Combined Age with Mean Decrease Rates of Total Bilirubin and MELD Score as a Novel and Simple Clinical Predictor on 90-Day Transplant-Free Mortality in Adult Patients with Acute Liver Failure Undergoing Plasma Exchange: A Single-Center Retrospective Study.

Background: Acute liver failure (ALF), previously known as fulminant hepatic failure, has become a common, rapidly progressive, and life-threatening catastrophic hepatic disease in intensive care unit (ICU) due to the continuous increase in drug abuse, viral infection, metabolic insult, and auto-immune cause. At present, plasma exchange (PE) is the main effective alternative treatment for ALF in ICU clinical practice, and high-volume plasma exchange (HVP) has been listed as a grade I recommendation for ALF management in the American Society for Apheresis (ASFA) guidelines. However, no existing models can provide a satisfactory performance for clinical prediction on 90-day transplant-free mortality in adult patients with ALF undergoing PE. Our study aims to identify a novel and simple clinical predictor of 90-day transplant-free mortality in adult patients with ALF undergoing PE. Methods: This retrospective study contained adult patients with ALF undergoing PE from the Medical ICU (MICU) in the Second Affiliated Hospital of Harbin Medical University between January 2017 and December 2020. Baseline and clinical data were collected and calculated on admission to ICU before PE, including gender, age, height, weight, body mass index (BMI), etiology, total bilirubin, direct bilirubin, indirect bilirubin, prothrombin activity, model for end-stage liver disease (MELD) score, and sequential organ failure assessment (SOFA) score. Enrolled adult patients with ALF undergoing PE were divided into a survival group and a death group at discharge and 90 days on account of medical records and telephone follow-up. After each PE, decreased rates of total bilirubin and MELD score and increased rates of prothrombin activity were calculated according to the clinical parameters. In clinical practice, different patients underwent different times of PE, and thus, mean decrease rates of total bilirubin and MELD score and mean increase rate of prothrombin activity were obtained for further statistical analysis. Results: A total of 73 adult patients with ALF undergoing 204 PE were included in our retrospective study, and their transplant-free mortality at discharge and 90 days was 6.85% (5/73) and 31.51% (23/73), respectively. All deaths could be attributed to ALF-induced severe and life-threatening complications or even multiple organ dysfunction syndrome (MODS). Most of the enrolled adult patients with ALF were men (76.71%, 56/73), with a median age of 48.77 years. Various hepatitis virus infections, unknown etiology, auto-immune liver disease, drug-induced liver injury, and acute pancreatitis (AP) accounted for 75.34%, 12.33%, 6.85%, 4.11%, and 1.37% of the etiologies in adult patients with ALF, respectively. Univariate analysis showed a significant difference in age, mean decrease rates of total bilirubin and MELD score mean increase rate of prothrombin activity, decrease rates of total bilirubin and MELD score, and increase rate of prothrombin activity after the first PE between the death group and survival group. Multivariate analysis showed that age and mean decrease rates of total bilirubin and MELD score were closely associated with 90-day transplant-free mortality in adult patients with ALF undergoing PE. The 90-day transplant-free mortality was 1.081, 0.908, and 0.893 times of the original value with each one-unit increase in age and mean decrease rates of total bilirubin and MELD score, respectively. The areas under the receiver operatingcharacteristic (ROC) curve of age, mean decrease rates of total bilirubin and MELD score, and the three combined were 0.689, 0.225, 0.123, and 0.912, respectively. The cut-off values of age, mean decrease rates of total bilirubin and MELD score, and the three combined were 61.50, 3.12, 1.21, and 0.33, respectively. The specificity and sensitivity of combined age with mean decrease rates of total bilirubin and MELD score for predicting 90-day transplant-free mortality in adult patients with ALF undergoing PE were 87% and 14%. Conclusion: Combined age with mean decrease rates of total bilirubin and MELD score as a novel and simple clinical predictor can accurately predict 90-day transplant-free mortality in adult patients with ALF undergoing PE, which is worthy of application and promotion in clinical practice, especially in the identification of potential transplant candidates.

The therapeutic effect of CORM-3 on acute liver failure induced by lipopolysaccharide/D-galactosamine in mice.

