[Central female hypogonadism as a model of premature aging].

Central (hypogonadotropic) hypogonadism in women could also be a cause of persistent amenorrhea and hypoestrogenemia. The aim of this study was to evaluate symptoms of premature aging in women of young age with central hypogonadism. 88 young women (25 [21; 30] y.o.) with central hypogonadism (with isolated hypogonadotropic hypogonadism n=42, and associated with the other types of pituitary insufficiencies n=46), 53 healthy young women (24 [23; 28] y.o.) and 50 healthy postmenopausal women (56 [53; 58] y.o.) were examined. In young women with central hypogonadism frequency of psychoemotional, neurovegetative and urogenital disorders, peripheral sex steroid concentrations, lipid and mineral homeostasis parameters differed significantly from the healthy young women of similar age and were comparable with postmenopausal women of middle/older age. Thus, according to clinical, hormonal and biochemical abnormalities biological age of female patients with central hypogonadism advanced significantly chronological young age and corresponded to middle/older age. The central female hypogonadism is a model of premature aging.

[Diagnostic of oncology diseases by the flexible biomarker].

It is Known that the interest of express diagnostic oncology degasses is growing up every ear. Recently, researchers from different countries proved highly effective studies of exhaled air in the diagnosis of breast cancer, cancer of lung and gastrointestinal tract. The purpose of our study was to identify a biomarker in the air of patients using hrormato-mass-spectrometer. We examined 79 patients. 47 patients with clinically and histologically proven oncology proses (II-IV stage), and 32 patients as a control group--without cancer. Chromatograms were obtaining, which was defining from 50 to 70 individual compounds. The overwhelming majority of cancer patients present organic matter--a biomarker and absent in the healthy group. At this stage of the technical capabilities of the equipment made it possible to carry out only a qualitative determination of this biomarker.

[Value of adhesion molecules for evaluating the efficiency of therapy for ulcerative colitis and Crohn's disease].

AIM: To define the value of adhesion molecules (sVCAM-1 integrin, P-selectin, E-selectin, and L-selectin) for the prediction and evaluation of the efficiency of treatment in patients with ulcerative colitis (UC) and Crohn's disease. SUBJECTS AND METHODS: Twenty-six patients with UC and 14 patients with CD were examined. Of them, 16 patients took infliximab (INF) in a dose of 5 mg/kg of body weight according to the standard scheme; 14 patients received cultured mesenchymal stem stromal cells (MSSCs) in a quantity of 150 x 10(8) cells, and 10 had azathioprine (AZA) 2 mg/kg and glucocorticosteroids (GCS) 1 mg/kg of body weight. Enzyme immunoassay was used to determine the serum concentration of the adhesion molecules (L-selectin, E-selectin, P-selectin, and sVCAM-1 integrin) before and 2 months after treatment. RESULTS: The signs of bowel inflammatory disease activity and the elevated levels of adhesion molecules whose synthesis did not occur under normal conditions remained in the patients receiving GCS and AZA. INF treatment caused a decrease in P-selectin, E-selectin, and sVCAM-1 levels to 8.9 +/- 1.0, 5.5 +/- 1.7, and 9.5 +/- 4.4 ng/ml, respectively (p < 0.001). Incorporation of MSSCs was followed by a reduction of the concentrations of P-selectin and E-selectin to 6.9 +/- 1.1 and 5.7 +/- 1.3 ng/ml, respectively (p < 0.001). The level of integrin (cVCAM-1) fell to 12.2 +/- 2.2 ng/ml (p > 0.1); that of L-selectin did not drop after MSSC administration and INF induction therapy. CONCLUSION: P-selectin, E-selectin, L-selectin, and sVCAM-1 integrin are current inflammatory markers and may be used to evaluate the efficiency of standard and biological therapies for inflammatory bowel diseases and to predict disease course.

[Serum calprotectin as a marker for determining the activity of the inflammatory process and the effectiveness of therapy in inflammatory bowel disease].

