[Androgenic status of men with severe COVID-19: the role of testosterone and dihydrotestosterone [within the program FOUNDER (features of a new coronavirus infection course and options therapy depending on the androgenic status)]].

PURPOSE: The aim of this study was to assess the mens androgen status influence on the severity and outcomes (transfer of patients to the ICU or death) of COVID-19 required hospital hospitalization. MATERIALS AND METHODS: The study included 151 hospitalized men with a confirmed diagnosis of COVID-19. To measure the severity of disease have been used Symptomatic Hospital and Outpatient Clinical Scale for COVID-19 (SHOCS-COVID). It includes the severity of the clinical condition (hyperthermia, shortness of breath, oxygen saturation, need for ventilation), the degree of inflammation (CRP), markers of thrombosis (D-dimer), the degree of lung damage according to CT. The patients underwent a study of full blood count, some biochemical parameters, lung CT, and a study of testosterone (T) and dihydrotestosterone (DHT) levels. RESULTS: T deficiency was observed in 46.4% of patients (70/151 men). At the same time, DHT deficiency was observed only in 14.4% of patients (18/125 men). In patients with a T level below the median, there was a significant increase in inflammatory factors (CRP, lymphocytes/CRP index), markers of thrombosis (D-dimer and fibrinogen), extensive lung damage at admission according to CT 25.75% vs. 11.95% (p<0.001), the elevated number of points for SHOCKS-COVID 7 (IQR 5-10) versus 5 (IQR 3-7) (p<0.001) and the longer duration of hospital treatment (3 days difference, p<0.001) in comparison with a group of patients with a T level above the median. At the same time, the T level had no correlation with age. The level of DHT had a weak inverse correlation with the age of patients, but not with the main markers of the severity of COVID-19, including the number of SHOCK-COVID scores. During multivariate regression analysis, it was shown that SHOCKS-COVID is the most significant predictor of admission to the ICU while no association of T and DHT levels with outcomes in COVID-19 was found. However, it was found that the concentration of T, even adjusted for age, has a significant inverse association with the severity of the course of the disease and the number of SHOCK-COVID scores (p=0.041). An analysis of the evaluation of directed acyclic graphs suggests the main role of COVID-19 severity in reducing androgenic function and T concentration, at which its anti-inflammatory effects are lost. There were no correlations between the concentration of DHT and the number of SHOCK-COVID scores and the COVID-19 prognosis. CONCLUSION: SHOCK-COVID is the most sensitive predictor of the COVID-19 outcome in hospitalized men, including adjusting to age. T and DHT do not directly affect the outcomes of the disease. The greater severity of the infection and an increase in SHOCK-COVID scores are associated with a decrease in the concentration of T, and a weakening of its anti-inflammatory and anti-cytokine effects, which indirectly worsens the prognosis of male patients with a new coronavirus infection undergoing hospital treatment. There are no such relationships for DHT.

[Risk of postoperative complications in hyperglycemic conditions]. / Risk razvitiya posleoperatsionnykh oslozhnenii pri giperglikemicheskikh sostoyaniyakh.

The authors consider the influence of carbohydrate metabolism disorders on postoperative period. Data on the influence of diabetes mellitus on morbidity are summarized. Mechanisms and significance of stress-induced hyperglycemia are described. The authors also discuss modern approaches to the treatment of hyperglycemic conditions in perioperative period.

Proactive anti-inflammatory therapy in the advanced stages of a new coronavirus infection. Main results of the inpatient phase of the COLORIT study (Colchicin vs. Ruxolitinib and secukinumab in an open, prospective, randomized trial in patients with novel coronavirus infection COVID-19).

Aim      To evaluate clinical efficacy of the proactive anti-inflammatory therapy in patients hospitalized for COVID-19 with pneumonia and a risk of "cytokine storm".Material and methods  The COLORIT study was a comparative study with randomization into 4 groups: colchicine (n=21) 1 mg for the first 3 days followed by 0.5 mg/day through day 12 or discharge from the hospital; secukinumab 300 mg/day, s.c., as a single dose (n=20); ruxolitinib 5 mg, twice a day (n=10); and a control group with no anti-inflammatory therapy (n=22). The effect was evaluated after 12±2 days of inpatient treatment or upon discharge, what comes first. For ethical reasons, completely randomized recruitment to the control group was not possible. Thus, for data analysis, 17 patients who did not receive any anti-inflammatory therapy for various reasons not related with inclusion into the study were added to the control group of 5 randomized patients. Inclusion criteria: presence of coronavirus pneumonia (positive PCR test for SARS-CoV-2 RNA or specific clinical presentation of pneumonia; IDC-10 codes U07.1 and U07.2); C-reactive protein (CRP) concentration >60 mg/l or its threefold increase from baseline; at least 2 of 4 symptoms (fever >37.5 °C, persistent cough, shortness of breath with inspiratory rate >20 per min or blood saturation with oxygen <94 % by the 7th-9th day of disease. The study primary endpoint was changes in COVID Clinical Condition Scale (CCS-COVID) score. The secondary endpoints were the dynamics of CRP and changes in the area of lung lesion according to data of computed tomography (CT) of the lungs from the date of randomization to 12±2 days.Results All three drugs significantly reduced inflammation, improved the clinical course of the disease, and decreased the disease severity as evaluated by the CCS score: in the ruxolitinib group, by 5.5 (p=0.004); in the secukinumab group, by 4 (p=0.096); in the colchicine group, by 4 (p=0.017), and in the control group, by 2 (р=0.329). In all three groups, the CCS-COVID score was 2-3 by the end of observation period, which corresponded to a mild process, while in the control group, the score was 7 (р=0.005). Time-related changes in CRP were significant in all three anti-inflammatory treatment groups with no statistical difference between the groups. By the end of the study, changes in CT of the lungs were nonsignificant.Conclusion      In severe СOVID-19 with a risk of "cytokine storm", the proactive therapy with ruxolitinib, colchicine, and secukinumab significantly reduces the inflammation severity, prevents the disease progression, and results in clinical improvement.

