Effects of oral antiviral agents on long-term outcomes of treatment-naive patients with HBV-related decompensated cirrhosis: a retrospective cohort study / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy of nucleos(t)ide analogues (NA) treatment and to assess the long-term outcomes, including survival, liver function improvement and virologic response, in patients with decompensated cirrhosis due to hepatitis B virus (HBV) infection.</p><p><b>METHODS</b>Patients with Child-Turcotte-Pugh (CTP) scores more than or equal to 7, who had been treated with either lamivudine or other agents, but who were free of co-infection with other hepatitis virus were enrolled between January 2005 and December 2009. The study participants were subgrouped according to the antiviral drugs received or model for endstage liver disease (MELD) score for comparative analyses.Additionally, the 19 patients who were treated with NA for more than 5 years were investigated for changes in biochemical and virological indices, before and after the antiviral treatment.</p><p><b>RESULTS</b>A total of 166 patients (125 males; 89 e-negative) and 52 untreated healthy patients (as control) were analyzed.The cohort of patients receiving antiviral therapy had significantly better 5-year actuarial survival than the untreated patients (74.1% vs.34.9%, P less than 0.001). For patients with MELD score more than or equal to 18, actuarial survival was not significantly different between the two groups (P=0.073).</p><p><b>CONCLUSION</b>Antiviral therapy significantly increases survival and improves the clinical long-term outcome of patients with HBV-induced decompensated cirrhosis.Antiviral treatment should be initiated at an early stage to maximize benefit in the improvement of clinical status.</p>

Study on female sexual dysfunction in type 2 diabetic Chinese women / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To investigate the female sexual dysfunction (FSD) in type 2 diabetes patients, by comparing the sexual function between type 2 diabetic women and non-diabetic women with Female Sexual Function Index (FSFI).</p><p><b>METHODS</b>115 type 2 diabetic women and 107 age-matched non-diabetes women were enrolled with similar backgrounds. Their sexual functions were evaluated with FSFI. Metabolic parameters such as body mass index, blood lipid profile, hemoglobin A1C, plasma glucose were also collected.</p><p><b>RESULTS</b>Total score of FSFI of the type 2 diabetic women were significantly lower than that of the non-diabetic controls (18.27±8.96 vs. 23.02±5.78, P=0.000). Scores of the FSFI domains (desire, arousal, lubrication, orgasm, satisfaction, pain) of the type 2 diabetic group were also lower than those of the control group. According to the FSD criterion (FSFI<25) available in China, the percentage of FSD in the type 2 diabetic group was significantly higher than that of the control group (79.2%vs. 55.0%, P<0.001). These trends seemed more prominent in pre-menopause subgroups. The logistic regression analysis indicated that age and diabetes were independent risk factors of FSD. Body Mass Index (BMI) also had influence in the diabetes group.</p><p><b>CONCLUSION</b>Findings from this study showed that there are more FDS in Chinese type 2 diabetic women than in their non-diabetic counterparts, especially in pre-menopause participants.</p>

