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 first experience of non-interferon therapy of HCV infection in patients with Wilson-Konovalov's disease.

In the article we present three clinical observations demonstrating that HCV infection in patients with remission of Wilson disease causes an recrudescence of the disease, in one of the observations - decompensation of liver cirrhosis. In this study we first describe on the successful treatment of HCV infection with direct antiviral drugs in patients with Wilson disease. Establishment of all factors of liver damage and successful treatment (elimination of the virus, adequate lifelong medical treatment) allow to expect a favorable prognosis in patients with a combination of Wilson disease and HCV infection.

[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.

[Mathematic Model for Prediction of Liver Fibrosis Progression Rate in Patients with Chronic Hepatitis C Based on Combination of Genomic Markers].

AIM OF STUDY: To evaluate clinical significance of different combinations of gene polymorphisms IL-1b, IL-6, IL-10, TNF, HFE, TGF-b, ATR1, N0S3894, CYBA, AGT, MTHFR, FII, FV, FVII, FXIII, ITGA2, ITGB3, FBG, PAI and their prognostic value for prediction of liver fibrosis progression rate in patients with chronic hepatitis C (CHC). SUBJECTS AND METHODS: 118 patients with CHC were divided into "fast" and "slow" (fibrosis rate progression ≥ 0.13 and < 0.13 fibrosis units/yr; n = 64 and n = 54) fibrosis groups. Gene polymorphisms were determined. Statistical analysis was performed using Statistica 10. RESULTS: A allele (p = 0.012) and genotype AA (p = 0.024) of AGT G-6T gene, as well as T allele (p = 0.013) and MT+TT genotypes (p = 0.005) of AGT 235 M/T gene were significantly more common in "fast fibrosers" than in "slow fibrosers". Patients with genotype TT of CYBA 242 C/T had a higher fibrosis progression rate than patients with CC+CT genotype (p = 0.02). Our analysis showed a protective effect of TTgenotype of ITGA2 807 C/T on fibrosis progression rate (p = 0.03). There was a trend (p < 0.15) to higher fibrosis progression rate in patients with mutant alleles and genotypes of TGFb +915 G/C, FXIII 103 G/T, PAI-675 5G/4G genes. Other gene polymorphisms were not associated with enhanced liver fibrosis. To build a mathematical modelfor prediction of liverfibrosis progression rate we performed coding with scores for genotypes and virus genotype. Total score correlated with the fibrosis progression rate (R = 0.39, p = 0.000). CONCLUSION: Determination of genetic profile of the patient and virus genotype allows to predict the course of CHC.

[Viability and angiogenic activity of mesenchymal stromal cells from adipose tissue and bone marrow in hypoxia and inflammation in vitro].

Adult progenitor stromal cells derived from adipose tissue (ADSC) and bone marrow (BMDSC) hold great promise for use in cell-based therapy of ischemic diseases. Both cell lines secrete a various number of angiogenic cytokines which are regulated by hypoxia and improve vascularization of ischemic tissues being injected in damaged muscle or intravenously. However, such factors as low oxygen level and inflammation may impair the viability and functional activity of these cells after delivery to the ischemic area. We directly compared the reactions of ADSCs and BMDSCs to hypoxic and inflammatory conditions in vitro. Cultured ADSCs and BMDSCs from Balb/c mice were cultivated for 48 h under 1% O2 (hypoxia), 20% O2 (normoxia) or in the presence of inflammatory cytokines. Cell viability analyzed by annexin V-PE binding and 7AAD storage (flow cytometry), and by quantitative TUNEL showed no decrease under hypoxic condition. But cell apoptotic rates significantly increased (up to 70 %) under inflammatory condition. Inflammatory cytokines did not stimulate gene expression of angiogenic growth factors. Otherwise, gene expression profiles of angiogenesis-related cytokines showed activation of pro-angiogenic and suppression of anti-angiogenic factors in the cells under hypoxic condition. In general this effect was higher for ADSCs than for BMDSCs. Using in vitro and in vivo models of angiogenesis we have demonstrated that incubation under hypoxic condition increases stromal cells ability to stimulate blood vessels growth.

[Hypoxia as the main activator of angiogenesis and fatty tissue growth].

Poor content of oxygen indices gene expression for angiogenic growth factors both in adipocytes and in stromal cells of the fatty tissue. Stimulation of blood vessels by these factors leads to hyperplasia ofpregenitior cells and by their differentiation. This review mentions functional changes occurring in the fatty tissue cells under the effect of hypoxy.