[Features of a new corOnavirUs infection course and optioNs therapy DEpending on the andRogenic status (FOUNDER): androgenic status in men with COVID-19 and its relationship with the disease severity].

OBJECTIVE: Analysis of androgen status in men hospitalized with a moderate COVID-19 and its relationship with the severity of the disease. MATERIALS AND METHODS: The study included 152 males with a confirmed diagnosis of COVID-19 based on the results of a positive PCR for the SARS-CoV-2 virus and/or computed tomography of the lungs hospitalized at the MSU University Clinic due to the moderate and severe COVID-19. Examination of the level of biochemical blood parameters (CRP, creatinine, urea, glucose, total testosterone (T)); CT of the lungs. To objectify the severity of the clinical symptoms, the NEWS2 distress syndrome severity scales and the original scale for assessing the clinical condition of patients with COVID 19 (SHOCS-COVID) were used. RESULTS: The median T level in 152 examined patients was 2.14 [1.21; 3.40] ng/ml. In patients with a T level below the median, the CRP level was more than two times higher, and the D-dimer value was almost two times higher than in patients with T level above median. The duration of treatment in the hospital was longer in men with COVID 19 and an initial T level below the median than in patients with T about the median (13 days vs 10.5 days, p=0.003). Low T level was correlated with lung damage by lung CT. After improving the clinical condition, there was a linear increase in the level of T independent of its initial level. CONCLUSION: Among men with moderate and severe COVID-19, a decreased testosterone level is detected in 46.7% of cases. Patients with low testosterone levels on admission have more severe COVID-19. A significant increase in testosterone level was observed after successful COVID-19 treatment without any special action regarding testosterone level.

[Association of AGT, ACE, NOS3, TNF, MMP9, CYBA polymorphism with subclinical arterial wall changes].

Aim    Activation of the renin-angiotensin-aldosterone system, decreased nitric oxide production, chronic inflammation, and oxidative stress result in subclinical changes in the arterial wall, which favor the development of cardiovascular diseases (CVD). The effect of allelic gene variants that encode the proteins participating in pathogenetic pathways of age-associated diseases with subclinical changes in the arterial wall [increased pulse wave velocity (PWV), increased intima-media thickness, endothelial dysfunction (ED), presence of atherosclerotic plaques (ASP)] are understudied. This study analyzed the relationship between AGT, ACE, NOS3 TNF, MMP9, and CYBA gene polymorphism and the presence of subclinical changes in the arterial wall, including the dependence on risk factors for CVD, in arbitrarily healthy people of various age.Material and methods    The relationship of polymorphisms с.521С>Т of AGT gene, Ins>Del of AСE gene, с.894G>T of NOS3 gene, - 238G>A of TNF gene, - 1562С>T of MMP9 gene, and c.214Т>С of CYBA gene with indexes of changes in the arterial wall and risk factors for CVD was studied in 160 arbitrarily healthy people by building models of multiple logistic regression and also by analyzing frequencies of co-emergence of two signs with the Pearson chi-squared test (χ2) and Fisher exact test.Results    The DD-genotype of Ins>Del ACE gene polymorphism was correlated with increased PWV (p=0.006; odds ratio (OR) =3.41, 95 % confidence interval (CI): 1.48-8.67) and ED (p=0.014; OR=2.60, 95 % CI: 1.22-5.68). The GG genotype of с.894G>T NOS3 gene polymorphism was correlated with ED (p=0.0087; OR=2.65, 95 % CI: 1.26-5.72); the ТТ-genotype of с.894G>T NOS3 gene polymorphism was correlated with ASP (p=0.033; OR=0.034, 95 % CI: 0.001-0.549).Conclusion    Polymorphic variants of AСE and NOS3 genes correlated with ED, increased arterial wall stiffness, and the presence of subclinical changes in the arterial wall.