BACKGROUND: Acute liver failure (ALF) is a severe and life-threatening clinical syndrome resulting in a high mortality and extremely poor prognosis. Recently, a water-soluble CO-releasing molecule (CORM-3) has been shown to have anti-inflammatory effect. The present study was to investigate the effect of CORM-3 on ALF and elucidate its underlying mechanism. METHODS: ALF was induced by a combination of LPS/D-GalN in mice which were treated with CORM-3 or inactive CORM-3 (iCORM-3). The efficacy of CORM-3 was evaluated based on survival, liver histopathology, serum aminotransferase activities (ALT and AST) and total bilirubin (TBiL). Serum levels of inflammatory cytokines (TNF-alpha, IL-6, IL-1beta and IL-10) and liver immunohistochemistry of NF-kappaB-p65 were determined; the expression of inflammatory mediators such as iNOS, COX-2 and TLR4 was measured using Western blotting. RESULTS: The pretreatment with CORM-3 significantly improved the liver histology and the survival rate of mice compared with the controls; CORM-3 also decreased the levels of ALT, AST and TBiL. Furthermore, CORM-3 significantly inhibited the increased concentration of pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-1beta) and increased the anti-inflammatory cytokine (IL-10) productions in ALF mice. Moreover, CORM-3 significantly reduced the increased expression of iNOS and TLR4 in liver tissues and inhibited the nuclear expression of NF-kappaB-p65. CORM-3 had no effect on the increased expression of COX-2 in the ALF mice. An iCORM-3 failed to prevent acute liver damage induced by LPS/D-GalN. CONCLUSION: These findings provided evidence that CORM-3 may offer a novel alternative approach for the management of ALF through anti-inflammatory functions.

Uncovering the pathogenesis and identifying novel targets of pancreatic cancer using bioinformatics approach.

Pancreatic cancer is a uniformly lethal disease that can be difficult to diagnose at its early stage. Thus, our present study aimed to explore the underlying mechanism and identify new targets for this disease. The data GSE16515, including 36 tumor and 16 normal samples were available from Gene Expression Omnibus. Differentially expressed genes (DEGs) were screened out using Robust Multichip Averaging and LIMMA package. Moreover, gene ontology and pathway enrichment analyses were performed to DEGs. Followed with protein-protein interaction (PPI) network construction by STRING and Cytoscape, module analysis was conducted using ClusterONE. Finally, based on PubMed, text mining about these DEGs was carried out. Total 274 up-regulated and 93 down-regulated genes were identified as the common DEGs and these genes were discovered significantly enriched in cell adhesion and extracellular region terms, as well as ECM-receptor interaction pathway. In addition, five modules were screened out from the up-regulated PPI network with none in down-regulated network. Finally, the up-regulated genes, including MIA, MET and CEACAMS, and down-regulated genes, such as FGF, INS and LAPP, had the most references in text mining analysis. Our findings demonstrate that the up- and down-regulated genes play important roles in pancreatic cancer development and might be new targets for the therapy.

Association of Upregulated HMGB1 and c-IAP2 Proteins With Hepatocellular Carcinoma Development and Progression.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most important health problems in China. OBJECTIVES: This study analyzed expression of high-mobility group protein B1 (HMGB1) and inhibitor of apoptosis protein-2 (c-IAP2) proteins in HCC compared to paired para-tumor tissue samples to assess the association with HCC pathogenesis and progression. MATERIALS AND METHODS: Sixty-eight HCC and para-tumor tissue samples were collected for Western blot, qRT-PCR and immunohistochemical analyses of HMGB1 and c-IAP2. RESULTS: HMGB1 and c-IAP2 proteins were highly expressed in HCC tissue samples [85.3% (58/68) and 82.4% (56/68), respectively] compared to para-tumor tissue samples [32.3% and 27.9%, respectively]. Furthermore, expression of HMGB1 was significantly associated with enhanced c-IAP2 expression in HCC tissue samples (r = 0.878, P < 0.01). Expression of HMGB1 was associated with tumor multiplicity and size, alpha-fetoprotein (AFP) level and advanced TNM stage, while expression of c-IAP2 was associated with tumor size, AFP level and advanced TNM stage. CONCLUSIONS: Expression of HMGB1 and c-IAP2 proteins was associated with HCC development and progression, and the expression of HMGB1 and c-IAP2 proteins in HCC were significantly associated with each other. Additionally, these proteins may show promise as biomarkers to predict HCC progression.

Hepatitis C virus core protein induces hepatic metabolism disorders through down-regulation of the SIRT1-AMPK signaling pathway.