The increase in the concentration level of calprotectin in serum (ICP) in patients with inflammatory bowel disease (IBD) is closely associated with increased rates of acute phase of inflammation and combined with worsening of clinical and endoscopic disease activity. In the acute stage IBD concentration UPC hung on the degree of inflammatory activity, not localization. Test with the act is a highly sensitive method for assessing the degree of inflammatory activity and the effectiveness of therapy in IBD. After transplantation of mesenchymal stromal cells from bone marrow and standard therapy largely reduced levels SKP than selective immunosuppressive therapy with infliximab (INFL) in patients with IBD.

[Immunologic and oncological safety of autologous and allogenic mesenchymal bone marrow stromal cells].

It is indubitable that autologous transplantation of mesenchymal stromal cells (MSCs) is the golden standard for cell therapy. But also it is still in interest to explore the possibilities of allogeneic MSCs transplantation, because of their special role in lymphopoiesis, particularly in the positive selection of T-lymphocytes.

[Cell adhesion molecules in evaluation of Crohn's disease therapy].

The treatment of inflammatory bowel diseases (IBD), which include ulcerative colitis (UC) and Crohn's disease (CD) is one of actual problems of modern gastroenterology and coloproctology. In recent years a great attention is paid to the molecules of adhesion. Adhesion proteins play a significant role in the development of inflammation in patients with IBD. They cause the migration of cells from the capillaries into the center of inflammation, i.e. do much to increase the inflammatory infiltration of the mucosa and homing of lymphocytes. Changes in the levels of adhesion factors under the influence of biological therapy have been insufficiently studied. So the aim of our study was to determine the diagnostic value of adhesion molecules--integrin-sVCAM-1 and selectins P-, E-, L- for the assessment of the effectiveness of therapy in patients with UC and CD and prognosis of the disease. 15 patients with IBD were examined (15 patients with Crohn's disease (CD)). 9 patients were treated using infliximab 5 mg/kg according to the standard scheme (0-2-6 and then every 8 weeks). 3 patients with IBD received anti-inflammatory therapy with the introduction of the culture of MSC in the number of 150 x 108 cells suspended in 200 ml of physiological solution with the addition of heparin (10 IU/ml). 3 patients received azathioprine (2 mg/kg) and glucocorticosteroids (GCS) 1 mg/kg. The clinical symptoms, the level of leukocytes, erythrocyte sedimentation rate, C-reactive protein and also were analyzed before and after the treatment with infliximab and transplantation of MSC. The status of the colonic mucosa was evaluated using colonoscopy with biopsy. The concentration of adhesion molecules L-selectin, E-selectin, P-selectin, integrin-sVCAM-1 in blood serum was analyzed using immunoenzyme method twice before the beginning of treatment and after 2 months. It is established that after the standard therapy with the use of corticosteroids and azathioprine clinical and laboratory signs of IBD activity and increased levels of adhesion molecules remained in all patients. It is reliably determined that under the influence of infliximab the levels of P-selectin, E-selectin and integrin-sVCAM-1 decrease to 8.9 +/- 1.0 ng/ml, 5.5 +/- 1.7 ng/ml, 9.5 +/- 4.4 ng/ml, respectively (p < 0.001) in all patients with IBD. This point to the suppression of the synthesis of the main inflammatory cytokine alpha-TNF. Transplantation of MSC causes significant decrease of P-selectin, E-selectin to 6.9 +/- 1.1 ng/ml and 5.7 +/- 1.3 ng/ml, respectively (p < 0.001). Integrin-sVCAM-1 has decreased slightly to 12.2 +/- 2.2 ng/ml, p > 0.1. This is associated with the onset of the maximum therapeutic effect only in 1-2 months after transplantation. The levels of P-selectin, E-selectin, integrin-sVCAM-1, reflecting the acute phase of inflammation, decreased after MSC transplantation and infliximab induction therapy. The level of L-selectin, reflecting a chronic autoimmune inflammation, practically does not decrease after the MSC transplantation (8.9 +/- 0.5 ng/ml, p < 0.05) and infliximab induction therapy (9.6 +/- 0.8 ng/ml, p > 0.1). These include the appointment of long-term infliximab therapy and repeated MSC transplantations. P-selectin, E-selectin, L-selectin, integrin-sVCAM-1 are modern markers of inflammation and may be used to assess the effectiveness of standard and biological therapy in patients with IBD, and to predict the course of the disease.