Proactive anti-inflammatory therapy with colchicine in the treatment of advanced stages of new coronavirus infection. The first results of the COLORIT study.

Actuality The course of the novel coronavirus disease (COVID-19) is unpredictable. It manifests in some cases as increasing inflammation to even the onset of a cytokine storm and irreversible progression of acute respiratory syndrome, which is associated with the risk of death in patients. Thus, proactive anti-inflammatory therapy remains an open serious question in patients with COVID-19 and pneumonia, who still have signs of inflammation on days 7-9 of the disease: elevated C-reactive protein (CRP)>60 mg/dL and at least two of the four clinical signs: fever >37.5°C; persistent cough; dyspnea (RR >20 brpm) and/or reduced oxygen blood saturation <94% when breathing atmospheric air. We designed the randomized trial: COLchicine versus Ruxolitinib and Secukinumab in Open-label Prospective Randomized Trial in Patients with COVID-19 (COLORIT). We present here data comparing patients who received colchicine with those who did not receive specific anti-inflammatory therapy. Results of the comparison of colchicine, ruxolitinib, and secukinumab will be presented later.Objective Compare efficacy and safety of colchicine compared to the management of patients with COVID-19 without specific anti-inflammatory therapy.Material and Methods Initially, 20 people were expected to be randomized in the control group. However, enrollment to the control group was discontinued subsequently after the inclusion of 5 patients due to the risk of severe deterioration in the absence of anti-inflammatory treatment. Therefore, 17 patients, who had not received anti-inflammatory therapy when treated in the MSU Medical Research and Educational Center before the study, were also included in the control group. The effects were assessed on day 12 after the inclusion or at discharge if it occurred earlier than on day 12. The primary endpoint was the changes in the SHOCS-COVID score, which includes the assessment of the patient's clinical condition, CT score of the lung tissue damage, the severity of systemic inflammation (CRP changes), and the risk of thrombotic complications (D-dimer) [1].Results The median SHOCS score decreased from 8 to 2 (p = 0.017), i.e., from moderate to mild degree, in the colchicine group. The change in the SHOCS-COVID score was minimal and statistically insignificant in the control group. In patients with COVID-19 treated with colchicine, the CRP levels decreased rapidly and normalized (from 99.4 to 4.2 mg/dL, p<0.001). In the control group, the CRP levels decreased moderately and statistically insignificantly and achieved 22.8 mg/dL by the end of the follow-up period, which was still more than four times higher than normal. The most informative criterion for inflammation lymphocyte-to-C-reactive protein ratio (LCR) increased in the colchicine group by 393 versus 54 in the control group (p = 0.003). After treatment, it was 60.8 in the control group, which was less than 100 considered safe in terms of systemic inflammation progression. The difference from 427 in the colchicine group was highly significant (p = 0.003).The marked and rapid decrease in the inflammation factors was accompanied in the colchicine group by the reduced need for oxygen support from 14 (66.7%) to 2 (9.5%). In the control group, the number of patients without anti-inflammatory therapy requiring oxygen support remained unchanged at 50%. There was a trend to shorter hospital stays in the group of specific anti-inflammatory therapy up to 13 days compared to 17.5 days in the control group (p = 0.079). Moreover, two patients died in the control group, and there were no fatal cases in the colchicine group. In the colchicine group, one patient had deep vein thrombosis with D-dimer elevated to 5.99 µg/mL, which resolved before discharge.Conclusions Colchicine 1 mg for 1-3 days followed by 0.5 mg/day for 14 days is effective as a proactive anti-inflammatory therapy in hospitalized patients with COVID-19 and viral pneumonia. The management of such patients without proactive anti-inflammatory therapy is likely to be unreasonable and may worsen the course of COVID-19. However, the findings should be treated with caution, given the small size of the trial.

[Phenotyping of angiotensin-converting enzyme in the prostate in patients with prostate cancer and benign prostatic hyperplasia].