BACKGROUND: Steatosis and insulin resistance induced by hepatitis C virus (HCV) infection are, at least in part, critical factors for the progression of chronic hepatitis C (CHC) and can influence the outcome of antiviral treatment. Silent information regulator 1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK) play a key role in the regulation of hepatic glucose and lipid metabolism. The aim of this study was to investigate the possible effect of HCV core protein on energy, glucose, and lipid metabolism of hepatocytes and expression of SIRT1 and AMPK. METHODS: HCV core protein expression plasmid was transfected into HepG2 cells. The level of reactive oxygen species (ROS) and values of NAD(+)/NADH and ATP/ADP were detected. Intracellular levels of triacylglycerol (TG), cholesterol, glucose uptake by hepatocytes, and glucose production were measured. The expression levels of mRNA and protein of SIRT1 and AMPK were detected. The mRNA levels of SIRT1 and AMPK downstream glucose and lipid metabolism genes were measured. RESULTS: In HepG2 cells expressing HCV core protein, the level of ROS increased, the value of NAD(+)/NADH decreased, the activity and expression levels of mRNA and protein of SIRT1 and AMPK decreased, glucose uptake and its regulator gene GLUT2 mRNA levels decreased, glucose production and its regulator genes PEPCK and G6Pase mRNA levels increased, intracellular TG and cholesterol contents and their regulator gene (SREBP-1c, FAS, ACC, HMGR, and HMGS) mRNA levels increased, the glycolytic gene GK and fatty acid oxidation genes PPARα and CPT1A mRNA levels decreased. CONCLUSIONS: HCV core protein induces alterations in cellular redox state (decrease in the NAD(+)/NADH ratio), which could influence the activity of SIRT1 and secondarily AMPK, then change the expression profile of glucose and lipid metabolism-related genes, thereby causing metabolism disorders of hepatocytes.

Silent information regulator 1 inhibition induces lipid metabolism disorders of hepatocytes and enhances hepatitis C virus replication.

AIM: Hepatic steatosis is an important histopathological feature of chronic hepatitis C virus (HCV) infection. Silent information regulator 1 (SIRT1) plays key role in regulation of hepatic lipid metabolism. We investigated the possible effect of HCV replication on lipid metabolism of hepatocytes and expression of SIRT1 using Huh-7.5 cells harboring HCV replicon. METHODS: The level of reactive oxygen species (ROS) and malondialdehyde (MDA), the activity of superoxide dismutase (SOD), and the value of nicotinamide adenine dinucleotide (NAD(+) )/NADH was detected. The level of triacylglycerol (TG), total cholesterol (TC) and fatty acid ß-oxidation rate was detected. The activity and expression levels of SIRT1 and expression of its downstream lipid-metabolism genes were measured. RESULTS: In replicon cells, the level of ROS and MDA increased, SOD activity and the value of NAD(+) /NADH decreased, then the activity and expression level of mRNA and protein of SIRT1 reduced. Inhibition of SIRT1 decreased phosphorylation of forkhead box O1 (FoxO1), which not only upregulated SREBP-1c, FAS, ACC, SREBP-2, HMGR and HMGS genes and increased fatty acid synthesis; but also downregulated PPAR-α and CPT1A genes and decreased fatty acid ß-oxidation. Interferon treatment restored aforementioned changes. SIRT1 activator improved lipid metabolism disorders by an increase in fatty acid ß-oxidation and a decrease in TG and TC synthesis and inhibited HCV replication. CONCLUSION: HCV replication decreasing NAD(+) /NADH ratio may downregulate the activity and the expression of SIRT1, then change the expression profile of lipid metabolism-related genes, thereby cause lipid metabolism disorders of hepatocytes and promote HCV replication. Treatment with SIRT1 activator ameliorates lipid metabolic disorders and inhibits HCV replication.

Hepatoprotective effects of cathepsin B inhibitor on acute hepatic failure induced by lipopolysaccharide/D-galactosamine in mice.

