Value of peripheral blood lymphocyte count in evaluating the short－term prognosis of patients with acute－on－chronic liver failure / 临床肝胆病杂志

ObjectiveTo investigate the influencing factors for the prognosis of patients with acute－on－chronic liver failure （ACLF）， and to establish a short－term prognostic model. MethodsA retrospective analysis was performed for the baseline clinical data of 247 patients with ACLF who were hospitalized in Department of Infectious Diseases， The First Affiliated Hospital of Xi’an Jiaotong University， from January 2011 to December 2016， and the patients were divided into survival group and death group. The two groups were compared to identify the influencing factors for prognosis； a prognostic model was established， and the receiver operating characteristic （ROC） curve was used to assess its predictive efficacy and determine the optimal cut－off value. The independent－samples t test was used for comparison of normally distributed continuous data between groups， and the Mann－Whitney U rank sum test was used for comparison of non－normally distributed continuous data between groups； the Fisher’s exact test or the Pearson’s chi－square test was used for comparison of categorical data between groups. The univariate and multivariate logistic regression analyses were used to investigate the independent risk factors for 28－ and 90－day prognosis， and the Kaplan－Meier method was used to plot the 28－day survival curves. ResultsA total of 220 patients with ACLF were included based on the inclusion and exclusion criteria； there were 148 patients in the 28－day survival group and 72 patients in the 28－day death group， with a 28－day transplantation－free survival rate of 67.27%； there were 115 patients in the 90－day survival group and 105 patients in the 90－day death group， with a 90－day transplantation－free survival rate of 52.27%. The logistic regression analysis showed that female sex （odds ratio ［OR］=2.149， P=0.030）， high Model for End－Stage Liver Disease （MELD） score （OR=1.120， P<0.001）， and low lymphocyte count （OR=0.411， P=0.002） were independent risk factors for 28－day prognosis， and an LS－MELD model for 28－day prognosis was established as Logit （28－day prognosis）=－3.432+0.765×sex－0.890×lymphocyte count×10－9+0.113×MELD（1 for male sex and 2 for female sex）. The ROC curve analysis showed that this model had an optimal cut－off value of 0.35， and then the patients were divided into low LS－MELD group （≤0.35） and high LS－MELD group （>0.35）； the low LS－MELD group had a significantly higher 28－day survival rate than the high LS－MELD group （P<0.001）. ConclusionPeripheral blood lymphocyte count combined with sex and MELD score has a certain value in predicting the short－term prognosis of ALCF patients.

Clinical characteristics of patients with hemorrhagic fever with renal syndrome during pregnancy: a multicenter clinical study / 中华传染病杂志

Objective:To analyze the clinical characteristics and prognosis of pregnant women with hemorrhagic fever with renal syndrome (HFRS).Methods:A total of 11 pregnant women with HFRS admitted to The Second Affiliated Hospital of Xi′an Jiaotong University (four cases), The Second Affiliated Hospital of Air Force Medical University (four cases), The First Affiliated Hospital of Xi′an Jiaotong University (one case) and Central Hospital of Xianyang City (two cases) between November 2009 and February 2019 were included as the study group, and 24 age-matched non-pregnant women with HFRS were selected as the control group. The age, complications, clinical classification and laboratory indexes of the two groups were analyzed retrospectively, and the clinical outcomes of pregnant women and their fetuses in the study group were followed up. The data between two groups were compared using Mann-Whitney U test or chi-square test. Results:Patients in the study and control groups were 29 (22, 33) and 32 (24, 37) years old, respectively. Seven of 11 patients in study group were severe and critical cases, which was significantly higher than that in the control group (16.7%(4/24), χ2=7.722, P=0.015). In the study group, 10 patients had hypervolemic syndrome, 10 patients had pulmonary edema and six patients had overlapping hypotension shock phase and oliguria phase, which were all higher than those in the control group ((2/24, 8.3%), (2/24, 8.3%) and (2/24, 8.3%), respectively; χ2=22.828, 22.828 and 9.135, respectively, all P<0.01). Compared with the control group, the pregnant patients in study group had a higher urea nitrogen maximum and serum creatinine maximum, and the differences were both statistically significant ( Z=-2.453 and -2.336, respectively, both P<0.05), while they had a lower serum albumin minimum, hemoglobin maximum and hemoglobin minimum, and the differences were all statistically significant ( Z=-3.742, -3.350 and -4.034, respectively, all P<0.01). All pregnant women with HFRS recovered. Nine pregnant women gave birth to nine healthy infants. All of them received breastfeeding and the feeding duration were more than six months. No abnormal growth and development were found during an average follow-up of three years. Conclusions:Pregnancy can aggravate the severity of HFRS, and pregnant women have higher risk of the multiple stages overlap and the complications such as hypervolemic syndrome and acute pulmonary edema. After recovery from HFRS, mother may carry to full-term pregnancy.