BACKGROUND: Angiotensin-converting enzyme (ACE) is expressed by all epithelial cells of the human body. Although the main proportion of ACE is synthesized by the lungs, in men, ACE is also secreted by the testes (testicular form), seminal vesicles and the prostate. In semen, the level of ACE is up to 50 times higher than in blood plasma. The substitution of highly specific epithelial cells of the prostate by tumor cells causes a dramatic decrease in ACE production by the prostate cells. AIM: To assess the possibility of using prostatic ACE as a new marker of prostate cancer (PCa). MATERIALS AND METHODS: ACE phenotyping in prostate of patients with PCa and benign prostatic hyperplasia (BPH) included measurement of the activity of two ACE substrates (HHL and ZPHL); calculation of the ratio of their hydrolysis rates (ZPHL/HHL ratio); quantitative assessment of the ACE immunoreactive protein, the ratio of the immunoreactive protein to the ACE activity, as well as the conformation of ACE using a panel of monoclonal antibodies (mAb) to different epitopes of ACE. RESULTS: ACE activity in tumor cells was markedly reduced and the ratio of immunoreactive ACE to its activity increased. The ratio of the hydrolysis rates of two substrates (ZPHL/HHL ratio) in patients with PCa increased compared to control group, while it was not observed in the vast majority of patients with BPH. There were several tissue samples with a histological diagnosis of BPH, but ACE phenotype was typical for PCa. DISCUSSION: Since a decrease in ACE activity was found in all patients with PCa, we suggest that it may serve as a reliable and early marker of the tumor development. Changes in the ACE phenotype, which are typical for PCa, but found in patients with BPH, may indicate earlier malignant changes in prostate cells, which are not visible on routine prostate biopsy. CONCLUSIONS: ACE activity and its conformation in prostatic biopsies has the potential to be an early biomarker or a differential criterion for PCa. In PCa, the ACE activity in the prostate is significantly reduced, and the ZPHL/HHL ratio is markedly increased in comparison to control group. However, there were no such changes in patients with BPH. In hyperplastic processes of the prostate (BPH, PCa), there is a change in ACE sialylation, which is accompanied by an increase in the binding of ACE to mAb 3F10 compared to the control group. Patients with negative biopsy result, but properties of prostate ACE, which are typical for PCa, require close follow-up, since they may have an increased risk of subsequent developing PCa. However, due to a small sample of patients, the diagnostic potential of prostate ACE for PCa and BPH requires to be validated in a larger number of patients to confirm its predictive accuracy.

[Combination therapy at an early stage of the novel coronavirus infection (COVID-19). Case series and design of the clinical trial "BromhexIne and Spironolactone for CoronаvirUs Infection requiring hospiTalization (BISCUIT)"].

The article focuses on effective treatment of the novel coronavirus infection (COVID-19) at early stages and substantiates the requirement for antiviral therapy and for decreasing the viral load to prevent the infection progression. The absence of a specific antiviral therapy for the SARS-CoV-2 virus is stated. The authors analyzed results of early randomized studies using lopinavir/ritonavir, remdesivir, and favipiravir in COVID-19 and their potential for the treatment of novel coronavirus infection. Among the drugs blocking the virus entry into cells, the greatest attention was paid to the antimalaria drugs, chloroquine and hydroxychloroquine. The article addresses in detail ineffectiveness and potential danger of hydroxychloroquine, which demonstrated neither a decrease in the time of clinical recovery nor any improvement of prognosis for patients with COVID-19. The major objective was substantiating a possible use of bromhexine, a mucolytic and anticough drug, which can inhibit transmembrane serin protease 2 required for entry of the SARS-CoV-2 virus into cells. Spironolactone may have a similar feature. Due to its antiandrogenic effects, spironolactone can inhibit X-chromosome-related synthesis of ACE-2 receptors and activation of transmembrane serin protease 2. In addition to slowing the virus entry into cells, spironolactone decreases severity of fibrosis in different organs, including the lungs. The major part of the article addresses clinical examples of managing patients with COVID-19 at the University Clinic of the Medical Research and Educational Centre of the M. V. Lomonosov Moscow State University, including successful treatment with schemes containing bromhexine and spironolactone. In conclusion, the authors described the design of a randomized, prospective BISCUIT study performed at the University Clinic of the M. V. Lomonosov Moscow State University with an objective of evaluating the efficacy of this scheme.

[Proactive anti-inflammatory and anticoagulant therapy in the treatment of advanced stages of novel coronavirus infection (COVID-19). Case Series and Study Design: COLchicine versus ruxolitinib and secukinumab in open prospective randomIzed trial (COLORIT)].

The article is devoted to the treatment of the new coronavirus infection (COVID-19) in the advanced stages of the disease. The types of response of the immune system to the viral load of SARS-CoV-2 with the start of the inflammation process are considered. The situation is analyzed in detail in which the growing autoimmune inflammation (up to the development of a "cytokine storm") affects not only the pulmonary parenchyma, but also the endothelium of the small vessels of the lungs. Simultaneous damage to the alveoli and microthrombosis of the pulmonary vessels are accompanied by a progressive impairment of gas exchange, the development of acute respiratory distress syndrome, the treatment of which, even with the use of invasive ventilation, is ineffective and does not really change the prognosis of patients with COVID-19. In order to interrupt the pathological process at the earliest stages of the disease, the necessity of proactive anti-inflammatory therapy in combination with active anticoagulation treatment is substantiated. The results of the first randomized studies on the use of inhibitors of pro-inflammatory cytokines and chemokines (interleukin-6 (tocilizumab), interleukin-17 (secukinumab), Janus kinase blockers, through which the signal is transmitted to cells (ruxolitinib)), which have potential in the early treatment of COVID- 19. The use of a well-known anti-inflammatory drug colchicine (which is used for gout treatment) in patients with COVID-19 is considered. The design of the original COLORIT comparative study on the use of colchicine, ruxolitinib and secukinumab in the treatment of COVID-19 is presented. Clinical series presented, illustrated early anti-inflammatory therapy together with anticoagulants in patients with COVID-19 and the dangers associated with refusing to initiate such therapy on time.