BACKGROUND: Increasing evidence suggests that the inactivation of cathepsin B attenuates hepatocyte apoptosis and liver damage. This study aimed to investigate the protective effects of a cathepsin B inhibitor (CA-074me) on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute hepatic failure (AHF) in mice. METHODS: Mice were intraperitoneally injected with a combination of LPS/D-GalN to induce AHF with or without CA-074me pretreatment. The cumulative survival rates were calculated 48 hours after the induction of AHF. As well as changes in biochemical indicators and liver histology, hepatocyte apoptosis was assessed using a TUNEL method. Serum tumor necrosis factor-alpha (TNF-alpha) production, caspase-3, caspase-8, and caspase-9 activity was evaluated. Cytosolic cytochrome c and Bcl-2 expression were measured by Western blotting. RESULTS: The marked elevation in serum aminotransferase activity and prothrombin time found in LPS/D-GalN-treated mice was significantly improved by pretreatment with CA-074me. The efficacy of CA-074me was also confirmed by histological analysis and TUNEL assay. The survival rate significantly improved in LPS/D-GalN-induced mice given CA-074me compared with untreated mice. LPS/D-GalN-induced caspase-3 and caspase-9 activation was remarkably suppressed by CA-074me. However, the increased levels of serum TNF-alpha and elevated caspase-8 activity in AHF mice were not significantly reduced by CA-074me. Moreover, CA-074me sharply reduced the increased expression of cytosolic cytochrome c and markedly augmented Bcl-2 expression. CONCLUSION: These results suggest that CA-074me has a protective effect in acute hepatic failure induced by LPS/D-GalN.

Inhibition of silent information regulator 1 induces glucose metabolism disorders of hepatocytes and enhances hepatitis C virus replication.

BACKGROUND AND OBJECTIVE: Glucose metabolism disorders including insulin resistance (IR) and type 2 diabetes are frequent and important cofactors of chronic hepatitis C (CHC). Silent information regulator 1 (SIRT1) plays a key role in the regulation of hepatic glucose metabolism. We investigated the possible effect of HCV replication on glucose metabolism of hepatocytes and expression of SIRT1 using Huh-7.5 cells harboring the HCV replicon. METHODS: The level of reactive oxygen species (ROS) and value of NAD(+)/NADH and ATP/ADP were detected. Glucose uptake by hepatocytes and glucose production were measured. The activity and expression levels of SIRT1 and expression of its downstream glucose-metabolism genes were measured. RESULTS: In replicon cells, the level of ROS increased and the value of nicotinamide adenine dinucleotide (NAD(+))/NADH decreased, then the activity and expression level of mRNA and protein of SIRT1 decreased. Inhibition of SIRT1 not only increased insulin receptor substrate-1 phosphorylation and decreased Akt phosphorylation, inhibited cell surface expression of glucose transporter 2 and suppressed cellular glucose uptake, but it also decreased phosphorylation of forkhead box O1, then upregulated phosphoenolpyruvate carboxykinase and glucose 6-phosphatase genes and downregulated the glucokinase gene, thus promoting glucose production. Interferon treatment restored the aforementioned changes. SIRT1 activator improved glucose metabolism disorders by an increase in glucose uptake and a decrease in glucose production, and it inhibited HCV replication. CONCLUSIONS: HCV replication decreasing the NAD(+)/NADH ratio may downregulate the activity and expression of SIRT1, then change the expression profile of glucose metabolism-related genes, thereby causing glucose metabolism disorders of hepatocytes and promoting HCV replication. Treatment with SIRT1 activator improves glucose metabolic disorders and inhibits HCV replication, suggesting that restoration of SIRT1 activity may be a promising new therapeutic approach for CHC patients with IR.

Regulatory T-cell responses in chronic hepatitis B patients treated with nucleos(t)ide analogs compared with healthy subjects and untreated infected individuals.

BACKGROUND/AIMS: The purpose of this prospective case-control study was to evaluate the clinical effects and host immune response in patients with chronic hepatitis B (CHB) treated with either entecavir (ETV)or adefovir dipivoxil (ADV). METHODOLOGY: Forty-two patients diagnosed with CHB were recruited and randomly assigned to receive either ADV (n=19) or ETV(n=18) and were followed for a minimum of 96 weeks.Serum hepatitis B virus (HBV) DNA, hepatitis B e antigen and antibody (HBeAg, HBeAb), alanine amino-transferase (ALT) and aspartate aminotransferase(AST) were measured at baseline and every 24 weeks until study completion. After 96 weeks of therapy, regulatory T-cells (Tregs) were measured in the patients treated with ETV or ADV. RESULTS: Significant decreases in serum ALT, AST and HBV DNA, but not in HBeAgor HbeAb, were noted in the treatment group. The ra-tios of CD4+CD25+ and CD4+CD25+CD45RO+CD125+in CD4+ T-cells were significantly higher in the untreated group compared to those in the ETV and ADV groups. Treg profiles were significantly altered in CHB patients after 96 weeks of nucelos(t)ide therapy HBV-infected individuals. CONCLUSIONS: Study results support the hypothesis that Tregs play a role in regulating the immune response in patients with CHB.