[Antibodies to Saccharomyces cerevisiae as predictors of the complicated flow of Crohn disease].

Among the 143 patients in the acute phase of IBD the ASCA detected in 34 people, accounting for 23.8%, and in 60 patients with CD the increased level of ASCA was found in 24 people (40%), in 83 patients with UC the increased level of ASCA was found in 9 (10, 8%). The appearance of antibodies to Saccharomyces cerevisiae in the blood serum of patients with CD is regarded as a prognostically unfavorable sign, indicating that the disease may have a complicated course. Also, high titers of ASCA combined with complicated CD, requiring surgical treatment.

[Diagnostic value of serum markers of fibrosis in chronic liver diseases].

AIM: To estimate the diagnostic value (DV) of direct markers of liver fibrosis, such as type IV collagen (C-IV), hyaluronic acid (HA), tissue inhibitor of metalloproteinases-1 (TIMP-1) in combination with indirect markers of fibrosis, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (gamma-GTP), alkaline phosphatase (ALP), platelets, tumor necrosis factor-alpha (TNF-alpha) in evaluating liver fibrosis. SUBJECTS AND METHODS: Sixty-seven patients with chronic diffuse liver diseases were examined. ALT, AST, gamma-GTP, and ALP were determined as indirect indicators of fibrosis. The levels of TIMP-1, HA, C-IV, and TNF-alpha were estimated by ELISA; the stage of fibrosis was determined by the results of indirect liver ultrasound fibroelastography (FE). RESULTS: According to the results of FE, the patients were divided into 2 groups: 1) (n = 25) F < or = 2 METAVIR and 2) (n = 42) F3-F4. While estimating DV of severe fibrosis stages (F3-F4), the area under the ROC curve (AUC) increased for platelets, HA, and C-IV. DV of ALT, AST declined with the higher degree of fibrosis. The highest ratio of test specificity and sensitivity (TSp and TSen) and AUC were observed for AST and HA. ALT and platelets showed low TSen, and TNF-alpha and TIMP-1 had no TSp. For evaluation of fibrosis (F4), a HA increase of over 57.7 ng/ml had 92.6% TSen and 67.5% TSp; for a C-IV elevation of above 133.1mkg/l, TSen was 85.2%, TSp was 57.5%; for a TIMP-1 rise from 24.4 ng/ml, TSen was 74.1% and TSp was 62.5%. For the diagnosis of fibrosis (F4) with a HA rise of more than 57.7 ng/ml, DV of a positive test was 65.8 (48.65-80.4; 95% CI) and that of a negative test was 93.1 (76.8-99.2; 95% CI). Thus, the negative rather than positive test results are of great diagnostic value for evaluation of the degree of fibrosis. CONCLUSION: The results of the investigation convincingly suggest that examination of the serum markers of fibrosis allows one to estimate with a high probability its presence and severity in patients with hepatic cirrhosis. The so-called direct markers (substances reflecting the biochemistry and regulation of fibrogenesis) are undoubtedly of great diagnostic value.

[Fecal calprotectin as a biomarker effectiveness of various interventions in patients with inflammatory bowel disease].

Among the chronic diseases of the gastrointestinal tract of the special place occupied by inflammatory bowel disease (IBD), in which the lining of the intestine produces a significant number of neutrophils, which has prompted researchers and clinicians use a protein derived from neutrophils as a biomarker for the assessment of the intestinal wall and the effectiveness of treatment in patients IBD. One of these proteins is calprotectin (CP), which can be considered as a biomarker of activation, destruction and loss of neutrophil cells, to a lesser extent-- the activated monocytes and macrophages. Various studies have shown that the concentration of fecal calprotectin (FCP) correlates well with endoscopic and histological parameters of intestinal inflammation. Test the FCP can be used in healthy first-degree relatives of patients with IBD to assess the possible presence of subclinical variant of intestinal inflammation in this population. Thus, a simple test of the FCP can reduce the needs of various expensive and invasive method, including costs associated with them, especially in younger patients, where in terms of differential diagnosis of IBD is often not included neoplasia of the intestine. FCP is a non-invasive, inexpensive and at the same time, highly sensitive and specific biomarker that can be used successfully in the diagnosis, evaluation of the efficacy of treatment and predicting recurrence.