[Steroid pulse -therapy in patients With coronAvirus Pneumonia (COVID-19), sYstemic inFlammation And Risk of vEnous thRombosis and thromboembolism (WAYFARER Study)].

Introduction Coronavirus pneumonia not only severely affects the lung tissue but is also associated with systemic autoimmune inflammation, rapid overactivation of cytokines and chemokines known as "cytokine storm", and a high risk of thrombosis and thromboembolism. Since there is no specific therapy for this new coronavirus infection (COVID-19), searching for an effective and safe anti-inflammatory therapy is critical.Materials and methods This study evaluated efficacy and safety of pulse therapy with high doses of glucocorticosteroids (GCS), methylprednisolone 1,000 mg for 3 days plus dexamethasone 8 mg for another 3-5 days, in 17 patients with severe coronavirus pneumonia as a part of retrospective comparative analysis (17 patients in control group). The study primary endpoint was the aggregate dynamics of patients' condition as evaluated by an original CCS-COVID scale, which included, in addition to the clinical status, assessments of changes in the inflammation marker, C-reactive protein (CRP); the thrombus formation marker, D-dimer; and the extent of lung injury evaluated by computed tomography (CT). Patients had signs of lung injury (53.2 % and 25.6 %), increases in CRP 27 and 19 times, and a more than doubled level of D-dimer (to 1.41 µg/ml and 1.15 µg/ml) in the active therapy and the control groups, respectively. The GCS treatment group had a more severe condition at baseline.Results The GCS pulse therapy proved effective and significantly decreased the CCS-COVID scores. Median score difference was 5.00 compared to the control group (р=0.011). Shortness of breath considerably decreased; oxygen saturation increased, and the NEWS-2 clinical status scale scores decreased. In the GCS group, concentration of CRP significantly decreased from 134 mg/dl to 41.8 mg/dl (р=0.009) but at the same time, D-dimer level significantly increased from 1.41 µg/ml to 1.98 µg/ml (р=0.044). In the control group, the changes were nonsignificant. The dynamics of lung injury by CT was better in the treatment group but the difference did not reach a statistical significance (р=0.062). Following the GCS treatment, neutrophilia increased (р=0.0001) with persisting lymphopenia, and the neutrophil/lymphocyte (N/L) ratio, a marker of chronic inflammation, increased 2.5 times (р=0.006). The changes in the N/L ratio and D-dimer were found to correlate in the GCS pulse therapy group (r =0.49, p=0.04), which underlined the relationship of chronic autoimmune inflammation with thrombus formation in COVID-19. No significant changes were observed in the control group. In result, four patients developed venous thromboembolic complications (two of them had pulmonary artery thromboembolism) after the GCS pulse therapy despite the concomitant antiplatelet treatment at therapeutic doses. Recovery was slower in the hormone treatment group (median stay in the hospital was 26 days vs 18 days in the control group, р=0.001).Conclusion Pulse therapy with high doses of GCS exerted a rapid anti-inflammatory effect but at the same time, increased the N/L ratio and the D-dimer level, which increased the risk of thromboembolism.

[Results of Open-Label non-Randomized Comparative Clinical Trial: "BromhexIne and Spironolactone for CoronаvirUs Infection requiring hospiTalization (BISCUIT)].

Introduction The aim of this study was to assess the efficacy and safety of a combination of bromhexine at a dose of 8 mg 4 times a day and spironolactone 50 mg per day in patients with mild and moderate COVID 19.Material and methods It was an open, prospective comparative non-randomized study. 103 patients were included (33 in the bromhexine and spironolactone group and 70 in the control group). All patients had a confirmed 2019 novel coronavirus infection (COVID 19) based on a positive polymerase chain reaction (PCR) for SARS-CoV-2 virus RNA and/or a typical pattern of viral pneumonia on multispiral computed tomography. The severity of lung damage was limited to stage I-II, the level of CRP should not exceed 60 mg / dL and SO2 in the air within 92-98%. The duration of treatment is 10 days.Results The decrease in scores on the SHOKS-COVID scale, which, in addition to assessing the clinical status, the dynamics of CRP (a marker of inflammation), D-dimer (a marker of thrombus formation), and the degree of lung damage on CT (primary endpoint) was statistically significant in both groups and differences between them was not identified. Analysis for the group as a whole revealed a statistically significant reduction in hospitalization time from 10.4 to 9.0 days (by 1.5 days, p=0.033) and fever time from 6.5 to 3.9 days (by 2.5 days, p<0.001). Given the incomplete balance of the groups, the main analysis included 66 patients who were match with using propensity score matching. In matched patients, temperature normalization in the bromhexine/spironolactone group occurred 2 days faster than in the control group (p=0.008). Virus elimination by the 10th day was recorded in all patients in the bromhexine/spironolactone group; the control group viremia continued in 23.3% (p=0.077). The number of patients who had a positive PCR to the SARS-CoV-2 virus on the 10th day of hospitalization or longer (≥10 days) hospitalization in the control group was 20/21 (95.2%), and in the group with bromhexine /spironolactone -14/24 (58.3%), p=0.012. The odds ratio of having a positive PCR or more than ten days of hospitalization was 0.07 (95% CI: 0.008 - 0.61, p=0.0161) with bromhexine and spironolactone versus controls. No side effects were reported in the study group.Conclusion The combination of bromhexine with spironolactone appeared effective in treating a new coronavirus infection by achieving a faster normalization of the clinical condition, lowering the temperature one and a half times faster, and reducing explanatory combine endpoint the viral load or long duration of hospitalization (≥ 10 days).

