enzymes were comparable to those in normal human erythrocytes.

In recent years, it has become apparent that autoimmune mechanisms play a leading role in the development of insulin-dependent diabetes mellitus (IDDM). According to modern concepts, IDDM is a classic organ-specific autoimmune disease in which -cells are destroyed by mechanisms mediated by T-lymphocytes and circulating autoantibodies. However, there is experimental evidence that the primary mechanism of damage to the p-cell is the action of cytokines. Thus, the destruction of -cells occurs in two phases: the first - independent of lymphocytes, the initial, the second - mediated by the action of T-lymphocytes. According to the Copenhagen model of the pathogenesis of IDDM, environmental and internal factors (viruses, chemicals, food factors, interleukin-1) trigger the activation of free radical oxidation in -cells. Under the influence of free radicals (O2-, NO), p-cell proteins change their natural properties (denature) and become antigens for their own immune system. The increased sensitivity of the -cell to the action of free radicals is due to the fact that it reduces the activity of antioxidant defense systems (superoxide dismutase, glutathione peroxidase, catalase). "In other words, -cells in IDDM die because they are b-cells." Toxic free radicals of oxygen (O2-) and nitric oxide (NO) cause disturbances in the DNA structure of insulin-producing cells, stimulate the pathological activation of poly (ADP-ribose) synthetase, responsible for DNA replication, which leads to increased utilization of NAD + with subsequent depletion of its reserves in the cell: this causes a decrease in the synthesis of proteins, including proinsulin, and the subsequent death of the -cell.

Expression of prolactin receptors (PR) in the nuclei and plasma membrane of the bile duct cells is demonstrated in 1-45-day-old male and female rats with the use of indirect immunoperoxidase technique. The intensity of PR staining in the bile duct cells is not sex-dependent; it increases from the 1st day till the 45th day and disappears by the 65th day of postnatal ontogeny. The PR-specific staining of hepatocytes also increases during the first 45 days of postnatal life and becomes sex-dependent by the 65th day.

Androgen receptors in the liver of pubertal male rats are identified by an indirect immunoperoxidase method. Hepatocyte nuclei predominate among positively stained structures. The intensity of staining varies from hepatocyte to hepatocyte and does not depend on its position in the liver lobule.

We studied the possibility of prolactin involvement in the regulation of water-salt metabolism in female rats in the model of cholestasis of pregnancy. For simulation of the prolactin level during pregnancy, hyperprolactinemia was simulated by transplantation the pituitary under the renal capsule of the recipient; for modeling cholestasis of pregnancy, a combination of induced hyperprolactinemia and bile duct obstruction was used. Diurnal diuresis, expression of aquaporin 1-4 mRNA in the renal medulla, glomerular filtration rate, and diurnal sodium excretion were evaluated in these models. Diuretic and natriuretic effects of prolactin in the model of cholestasis of pregnancy were demonstrated. These data and the fact that prolactin has no effect on glomerular filtration rate and aquaporin expression suggest that prolactin modulates activity of sodium transporters in the kidney.

Immunohistochemistry with semiquantitative image analysis showed that prolactin receptor in distal renal tubules of female rats is most sensitive to the negative effects of both cholestasis and hyperprolactinemia. The responses of medullary tubules to cholestasis and hyperprolactinemia were less pronounced: decrease and increase in prolactin receptor expression, respectively. Proximal tubules were characterized by stable levels of prolactin receptor expression insensitive to the effects of obstructive cholestasis and hyperprolactinemia. The cholestasis-induced changes in the intensity of prolactin receptor expression were opposite in kidney and liver cells. It is concluded that different parts of the nephron differ by the presence, type, and direction of regulation of prolactin receptor expression in obstructive cholestasis and hyperprolactinemia.

Strong expression of prolactin receptors in sinusoidal domains and cytoplasmic granules of hepatocytes, which is independent of cell location in the hepatic lobule and is positively regulated by estrogens, is revealed in pubertal female rats. In estrogen-treated animals, Prolactin receptors are also exposed in the perinuclear space of some hepatocytes surrounding the central veins. Estrogens regulate the intensity of prolactin receptors expression in hepatocytes, but not the number of cells containing these receptors.