[Effects of radiation of decimeter range on the motor function of the gastrointestinal and biliary tracts].

Characteristics of the motor function of the upper gastrointestinal tract, small intestine and colon and biliary tract under radiation of dm range were obtained. The radiation source was a mobile phone brand Nokya. Motor function of the gastrointestinal and biliary tract was evaluated recording electromyogram (EMG) from silver electrodes imposed on the body surface in the projection point of the corresponding abdominal organs; frequency (in minutes) and amplitude (mV) and EMG spikes are measured. The maximums of dm radiation induced stimulatory effect on motor function recorded at the esophagus, stomach, jejunum and descending part of the colon.

[Immunosuppressive effect of bone marrow MSC transplantation in patients with ulcerative colitis with six kinds of one family autoantibodies with cross-relationship between each other].

The 6 types of cross-linked autobodies of one family where identified during relapsing course of Ulcerativ Colities (UC) acompanied with deterioration of clinical and endoscopic activity and increasing rate of acut inflammatory phase (CRP, number of leukocytes and erythrocyte sedimentation rate) of the disease. On the background of transplantation of mesenchymal bone marrow stromal cells (BM MSC), and despit the identification of six types of autoantibodies to antigens of neutrophils, was observed moderate activity of UC and low concentration of autoantibodies than in immunosuppressive therapy without BM MSC transplantation. Discovered anti-inflammatory effect of BM MSCs transplantation in UC may be explained by the systemic influence of immunosuppressive effect: it is known that the BM MSCs inhibit dendritic cells, T-and B-lymphocytes participating in the immune response, activate regulatory T-cells, which produce antinflammatory cytokines, IL-10 and TGF-1beta, which suppress the inflammatory process.

[Transplantation of mesenchymal bone marrow stromal cells as new opportunity to overcome ineffectiveness of primary anti-cytokine therapy in Crohn's disease].

Clinical observations and studies have shown that among 34 patients with Crohn's disease (CD) under infliximab (INFX) therapy in 8.8% cases was observed the loss of response to anticytokine therapy (so-called primary ineffectiveness of anti-cytokine therapy (ACT)). The increasing of INFX dosage up to 10 mg/kg of body weight failed to achieve clinical and endoscopic remission. It should be noted that, despite the long anticytokine therapy in these patients the antibodies to INFX were not observed and INFX concentration in blood serum practically was not determined. In CD patients with primary ineffectiveness of anti-cytokine therapy (ACT) was detected clinical deterioration of CD: increase of WR Best Index (CDAI), appearance of pain, fever, increase of stool frequency with blood and mucus, improving performance of acute phase of inflammation. Transplantation of mesenchymal bone marrow stromal cells (MSC) enhanced the level of INFX in the serum and overcoming the primary ineffectiveness of anti-cytokine therapy (ACT) and increase in sensitivity to Infliximab.

[Calprotectin concentration in stool samples as a determinant of the activity degree of inflammatory process in inflammatory bowel diseases].

At IBD in the exacerbation phase was detected the increase of fecal calprotectin (FC) level in 98% of patients. With increasing of clinical disease activity in patients with UC as well as CD was marked a significantly increased content of calprotectin in stool samples, which was accompanied by increase of indicators of inflammation acute phase: rising RRF, leukocytosis, an increase of frequency of stool with blood and mucus, fever and abdominal pain. In the phase of exacerbation the increase in concentration of CRP depends on the degree of inflammatory activity, rather than on lesion localization. The highest concentration of CRP was revealed at a high degree of IBD activity with stool frequency up to 8-10 times/day with impurity of blood and abdominal pain. At moderate activity of IBD, it is less expressed diarrhea (stool frequency 2-3 times a day), without blood, detected lower lever of PCF concentration--from 250 to 380 ug/g. A study of calprotectin concentrations in stool samples is considered to be reliable and sensitive method for evaluation of inflammatory activity in patients with inflammatory bowel disease.