Dynamic changes of lymphocytes and the disease progression in patients with coronavirus disease 2019 in Xi’an / 西安交通大学学报(医学版)

【Objective】 To analyze the clinical characteristics of patients with coronavirus disease 2019 (COVID-19) in Xi’an so as to investigate the relationship between the dynamic changes of lymphocytes and the disease progression. 【Methods】 We retrospectively analyzed the clinical data of 15 patients with COVID-19 in The First Affiliated Hospital of Xi’an Jiaotong University from January 22 to February 16, 2020. 【Results】 Among the 15 patients with COVID-19, 8 were males and 7 were females, aged from 22 to 89 years. There were 12 ordinary cases (80%), 1 severe case (6.67%), and 2 critical cases(13.33%). There were 6 groups of family clusters.Most of the patients (14/15, 93.3%) had fever of different degrees. The average time from illness onset to admission was 2.80±1.66 days, and the average time from illness onset to diagnosis was 2.83±2.29 days. The main accompanying symptoms were dry cough (8/15, 53.33%) and shortness of breath (4/15, 26.67%). Nine patients (60%) who had low lymphocyte counts at admission, including of all of the critically ill patients (1 severe case and 2 critical cases) and 6 (6/12, 50%) ordinary patients. Lymphocyte counts in the ordinary cases increased gradually, but fluctuated in the severely ill patients. They were always at low level, or even decreased overall in critical cases. 【Conclusion】 In Xi’an City, COVID-19 mostly occurred in family clusters. Lymphocyte counts were reduced in most patients, especially in critically ill (severe and critical) ones. The lymphocyte count at admission and its kinetics during therapy may be an important predictor for the severity and prognosis of the disease.

Role and mechanism of hepatic stellate cells in the pathogenesis of mice with acute-on-chronic liver failure / 临床肝胆病杂志

ObjectiveTo investigate the role of hepatic stellate cell (HSC) inflammation in the pathogenesis of acute-on-chronic liver failure (ACLF). MethodsA total of 45 male Kunming mice were randomly divided into control group, model group, and N-acetylcysteine (NAC) group. The mice in the model group and the NAC group were given injection of human serum albumin to establish a model of chronic liver disease, followed by intraperitoneal injection of the endotoxins lipopolysaccharide (LPS) and D-galactosamine (D-GlaN) to induce ACLF, and those in the control group were given injection of an equal volume of normal saline; the mice in the NAC group were given NAC since 1 week before the induction of NAC. The mice in the model group and the NAC group were sacrificed at 48 hours after the injection of LPS and D-GlaN. ELISA was used to measure the serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and the levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in liver tissue; HE staining was used to determine liver pathological score; ELISA was used to measure the serum levels of LPS and interleukin-1β (IL-1β). LX2 cells were stimulated by LPS and H2O2 with the presence or absence of NAC, and ELISA was used to measure the levels of IL-1β and interleukin-6 (IL-6) in medium. LX2 cells were stimulated by LPS and H2O2, and then HL7702 cells were cultured with LX2 medium; Western blot was used to measure the expression of caspase-3 and caspase-8 in HL7702 cells, and flow cytometry was used to measure the apoptosis of HL7702 cells. A one-way analysis of variance was used for comparison of continuous data between multiple groups; the least significant difference t-test was used for comparison of data with homogeneity of variance between two groups, and the Tamhane’s T2 test was used for comparison of data with heterogeneity of variance. The Kaplan-Meier survival analysis was used to evaluate survival time, and the log-rank test was used for comparison. ResultsAt 48 hours, all mice in control group survived, while 3 mice in the model group and 8 mice in the NAC group survived, suggesting that the NAC group had a better survival rate of mice than the model group (P＜0.001). Compared with the control group and the NAC group, the model group had significant increases in the serum levels of AST and ALT and the level of MDA in liver tissue, as well as a significant reduction in the level of SOD in liver tissue (all P＜0.01). The model group had a significantly higher liver pathological score than the control group and the NAC group (both P＜0.05). Both LPS and H2O2 promoted the secretion of IL-1β and IL-6 in LX2 cells, and NAC effectively inhibited the pro-inflammatory effect of H2O2 and LPS (all P＜0.05). H2O2 and LPS acted on LX2 cells and promoted the apoptosis of HL7702 cells (all P＜0.05). ConclusionLPS can promote HSC inflammation via reactive oxygen species and participates in the progression of liver failure by inducing hepatocyte apoptosis.