Efficacy and factors influencing treatment with peginterferon alpha-2a and ribavirin in elderly patients with chronic hepatitis C.

BACKGROUND: In China, hepatitis C virus (HCV) infection is characterized by an increasing prevalence during aging. This study was undertaken to evaluate the efficacy of treatment with peginterferon alpha-2a and ribavirin in elderly chronic hepatitis C (CHC) patients and study the factors related to the sustained virologic response (SVR). METHODS: The medical records of 417 patients treated with peginterferon and ribavirin were retrospectively analyzed. These patients were divided into two groups according to age: patients aged ≥ 65 years (n=140) and patients aged <65 years (n=277). The rate of ribavirin reduction or discontinuation and virologic response rates of the two groups were compared. The factors influencing SVR were studied by multivariate analysis. RESULTS: Ribavirin reduction or discontinuation was more frequent in patients aged ≥ 65 years than patients aged <65 years (37.1%, 52/140 vs 20.2%, 56/277; X2=13.883, P<0.001). For genotype 1, patients aged ≥ 65 years had a higher relapse rate (50.0%, 42/84 vs 29.2%, 52/178; X2=10.718, P=0.001) and a lower SVR rate (40.0%, 42/105 vs 60.0%, 126/210; X2=11.250, P=0.001) than patients aged <65 years. There were no significant differences in virologic response rates between the two groups for patients with genotype 2. For genotype 1, in patients aged ≥ 65 years, the SVR rate of females was lower than that of males (28.6%, 12/42 vs 47.6%, 30/63; X2=8.150, P=0.004); in the high viral load group, patients aged ≥ 65 years had a lower SVR rate than patients aged <65 years (30.0%, 18/60 vs 54.8%, 69/126; X2=10.010, P=0.002). In multivariate logistic regression analysis, the independent factors associated with SVR in patients aged ≥ 65 years were sex (P=0.020), genotype (P=0.005), ribavirin reduction or discontinuation (P=0.009) and presence of rapid virologic response (RVR) (P=0.001). CONCLUSIONS: The rate of ribavirin reduction or discontinuation and relapse rate of patients aged ≥ 65 years with genotype 1 are high, and the SVR rate is low. Age has no impact on virologic responses rates for genotype 2. Among patients ≥ 65 years old, genotype 2 patients and genotype 1 patients with a low baseline viral load or achieving RVR or male may benefit from combination therapy.

The effect of metformin on the efficacy of antiviral therapy in patients with genotype 1 chronic hepatitis C and insulin resistance.

OBJECTIVES: Insulin resistance (IR) affects sustained virological response (SVR) in chronic hepatitis C (CHC). The aim of this study was to investigate the effect of adding metformin to peginterferon alfa-2a and ribavirin on the efficacy in patients with genotype 1 CHC and IR. METHODS: Ninety-eight patients with genotype 1 CHC and IR were randomized into the treatment group (n=49) and the control group (n=49). Patients in the control group received peginterferon alfa-2a and ribavirin, and patients in the treatment group received metformin in addition to peginterferon alfa-2a and ribavirin. The rate of virological response, changes in the homeostasis model assessment of insulin resistance (HOMA-IR) index, and the incidence of side effects were compared between the two groups. Factors influencing the SVR were studied by multivariate analysis. RESULTS: The SVR rate of the treatment group was significantly higher than that of the control group (59.2%, 29/49 vs. 38.8%, 19/49; Chi-square=4.083, p=0.043). The HOMA-IR index of patients in the treatment group was lower than that of patients in the control group at weeks 12, 24, and 48 of the treatment period, and at week 24 of follow-up (3.00±0.65 vs. 3.50±0.72, 1.90±0.45 vs. 2.90±0.64, 1.75±0.40 vs. 2.74±0.48, and 1.60±0.35 vs. 2.60±0.55, respectively; t=3.610, 8.947, 11.091, and 10.738, respectively; p<0.01). Diarrhea was more often seen in the treatment group (28.6%, 14/49 vs. 10.2%, 5/49; Chi-square=5.288, p=0.021). In the multivariate logistic regression analysis, the independent factors associated with SVR were treatment method (p=0.009) and HOMA-IR <2 at week 24 (p=0.011). CONCLUSIONS: A combination of metformin, peginterferon alfa-2a, and ribavirin improved insulin sensitivity and increased the SVR rate of patients with hepatitis C genotype 1 and IR, with a good safety profile.