[Immune response to biological therapy of inflammatory bowel diseases].

AIM: To study biological (cell and anticytokine) therapy-induced changes in the levels of proinflammatory cytokines in patients with inflammatory bowel diseases (IBD). SUBJECTS AND METHODS: Forty-four patients with chronic continuous or chronic recurrent IBD were examined. According to the performed therapy, the patients were divided into 3 groups: 1) 16 patients who took infliximab; 2) 14 patients who received combination anti-inflammatory therapy with the cultured mesenchymal stromal cells (MSC) being administered; 3) 14 patients who had standard anti-inflammatory therapy with 5-aminosalycilic acid preparations and glucocorticosteroids. The concentrations of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (INF-gamma), and interleukins (IL)-2, -5, -8, -12, and -15 were determined in the patients' sera before and 2 months after therapy initiation. RESULTS: The elevation in the serum levels of the proinflammatory cytokines TNF-alpha, INF-gamma, and IL-2, -5, -8, -12, and -15 indicates their implication in the pathogenesis of ulcerative colitis and Crohn's disease. Their levels may evaluate both the activity of an inflammatory process and the efficiency of the therapy. The higher level of these cytokines is accompanied by the enhanced activity of diseases, which may be used to diagnose their activity, to predict the course of IBD, and to perform adequate therapy. The decreased level of the proinflammatory cytokines is indicative of the efficiency of the therapy in patients with IBD. CONCLUSION: By reducing TNF-alpha levels, infliximab therapy results in a decrease in the concentrations of other proinflammatory cytokines (IL-1, -2, -5, -8), thus lowering the inflammatory activity of IBD. MSC transplantation also reduces the level of most proinflammatory cytokines, thus diminishing the intensity of immunopathological processes, which is shown by positive changes in the clinical picture of the disease.

[Non-invasive techniques in diagnosis of steatosis and fibrosis in nonalcoholic fatty liver disease].

UNLABELLED: Diagnosis and treatment of nonalcoholic fatty liver disease (NAFLD) is one of the most actual problems of modern hepatology. Ultrasound elastometry is alternative method to determine the density of the liver tissue. The efficiency of the method was confirmed by a large amount of data in patients with viral hepatitis. However, the diagnostic value of elastometry was not studied enough in patients with NAFLD. THE AIM OF THE RESEARCH: to study the possibility of non-invasive diagnostic methods of examination in a complex assessment of the liver in patients with NAFLD. MATERIALS AND METHODS: We studied 24 patients with signs of NAFLD and a long persistent elevation of liver enzymes. All patients underwent a needle biopsy of the liver. We conducted a comparative analysis of the results of the morphological study of the liver tissue with ultrasound elastometry, computed tomography of the liver, biochemical blood tests. RESULTS AND DISCUSSION: Among biochemical liver enzymes ALT was a marker of NAFLD which characterized the transformation of steatosis to steatohepatitis. The combined ALT and GGT increase reflected the high activity of inflammation in the liver tissue. Elastometry results were comparable to the histological features in all liver fibrosis stages, but the maximum diagnostic accuracy was observed at the late stages. The area under the ROC-curves showed the highest precision in the F2-F3 stages, the lowest value - in the F1 stage. Imprecision of the method in the early stages of fibrosis may be due to the hepatic steatosis in NAFLD and high biochemical activity with cholestasis signs. Patients with early-stage liver fibrosis diagnosed with elastometry need additional examination using other methods of noninvasive diagnostic tools.

[Level of adalimumab and its antibody titers define the effectiveness of the biological (anticytokine) therapy in Crohn's disease].