A phase II, single-arm, open-label, multicenter clinical study to evaluate the efficacy and safety of sofosbuvir combined with ribavirin in patients with genotype 2 chronic hepatitis C virus infection / 中华肝脏病杂志

Objective@#To evaluate the efficacy and safety of sofosbuvir (Nanjing Zhengda Tianqing Pharmaceutical Co., Ltd.) combined with ribavirin in patients with genotype 2 chronic hepatitis C virus infection.@*Methods@#Treatment-naïve or treatment experienced genotype 2 chronic hepatitis C patients from sixteen research centers of China were screened. All subjects received once-daily dose of sofosbuvir (400 mg) combined with ribavirin (body weight < 75 kg, 1 000 mg/day, 400 mg in the morning and 600 mg in the evening; body weight > 75 kg, 1 200 mg/d, 600 mg in the morning and 600 mg in the evening) for 12 weeks. Patients were followed-up for a period of 12 weeks after discontinuation of treatment. Continuous variables were expressed as mean ± standard deviation. The proportion of subjects with virologic response at different follow-up time points and 95% confidence intervals were estimated by maximum likelihood ratio and Clopper-Pearson interval.@*Results@#132 cases with genotype 2 chronic hepatitis C virus infection from sixteen research centers of China were included, 12 cases of whom were associated with cirrhosis, and the remaining 120 cases were not associated with cirrhosis. One hundred and thirty-one cases completed the study, and one patient lost to follow-up at week 4 after the end of treatment. The sustained virological response rate was 96.2% (95% confidence interval: 92.37% - 99.16%) after 12 weeks of drug withdrawal. Virological relapse occurred in four cases. Of the 132 subjects enrolled in the study, 119 (90.2%) reported 617 adverse events during treatment, of which 359 (76.5%) were TEAE related to sofosbuvir and/or ribavirin. There were nine TEAEs of grade 3 and above, and six cases (4.5%) of them had six severe adverse events. Only one serious adverse event was associated with sofosbuvir and ribavirin (unstable angina pectoris). There were no adverse events leading to drug discontinuation or death.@*Conclusion@#Sofosbuvir combined with ribavirin has a high SVR rate in the treatment of genotype 2 chronic hepatitis C virus infection, and most of the adverse events occurred were mild with acceptable safety profile.

The dynamic characteristics and predictive value of hepatitis B core antibody titers in chronic hepatitis B patients treated with interferon / 中华传染病杂志