[Biomarkers of prostate cancer and potential for using ace produced in prostate gland for diagnosis of prostate cancer and benign prostatic hyperplasia].

Prostate cancer (PCa) is the 4th most commonly diagnosed cancer in the male population and incidence of different stages is increasing every year. The efficiency of PCa treatment is strongly dependent on the its stage. Prostate Specific Antigen (PSA) is the most widely used and universal biomarker of PCa worldwide. Considering its limited predictive value, particularly in patients older than 50 with PSA level ranging from 4.5 to 10 ng/ml, there is a need to introduce new serum biomarkers of PCa. Current data on different PCa biomarkers are reviewed in the article as well as a role of angiotensin-converting enzyme (ACE) as a novel PCa biomarker.

Prediction of features of the course of chronic hepatitis C using Bayesian networks.

MATERIALS AND METHODS: 253 patients with chronic hepatitis C (CHC) and liver cirrhosis were included in the study. Assessment of gene polymorphisms of genes involved in inflammatory reactions and antiviral immunity (IL-1ß-511C/T, IL-10 -1082G/A, IL28B C/T, IL28B T/G, TNF-α -238G/A, TGF-ß -915G/C, IL-6 -174G/C), activators of local hepatic fibrosis (AGT G-6A, AGT 235 M/T, ATR1 1166 A/C), hemochromatosis (HFE C282Y, HFE H63D), platelet receptors (ITGA2 807 C/T, ITGB3 1565 T/C), coagulation proteins and endothelial dysfunction (FII 20210 G/A, FV 1691G/A, FVII 10976 G/A, FXIII 103 G/T, eNOS 894 G/T, CYBA 242 C/T, FBG -455 G/A, PAI-675 5G/4G, MTHFR 677 C/T) was carried. Using Bayesian networks we studied the predictor value of clinical and laboratory factors for the following conditions - end points (EP): development of cirrhosis (EP1), fibrosis rate (EP2), presence of portal hypertension (EP3) and cryoglobulins (EP4). RESULTS AND DISCUSSION: In addition to traditional factors we have shown the contribution of the following mutations. Predicting EP1- liver cirrhosis - HFE H63D, C282Y, CYBA 242 C/T, AGT G-6G, ITGB31565 T/C gene mutations were significant. We also found a link between the rate of progression of liver fibrosis and gene polymorphisms of AGT G-6G, AGT M235T, FV 1691G/A, ITGB31565 T/C. Among the genetic factors associated with portal hypertension there are gene polymorphisms of PAI-I-675 5G/4G, FII 20210 G/A, CYBA 242 C/T, HFE H63D and Il-6 174GC. Cryoglobulins and cryoglobuliemic vasculitis (EP4) are associated with gene mutations MTHFR C677T, ATR A1166C and HFE H63D. CONCLUSION: The results obtained allow to detect the major pathophysiological and genetic factors which determine the status of the patient and the outcome of the disease, to clarify their contribution, and to reveal the significance of point mutations of genes that control the main routes of HCV course and progression.

[The comparative characteristic of methods of flow cytofluorometry and optical microscopy in qualitative study of urine elements.]

The comparative study was carried out concerning methods of flow cytofluorometry and optical microscopy in analysis of urine elements with the purpose of establishing the necessity of verification by physician the results of clinical diagnostic laboratory obtained by the analyzer. The final data concerning comparison of results obtained by two methodologies for various groups of pathology. The participation of physician in validation of results can be avoided in the groups with normal and exceeding standard values of content of corpuscular elements of urine. In the subgroups with pathological elements of urine (transitional and renal epithelium, pathological cylinders, crystals) it is recommended to implement analysis using cytofluorometric technique with subsequent verification by optical microscopy.

[The disturbance of unification of coupled biochemical reactions in synthesis of endogenous ω-9 oleic acid. The resistance to insulin, stearic triglycerides and pathogenesis of eruptive xanthomata].