[A study of the relationship between neutropenia and clinical infection risk during treatment with peginterferon alfa-2a and ribavirin for chronic hepatitis C].

OBJECTIVE: To investigate the correlation between neutropenia (ANC) incidence and infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C. METHODS: A retrospective cohort study of 399 patients treated with peginterferon and ribavirin derived from database of Department of Infectious Diseases, the Second Affiliated Hospital, Harbin Medical University was conducted. The incidence of infections and their relation with ANC were investigated. Potential risk factors for infection were identified by multivariate analysis. RESULTS: During treatment, neutropenia (ANC < 1.50 × 10(9)/L) occurred in 251 patients. Among which, mild neutropenia [ANC: (> 0.75 - < 1.50) × 10(9)/L], moderate neutropenia [ANC: (0.50 - 0.75) × 10(9)/L] and severe neutropenia (ANC < 0.50 × 10(9)/L) occurred in 132 patients, 103 patients and 16 patients, respectively. A total of 80 infections (20.1%) occurred, among which, 14 infections were defined as severe. There was no significant difference in infection rate between patients with and without neutropenia (19.9%, 50/251 vs 20.3%, 50/251; χ(2) = 0.007, P = 0.933). There was no significant difference in infection rate between patients with and without peginterferon dose reduction (21.5%, 31/144 vs 19.2%, 49/255; χ(2) = 0.307, P = 0.580). In multivariate logistic regression analysis, the independent factors associated with infection were age (P = 0.021), diabetes (P = 0.004) and cirrhosis (P = 0.012). CONCLUSIONS: Infections during treatment with peginterferon alfa and ribavirin for chronic hepatitis C are irrelevant to neutropenia. The independent factors associated with infection are age, diabetes and cirrhosis.

The study of relationship between neutropenia and infection during treatment with peginterferon α and ribavirin for chronic hepatitis C.

OBJECTIVE: Neutropenia is frequent during treatment of chronic hepatitis C (CHC) with peginterferon and ribavirin. It remains unclear whether neutropenia is associated with infection in CHC. The aim was to study the relationship between neutropenia and infection during treatment with peginterferon and ribavirin for CHC. METHODS: A retrospective cohort on 399 patients treated with peginterferon α and ribavirin derived from our hospital database was conducted. The occurrence of infections and their relationship to neutropenia were investigated. Potential risk factors for infection were identified by multivariate analysis. RESULTS: During treatment, neutropenia [absolute neutrophil counts (ANC) <1.5 × 109/l] occurred in 251 patients, mild neutropenia [ANC (0.75-1.5) × 109/l] occurred in 132 patients, moderate neutropenia [ANC (0.50-0.75) × 109/l] occurred in 103 patients, and severe neutropenia (ANC<0.50 × 109/l) occurred in 16 patients. Eighty infections (20.1%) occurred, 14 infections (17.5%) were defined as severe. There was no significant difference in infection rate between patients with and without moderate and severe neutropenia (21.0%, 25/119 vs. 19.6%, 55/280; χ²=0.097, P=0.755). There was no significant difference in infection rate between patients with and without peginterferon dose modifications (21.5%, 31/144 vs. 19.2%, 49/255; χ²=0.307, P=0.580). In multivariate logistic regression analysis, the independent factors associated with infection were age (P=0.021), diabetes (P=0.004), and cirrhosis (P=0.012). CONCLUSION: Infections during treatment with peginterferon α and ribavirin for CHC are not associated with neutropenia. The independent factors associated with infection are age, diabetes, and cirrhosis.

Impact of sex on virologic response rates in genotype 1 chronic hepatitis C patients with peginterferon alpha-2a and ribavirin treatment.