Viral factors influencing histological changes of HBeAg-negative chronic hepatitis B patients with persistently normal serum ALT levels / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the correlation between viral factors and liver histological changes of HBeAg-negative chronic hepatitis B patients with persistently normal serum ALT levels (PNAL).</p><p><b>METHODS</b>HBV DNA level, HBV genotype, basal core promoter (BCP) and precore mutation were examined in 52 HBeAg-negative chronic hepatitis B patients with PNAL (defined as normal ALT measured on at least 3 occasions in the intervals of about two months over a period of 12 months or more prior to the biopsy).</p><p><b>RESULTS</b>Subjects with both BCP and precore mutations had significantly higher HBV DNA levels than those without mutations [(4.9+/-1.4) vs (4.1+/-1.1) log(10)copies/ml, t = 2.308, P < 0.05]. A higher proportion of patients with histological activity index (HAI) > or = to 4 was found in patients with both mutations (32.1% vs 16.7%) than in patients without mutation, however, the proportion of patients with histological activity index (HAI) > or = to 3 in patients with mutations was not significantly different from that in patients without mutations (14.3% vs. 12.5%, x(2)=0.000, P > 0.05). In patients without precore or BCP mutations, there was a strong positive correlation between viral load and liver inflammation as well as fibrosis (precore: r=0.626, 0.592, P < 0.01; BCP: r=0.730, 0.641, P < 0.01). In patients without both mutations, HBV DNA has shown a high accuracy for predecting fibrosis (F > or = 3) (AUC = 0.905, 95% CI: 0.771-1.039, P < 0.05) with the cutoff value of 4.5 log(10) copies/ml (sensitivity = 1.000, specificity = 0.778, PPV = 42.9%, NPV = 100.0%). Results of both genotypes and mutations were successfully obtained in 40 samples with HBV DNA is > or = to 10(4) copies/ml. The higher viral load was observed in the patients with genotype B than genotype C (5.1 vs 4.3 log(10)copies/ml, t = 2.059, P < 0.05), but no difference was seen of liver pathologic changes between these two genotypes.</p><p><b>CONCLUSIONS</b>Virus harboring both BCP and precore mutants has the higher replication level than wild type virus. 32.1% and 14.3% of the patients with both mutations have moderate or severe inflammation and fibrosis. There was a strong positive correlation between viral load and liver histological changes in patients without precore or BCP mutations, and viral load shows a high accuracy for predecting significant fibrosis (F > or = 3).</p>

Effect of silencing connective tissue growth factor on rat liver fibrosis and the accumulation of extracellular matrix / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the anti-fibrogenesis property of intraportal vein injection of small interfering RNA targeting connective tissue growth factor (CTGF) in a rat model of liver fibrosis and its effect on the accumulation of extracellular matrix (ECM).</p><p><b>METHODS</b>Thirty male rats were randomly divided into five groups. Some rats received CCl4 subcutaneously every three days for 6 consecutive weeks, and in the meantime they also received either siRNA targeting CTGF (preventive group), saline (model group) or siRNA (siRNA control group) by intraportal vein injections. Other rats received CCl4 by subcutaneous injection for 2 weeks, followed by CCl4 and CTGF siRNA intraportal vein injection for 4 more weeks (as treatment group). The expressions of CTGF and type I and III collagen genes were detected by means of reverse transcription-polymerase chain reaction (RT-PCR) and/or Western blot respectively. Hepatic histology was evaluated by HE and Sirius red stained sections. The collagen staining areas were measured quantitatively using a computer-aided manipulator with slight modifications. Serum procollagen type III and hyaluronic acid were determined by radioimmunoassay.</p><p><b>RESULTS</b>Six weeks after CCl4 injection, prominent upregulation of gene expressions of CTGF, type I and III collagen, and laminin in saline or siRNA-treated rat livers were observed. The expressions of CTGF at mRNA and protein level and type I and III collagen at mRNA level were markedly reduced in rats with CTGF siRNA treated for four or six weeks. Expressions of CTGF at mRNA and protein levels decreased by 76%+/-8%, 80%+/-3% (F = 68.630) and 95%+/-2%, 93%+/-3% (F = 21.234, P < 0.01); type I and III collagen and laminin at mRNA levels decreased by 74%+/-8%, 78%+/-8%, 31%+/-7% and 57%+/-6%, 59%+/-10%, 43%+/-9% (F = 24.219, 16.315, 9.716, P < 0.01) compared with rats in the model group at 72 h. The CTGF siRNA treatment markedly reduced serum levels of procollagen type III and hyaluronic acid and the degrees of liver fibrosis.</p><p><b>CONCLUSION</b>Intraportal vein siRNA injection targeting CTGF could significantly inhibit CTGF gene expression in rats, thereby attenuating liver fibrosis by reducing ECM accumulation.</p>