The eruptive xanthomata are formed in vivo under realization of biological function of endoecology. The xanthomata are formed in tissues by early in phylogenesis resident macrophages at absorption of secreted by hepatocytes aphysiological stearic lipoproteins of very low density with high content of the same name triglycerides down to tristearate. In these lipoproteins of very low density, by force of aphysiologically high hydrophobicity, stearic triglycerides are not hydrolyzed by post-heparin lipoproteinlipase. They both do not associate apoE and form apoE/B-J00 ligands. The formation of stearic lipoproteins of very low density occurred at impairment of function of coupled biochemical reactions in synthesis of physiological ω-9 oleic mono unsaturated fatty acid in hepatocytes. To synthesize endogenous oleic mono unsaturated fatty acid the late in phylogenesis insulin expresses two enzymes of coupled biochemical reactions: palmitoyl-KoA-elongase andstearyl-KoA-desaturase, activating synthesis of fatty acids following the path glucose-endogenous palmitic unsaturated fatty acid-stearic unsaturated fatty acid-oleic mono unsaturated fatty acid. The uncoupling of enzymes of coupling synthesis forms in hepatocytes surplus of stearic mono unsaturated fatty acid, stearic triglycerides and of the same name aphysiologic lipoproteins of very low density. During inhibition of the second enzyme the first one continues to actively produce stearic unsaturated fatty acid which the second enzyme, already uncoupled, does not convert into oleic unsaturated fatty acid. By absorbing aphysiologic ligand-free stearic lipoproteins of very low density in biologic reaction of endoecology, phylogenetically early macrophages convert into foam cells initiating aphysiologic biological reaction of transcytosis, biologic reaction of inflammation, biologic reaction of apoptosis and formation of eruptive xanthomata. The lipids of eruptive xanthomata: such endogenous stearic triglycerides as tristearate, tripalmitate, exogenous carotenoids, phospholipids and unesterified cholesterol.

[Role of polymorphic markers for the genes of hemostasis and platelet receptors in liver fibrosis progression in patients with chronic hepatitis C]. / Rol' polimorfnykh markerov genov gemostaza i trombotsitarnykh retseptorov v progressirovanii fibroza pecheni u bol'nykh khronicheskim gepatitom S.

AIM: to estimate the clinical and prognostic value of the carriage of different allele variants of the gene polymorphisms of the coagulation system and platelet receptors in the progression of liver fibrosis (LF) in patient with chronic hepatitis C (CHC). SUBJECTS AND METHODS: The investigation enrolled 177 patients with CHC and liver cirrhosis at its outcome who were divided into 2 groups according to the rate of LF progression: 1) 89 patients with rapid (rapid fibrosis) and 2) 88 patients with slow (slow fibrosis) progression. The polymorphism of the study genes was studied using a real-time polymerase chain reaction and a melting curve analysis. RESULTS: In CHC patients, the FV 1691G/A genotype was more often in the rapid progressors than that in the slow progressors (10.11% vs 1.14%; p=0.011). The A allele of the 1691 G/A FV gene was more common in the rapid fibrosis group than that in the slow fibrosis group (1.7% vs 5.56%, odd ratio 9.787; p=0.139). In our investigation, the polymorphic marker GA in the FII 20210 G/A gene, as well as the 4G allele (5G4G + 4G4G genotypes) and the 4G allele of PAI-I -675 5G/4G were more often seen in the rapid fibrosis group than that in the slow fibrosis group; the detection rate was only at the trend level (p=0.118, p=0.112, and p=0.117 respectively). There were no significant differences between the groups in the spread of variant genotypes and alleles of other study genes. Integral model construction by coding «profibrogenic¼ genotypes (FV 1691 G/A, FII 20210 G/A, PAI-I -675 5G/4G) showed that the fibrosis progression rate expressed as fibrosis units annually also increased with higher total scores (p=0.039), indicating the combined effect of these genes. CONCLUSION: The carriage of mutant genotypes of FV 1691 G/A, FII 20210 G/A, and PAI-I -675 5G/4G genes is a prognostic factor for rapid CHC progression.

[The positional specificity of individual triglycerides-substrates for lipase action. The oleic triglycerides of palm oil, palmitic triglycerides of milk, ions of calcium and magnesium.]

The counter-insulin effect of surplus of palmitic fatty acid in food is implemented under: a) formation in vivo of palmitic type of fatty acids metabolism with deficiency of substrate for ATP synthesis and permanent shortage of energy for accomplishment of biologic functions; b) compensatory activation of biologic function of adaptation, biologic reaction of compensation. The activation with catecholamines in visceral fatty cells of gland the hormone-dependent lipase which is not blocking insulin, increases content of unesterified fatty acids in blood plasma. Until in blood plasma the level of unesterified fatty acids is increased the cells phylogenetically justified stop absorption of glucose along with development of hyperglycemia and hypertriglyceridemia - insulin resistance syndrome. Thew increasing of content of triglycerides (alcohol glycerin) always increases cholesterol - low density lipoproteins; the highest numbers of cholesterol result in no increasing of triglycerides concentration in blood. All triglycerides of milk positionally are palmitic ones and all triglycerides of palm oil are oleic ones. The surplus of palmitic unesterified fatty acids in small intestine under hydrolysis of oleic triglycerides decreases bio-availability and absorption of ions of Ca++ and Mg++ by enterocytes. This occurrence is absent in case of hydrolysis of palmitic triglycerides of maternal milk in intestine since all released unesterified fatty acids are oleic ones. The position of fatty acids in the composition of triglyc erides is a functional characteristic of substrate under impact of positionally specific lipases in all biologic mediums.