OBJECTIVES: The relationship between patient sex and the effectiveness of peginterferon alpha-2a and ribavirin treatment in chronic hepatitis C (CHC) patients remains unclear. The aim of this study was to investigate the impact of sex on virologic responses rates in genotype 1 CHC patients. METHODS: A matched retrospective cohort study of 630 genotype 1 patients treated with peginterferon and ribavirin derived from our hospital database was conducted. These patients were divided into three groups according to age: patients aged <40 years (n=200), patients aged 40-50 years (n=210), and patients aged 51-60 years (n=220). The rate of patients receiving ≥ 80% of the planned drug dose and virologic response rates were compared between males and females in the three groups. Factors influencing the sustained virologic response (SVR) were studied by multivariate analysis. RESULTS: In patients aged 51-60 years, the rate of female patients receiving ≥ 80% of the planned ribavirin dose was significantly lower than that of males (42.7%, 47/110 vs. 61.8%, 68/110; Chi-square=8.035, p=0.005). In patients aged <40 years, the SVR rate of females was significantly higher than that of males (75%, 75/100 vs. 54%, 54/100; Chi-square=9.630, p=0.002); in patients aged 40-50 years, there was no significant difference in the SVR rate between males and females (50.5%, 53/105 vs. 54.3%, 57/105; Chi-square=0.305, p=0.580); in patients aged 51-60 years, the SVR rate of females was significantly lower than that of males (33.6%, 37/110 vs. 48.2%, 53/110; Chi-square=4.814, p=0.028). In multivariate logistic regression analysis, the independent factors associated with SVR in patients aged 51-60 years were sex (p=0.013), ≥ 80% of the planned ribavirin dose (p=0.008), and the presence of a rapid virologic response (p=0.001). CONCLUSIONS: In the group of patients aged <40 years, the SVR rate of females was higher than that of males; in the group of patients aged 40-50 years, females and males shared similar SVR rates; in the group of patients aged 51-60 years, the SVR rate of females was lower than that of males.

Lamivudine treatment is associated with improved survival in fulminant hepatitis B.

OBJECTIVE: Fulminant hepatitis B is a clinical syndrome that results from massive necrosis of liver cells leading to the development of hepatic encephalopathy. The aim of this study was to evaluate the efficacy of lamivudine in patients with fulminant hepatitis B and study the prognostic factors. METHODS: A matched retrospective cohort study using data on fulminant hepatitis B patients derived from our hospital database was conducted. Forty patients receiving lamivudine treatment were selected into the lamivudine treatment group with another 40 without lamivudine treatment studied as control. They were matched for sex, age and HBeAg status with lamivudine treatment group. The mortality of patients in two groups was compared. The influential factors on the mortality were studied by Cox proportional hazards model. RESULTS: The mortality of patients in the lamivudine group (n=38) was significantly lower than that of the control group (n=39) (63.2 vs. 84.6%; χ(2) =4.609, P=0.032). For patients without systemic inflammatory response syndrome (SIRS), the mortality of patients in the lamivudine group (n=25) was significantly lower than that of the control group (n=26) (52.0 vs. 80.8%; χ(2) =4.747, P=0.029). In multivariate Cox proportional hazards analyses, for patients without SIRS, age (P=0.037), ratio of total to direct bilirubin (P=0.008), treatment method (P=0.005) and the decline of hepatitis B virus (HBV) DNA load during therapy (P=0.019) were independent predictors of prognosis. CONCLUSIONS: Treatment with lamivudine significantly decreases the mortality of fulminant hepatitis B patients without SIRS, and a rapid decline of HBV DNA load is one of the good predictors for the treatment outcome.

[Impact of age and sex on virologic responses of peginterferon alfa-2a and ribavirin treatment in chronic hepatitis C].

OBJECTIVE: To investigate the impact of age and sex on virologic responses rates to peginterferon alfa-2a and ribavirin treatment in patients with chronic hepatitis C. METHODS: The medical records of 449 chronic hepatitis C patients, treated with peginterferon and ribavirin in Department of Infectious Diseases, the Second Affiliated Hospital, Harbin Medical University, were retrospectively analyzed. These patients were divided into three groups according to age: patients < 40 years (n = 131), patients 40 - 50 years (n = 131) and patients > 50 years (n = 187). The virologic response rates, the incidences of side events, and the rates of patients receiving ≥ 80% of planned peginterferon alfa-2a or ribavirin dose were compared between male and female patients in the three groups. The influential factors on sustained virologic response (SVR) of patients were studied by multivariate analysis. RESULTS: For genotype 1, in patients < 40 years group, the SVR rate of female was significantly higher than that of male (75.0%, 30/40 vs 54.0%, 27/50; P < 0.05); in patients 40-50 years group, there was no significant difference in the SVR rate between male and female (51.0%, 25/49 vs 53.7%, 22/41; P > 0.05); in patients > 50 years group, the SVR rate of female was significantly lower than that of male (31.1%, 19/61 vs 50.7%, 34/67; P < 0.05). For genotype 2, there were no significant differences in virologic response rates between male and female in the three groups. The incidence of adverse events of patients aged < 40 years group, 40 - 50 years group, > 50 years group, were 51.1% (67/131), 51.1% (67/131), and 70.6% (132/187), respectively, and the incidence of adverse events of patients aged > 50 years was significantly higher than those of other groups (P < 0.001). For genotype 1, in patients > 50 years group, the rate of patients receiving ≥ 80% of planned ribavirin dose of female was significantly lower than that of male (42.6%, 26/61 vs 62.7%, 42/67; P < 0.05). In multivariate analysis, the independent factors associated with SVR of patients aged > 50 years were sex (P = 0.013), genotypes (P = 0.002), cirrhosis (P = 0.004), ≥ 80% of planned ribavirin dose (P = 0.008) and presence of rapid virologic response (RVR) (P = 0.001). CONCLUSIONS: For genotype 1 patients, in patients < 40 years group the SVR rate of female is higher than that of male; in patients 40 - 50 years group, male and female share similar SVR rates; in patients > 50 years group the SVR rate of female is lower than that of male. Age and sex has no impact on virologic responses rates for genotype 2 patients.