Effects of CpG-ODN combined with HBsAg on the phenotype, function and the activity of NF-kappa B and AP-1 of monocyte-derived dendritic cells in chronic hepatitis B patients / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the effect of synthetic non-methylated CpG-ODN combined with recombined HBsAg on the phenotype, function and the expression level of nucleic transcription factor NF-kappa B (NF-kB) and AP-1 of monocyte-derived dendritic cells (DC) in patients with chronic hepatitis B (CHB).</p><p><b>METHODS</b>Purified monocytes were isolated from the peripheral blood of CHB patients and healthy volunteers and cultured with human granulocyte-monocyte colony stimulating factor added together with interleukin-4. On the fifth day of culture, CpG-ODN, HBsAg and other reagents, such as TNF alpha and PBS, were added to the medium, and 18 hours later cells were collected for the detection of surface molecules (HLA-DR/CD86/CD1a). IL-12p70 levels in the supernatant and stimulating capacity to allogenic T lymphocytes were detected. The nucleic proteins of NF-kB and AP-1 in DC were extracted and purified for the gel shift assay.</p><p><b>RESULTS</b>Compared with those of the PBS group, the expression rates of HLA-DR of DC treated with CpG-ODN and/or HBsAg were obviously increased. Both the IL-12p70 level and the stimulating capacity of DC to allogenic T lymphocytes in mixed lymphocyte reaction increased significantly in the CpG-ODN group and in the CpG-ODN/HBsAg combination group (P less than 0.01 and 0.05, respectively). The expression rates of CD1a were raised only in the CpG-ODN/HBsAg combination group. Three kinds of immunological adjuvants, TNF alpha, CpG-ODN and CpG-ODN/HBsAg enhanced the expression of nucleic NF-kB and inhibited the expression of AP-1 in DC.</p><p><b>CONCLUSION</b>CpG-ODN, like TNF alpha, has remarkable stimulatory effect on the impaired phenotype and function of monocyte-derived DC in patients with CHB; CpG-ODN and HBsAg have a synergetic effect in increasing the antigen presenting function. The regulating ability of CpG-ODN and TNF alpha on the expression levels of NF-kB and AP-1 might be one of the mechanisms of their immunostimulatory effects on DC of the CHB patients.</p>

Caspase-12 expression and activation in the pathogenesis of acute hepatic failure induced by lipopolysaccharide and D-galactosamine / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To study the role of caspase-12 expression on hepatocyte apoptosis in an experimental model of acute hepatic failure (AHF).</p><p><b>METHODS</b>A mouse experimental model of AHF was developed by intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (D-Gal). Hepatocyte apoptosis was examined by DNA agarose gel and liver pathology. Caspase-12 mRNA expression in liver was detected by reverse transcriptase PCR (RT-PCR) method. The expression of caspase-12, GRP78 proteins in livers was determined by Western blot.</p><p><b>RESULTS</b>Caspase-12 mRNA expression in the livers increased significantly from 5 to 7 hours after administration of LPS and D-Gal. Typical manifestation of hepatocyte apoptosis appeared at 5 hours after the drug administration. After 5 hours the level of serum ALT and AST were remarkably increased, and they reached the peak at 7 hours. The expression of procaspase-12 protein decreased obviously at 7 hours. Seven hours after the drug administration, hepatocyte apoptosis and necrosis both started. The marker of endoplasmic reticulum (ER) stress, Bip/GRP78 was activated during the development of hepatocyte apoptosis. The level of Bip/GRP78 protein was gradually increased at 5 hours after the drug induction.</p><p><b>CONCLUSION</b>Hepatocyte apoptosis plays an important role in the pathogenesis of AHF. Caspase-12 induced ER stress involves in hepatocyte apoptosis. It suggests that inhibition of caspase-12 activation might be a potential strategy in the treatment of AHF in the future.</p>