[Impact of interleukin-10 and interleukin-28 gene polymorphisms on the development and course of lupus nephritis].

AIM: To assess the relationship of the carriage of IL-10-1080 G/A and IL-28 rs8099917 C/T polymorphisms to the course of lupus nephritis (LN). SUBJECTS AND METHODS: Ninety-nine patients with systemic lupus erythematosus (SLE), including 68 with LN, were examined. Gene polymorphisms were analyzed using standard molecular genetic techniques. The frequency of the clinical manifestations of LN was analyzed; renal survival (RS) was estimated by the Kaplan-Meier method. RESULTS: Ten-year RS rates were 80 and 86% of the patients with and without the mutant IL-10 allele, respectively (p = 0.78). The 10-year RS was lower (75%) in carriers of the mutant IL-28 rsl2979860 allele than in patients without this mutant allele (83%; p = 0.049) and in those of the mutant IL28 rs8099917 allele than in patients without the above mutant allele (67 and 88%, respectively; p = 0.047). LN patients, carriers of the mutant IL-10-1028 G/A allele, were observed to have higher-grade proteinuria in the presence of nephritic syndrome (mean 6.1 g/l) than those without the mutant allele of this gene (mean 2.9 g/l; p = 0.034). However, the mutant allele carriers responded to treatment better (p = 0.050). The mutant IL-10 and IL-28 alleles were unassociated with the development of rapidly progressive nephritis, the activity of a renal lupus process, and the rate of onset of SLE and LN. CONCLUSION: In the LN patients, the carriage of the mutant IL-10 allele A is associated with a better response to treatment and that of the mutant IL-28 allele is linked to the severe course of the disease.

[Single Nucleotide Polymorphisms in T-Cadherin Gene (CDH13) Have Cumulative Effect on Body Mass in Patients With Ischemic Heart Disease].

BACKGROUND: Low adiponectin concentration observed in obese patients is associated with a high risk of metabolic disorders and cardiovascular diseases and could be related to single nucleotide polymorphisms (SNPs) in T-cadherin gene (CDH13). T-cadherin is a receptor for adiponectin and low-density lipoprotein. Aim of this study was to investigate association of CDH13 SNPs with the development of obesity in patients with ischemic heart disease (IHD). RESULTS: We established a statistically significant correlation between the number of minor alleles of rs11646213, rs4783244 and rs12444338 in CDH13 gene with body mass index: patients with smaller number of minor alleles tended to have normal body weight (odds ratio 3.03, 95% confidence interval 1.03-8.87). CONCLUSION: The obtained results are indicative of the cumulative effect of SNPs in CDH13 (rs11646213, rs4783244, rs12444338) on BMI in patients with IHD.

[Endothelial NO synthase and connexin 37 gene polymorphisms as a risk factor for myocardial infarction in subjects without a history of coronary artery disease].

AIM: To define a role of connexin37 (Cx37) C1019T and endothelial nitric oxide synthase (eNOS) G894T polymorphisms in the development of myocardial infarction (MI) in subjects without a history of coronary artery disease. SUBJECTS AND RESULTS: The investigation enrolled 183 male patients, of whom 56 (18.1%) developed MI in the presence of clinically and instrumentally verified coronary heart disease (CHD) (except MI) and 127 (81.9%) patients did without any previous clinical signs of CHD. The gene polymorphisms were identified using polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: The spread of the G allele in the eNOS gene was 59.8% in the patients with MI in the presence of CHD and 75.6% in those with MI without a history of coronary artery disease (p<0.01). The GG genotype was found in 32.1 and 54.3%, respectively (p=0.01; the odds ratio (OR) was 2.5 with 95% confidence interval (CI) 1.3 to 4.9). The spread of the mutant T allele in the Cx37 gene was 29.5% in the patients with MI in the presence of CHD and 59.8% in those with MI without a history of coronary artery disease (p<0.01). The TT genotype was encountered in 7.1 and 42.5% of cases, respectively (p=0.01; OR 9.6 with 95% CI 3.3 to 28.4). There was no case of a combination of GG and TT genotypes among the patients with MI in the presence of CHD whereas this was found in 23.6% of the MI cases without a history of coronary artery disease (p<0.01). CONCLUSION: Determination of Cx37 C1019T and eNOS G894T polymorphisms may be used to detect a genetic predisposition to the development of MI in patients with hemodynamically insignificant atherosclerosis and in apparently healthy individuals.