Role of cathepsin B-mediated apoptosis in fulminant hepatic failure in mice.

AIM: To investigate the pathogenic role of cathepsin B and the protective effect of a cathepsin B inhibitor (CA-074Me) in fulminant hepatic failure in mice. METHODS: LPS/D-Gal N was injected into mice of the model group to induce fulminant hepatic failure; the protected group was administered CA-074me for 30 min before LPS/D-Gal N treatment; the normal group was given isochoric physiologic saline. Liver tissue histopathology was determined with HE at 2, 4, 6 and 8 h after Lps/D-Gal injection. Hepatocyte apoptosis was examined by TUNEL method. The expression of cathepsin B in liver tissues was investigated by immunohistochemistry, Western blot and RT-PCR. RESULTS: Compared with the normal group, massive typical hepatocyte apoptosis occurred in the model group; the number of apoptotic cells reached a maximum 6 h after injection. The apoptosis index (AI) in the protected group was clearly reduced (30.4 +/- 2.8 vs 18.1 +/- 2.0, P < 0.01 ). Cathepsin B activity was markedly increased in drug-treated mice compared with the normal group (P < 0.01). Incubation with LPS/D-Gal N at selected time points resulted in a time-dependent increase in cathepsin B activity, and reached a maximum by 8 h. The expression of cathepsin B was significantly decreased in the protected group (P < 0.01). CONCLUSION: Cathepsin B plays an essential role in the pathogenesis of fulminant hepatic failure, and the cathepsin B inhibitor CA-074me can attenuate apoptosis and liver injury.

Protective effect and mechanism of stronger neo-minophagen C against fulminant hepatic failure.

AIM: To investigate the protective effect of stronger neo-minophafen C (SNMC) on fulminant hepatic failure (FHF) and its underlying mechanism. METHODS: A mouse model of FHF was established by intraperitoneal injection of galactosamine (D-Gal N) and lipopolysaccharide (LPS). The survival rate, liver function, inflammatory factor and liver pathological change were obtained with and without SNMC treatment. Hepatocyte survival was estimated by observing the stained mitochondria structure with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate fluorescence nick end labeling (TUNEL) method and antibodies against cytochrome C (Cyt-C) and caspase-3. RESULTS: The levels of plasma tumor necrosis factor alpha (TNF-alpha), nitric oxide (NO), ET-1, interleukin-6 (IL-6), and the degree of hepatic tissue injury were decreased in the SNMC-treated groups compared with those in the model group (P < 0.01). However, there were no differences after different dosages administered at different time points. There was a significant difference in survival rates between the SNMC-treated groups and the model group (P < 0.01). The apoptosis index was 32.3% at 6 h after a low dose of SNMC, which was considerably decreased from 32.3% +/- 4.7% vs 5% +/- 2.83% (P < 0.05) to 5% on d 7. The expression of Cyt-C and caspase-3 decreased with the prolongation of therapeutic time. Typical hepatocyte apoptosis was obviously ameliorated under electron microscope with the prolongation of therapeutic time. CONCLUSION: SNMC can effectively protect liver against FHF induced by LPS/D-Gal N. SNMC can prevent hepatocyte apoptosis by inhibiting inflammatory reaction and stabilizing mitochondria membrane to suppress the release of Cyt-C and sequent activation of caspase-3.