Formation of immune antibodies to adalimumab (ADM) in patients with Crohn's disease currently has high clinical value, as antibodies (AT) influence on bioavailability, pharmacokinetic, pharmacodynamic indicators, that eventually affects expression of clinical response to treatment. The results of this study indicate that after treatment with adalimumab in 12-14 weeks in any case there was not an increase of antibodies to adalimumab. Synchronous study of concentration of adalimumab (ADA) and antibodies to ADA in serum to determine the effectiveness of anti-cytokine therapy with adalimumab in Crohn's disease.

[Optimization of cell therapy in patients with inflammatory bowel diseases].

AIM: To elaborate optimal cell culture administration regimens to enhance the efficiency of anti-inflammatory therapy for inflammatory bowel diseases. SUBJECTS AND METHODS: Three groups of patients with chronic continuous or chronic recurrent ulcerative colitis (UC) were formed according to the treatment option: 1) 15 patients with UC, in whom mesenchymal stromal cells (MSC) were thrice administered for a month at a one-week interval; 2) 20 patients with UC who received MSC once; 3) 20 patients with UC who had standard anti-inflammatory therapy with 5-aminosalycilic acid (5-ASA) preparations and glucocorticosteroids (GCS). The clinical activity of UC was evaluated using the Rachmilewitz index; its endoscopic pattern was assessed with the Mayo index. UC histological specimens were scored using the Gebs scale. To ascertain the duration of remission, the authors used the Kaplan-Maier survival curve method and calculated relative risk (RR) and odds ratio with 95% confidence intervals. RESULTS: Following 12 months, allogeneic bone marrow (BM) MSC transplantation performed thrice during a month caused the greatest reduction in the Rachmilewitz clinical activity index, Mayo endoscopic activity index, and Gebs pathohistological index in patients with UC as compared to those who had underwent one transplantation or received 5-ASA preparations and GCS (p < 0.05). The duration of remission also depended on the chosen therapy option for UC and the frequency of cell culture administration: the longer duration was recorded in patients who were infused thrice with allogeneic BM MSC. CONCLUSION: In the patients who had undergone one MSC administration, the risk of recurrent UC was higher than in those who had received MSC thrice during a month (a 2-year follow-up) and comparable with the RR of recurrent UC in the patient receiving only 5-ASA preparations, GCS, and/or immunosuppressants.

[Immunogenetic predisposition to chronic nonspecific inflammatory bowel disease].

Immunology has grown beyond the classic doctrine of immunity to infectious diseases, and gradually covered the problems of general physiology and pathology, genetics, embryology, transplantation, oncology and many other disciplines. A new direction has appeared--immunogenetics, which should help to answer questions the disposition and/or resistance to disease, as well as influence of environmental factors on implementation of predisposition to the development of pathology. Much attention is paid to investigation of HLA in IBD. These data indicate a significant polymorphism of major histocompatibility complex antigens in this disease in different countries. The aim of our study was to investigate the immunogenetic susceptibility and resistance to the development of ulcerative colitis (UC), and Crohn's disease (CD), the character of their flow, as well as the associated extraintestinal manifestations, in particular predisposition development of bronchial obstruction (BO) in patients with inflammatory bowel disease (IBD). A study of DNA frozen blood samples of 75 patients with IBD of both sexes has been conducted. The obtained results have been compared with the results of the study 1700 of samples of umbilical cord blood of newborns (apparently healthy children), born at 37-41 weeks' gestation in Moscow (control). The group of patients with UC revealed a positive association of HLA specificities-B*38, HLA-Cw*12 and HLA-DRV1*15, which can be regarded as potentially high risk of developing the disease. The presence of the specificity of HLA-DQV1*02 can be considered as a factor in resistance to the development of UC. High risk of developing Crohn's disease among residents of Moscow associated with groups of alleles of HLA B*41, HLA-B*56, HLA-Cw*05, HLA-Cw*08, HLA-DRV1*01, HLA-DRV1*11, HLA-DQV1*04, and the presence of specificity of HLA-DQV1*05 can be considered as a factor of resistance to the development of BC. High risk of developing BO in patients with IBD is associated with specificities HLA-DQB1*02, DQB1*03, DRB1*15.