Objective To observe the dynamic characteristics of hepatitis B core antibody (anti-HBc) titers in chronic hepatitis B (CHB) patients treated with interferon and to explore the predictive value of anti-HBc for response to interferon.Methods The clinical information of the patients diagnosed with CHB in Department of Infectious Diseases , the First Affiliated Hospital of Xi′an Jiaotong University from October 2011 to October 2014 were collected.HBV DNA, liver function and HBV serological markers of CHB patients were tested dynamically during and after interferon treatment.The dynamic characteristics of anti-HBc titers in patients with different virological responses were analyzed.The predictive values of anti-HBc titer for the efficacy of interferon treatment of CHB patients were analyzed by binary logistic regression .Results Of the 42 CHB patients aging(30.8 ±10.1) years old, 34 patients were hepatitis B e antigen (HBeAg) positive and 8 were negative.All patients completed 48-week interferon treatment and 24-week follow-up after the end of treatment. Among them, 28.6%( 12/42), 26.2%( 11/42 ) and 45.2%( 19/42 ) of patients achieved sustained virological response (SVR), virological relapse ( VR) and non-response ( NR), respectively.Patients with different virological response presented various characteristics of anti -HBc titers.Compared with NR group, the anti-HBc titers at baseline and week 12 were significantly higher in SVR group (at baseline: [4.93 ±0.30] vs [4.70 ±0.33] lg IU/mL, t ＝2.147, P ＝0.013; at week 12: [4.83 ± 0.23] vs [4.44 ± 0.41] lg IU/mL, t＝3.032, P＝0.007).The anti-HBc titers in SVR group at week 12 and week 24 were significantly higher than those in VR group (at week 12: [4.83 ±0.23] vs [4.67 ±0.51] lg IU/mL, t＝2.400, P＝0.039; at week 24: [4.73 ±0.21] vs [4.55 ±0.50] lg IU/mL, t＝2.542, P＝0.039).By multivariate logistic regression analysis, the anti-HBc titer at baseline was the independent predictive factor for SVR in CHB patients treated with interferon (OR＝6.000, 95%CI: 1.118 -20.486, P＝0.037).The area under receiver operating characteristics curve was 0.753 and the optimal cutoff value of anti-HBc titer for the response to interferons in CHB patients was 5.03 lg IU/mL, with positive predictive value of 64.3%and negative predictive value of 89.3%.Conclusions Dynamic pattern of anti-HBc titers is correlated with different virological responses in CHB patients treated with interferon , and the baseline anti-HBc titer is the independent predictive factor for SVR.

Predictive value of single nucleotide polymorphisms of HLA-C and UBE2L3 in evaluating the effect of telbivudine antiviral therapy during pregnancy / 中华肝脏病杂志

Objective@#To investigate the association between single nucleotide polymorphisms (SNPs) of rs3130542 and rs4821116 in the HLA-C and UBE2L3 genes and the effect of telbivudine antiviral therapy during pregnancy in HBeAg-positive mothers through a large-sample control study, and to provide a basis for the development of individualized blocking strategies for pregnant women with a high viral load.@*Methods@#The genotypes of rs3130542 and rs4821116 were determined for 312 pregnant women with a high viral load who received telbivudine antiviral therapy during the second or third trimester of pregnancy, and the dominant model, recessive model, and additive model were used to analyze the association between the genotypes of these two loci and the reduction in HBV DNA load. The Shapiro-Wilk test and the Levene test were used to evaluate data normality and homogeneity of variances, and the t-test or the non-parametric Mann-Whitney U test was selected based on data type and was used for the comparison of means between groups. The Hardy-Weinberg equilibrium was used to determine the genotype of SNPs, and the dominant model, recessive model, and additive model were used for analysis.@*Results@#Mothers with an AA/AG genotype of rs3130542 in the HLA-C gene had a significantly higher probability of HBV DNA load ≥103 IU/ml at the time of delivery (P < 0.05) and a significantly higher risk of failure in the prevention of mother-to-child transmission, no matter whether they started to take telbivudine at week 24 or 28 of pregnancy. The association between the genotype of rs4821116 in the UBE2L3 gene and the reduction in viral load in pregnant women needed to be confirmed by studies with a larger sample size.@*Conclusion@#Pregnant women with a high viral load and an AA/AG genotype of rs3130542 in the HLA-C gene tend to have poor response to antiviral therapy during pregnancy, and early antiviral intervention is recommended for such patients.

Methylation status of the interferon-gamma gene promoter in chronic hepatitis B / 药物分析学报

Objective To evaluate the methylation status at CpG site -55 in the interferon-gamma (IFN-7) gene promoter and its effect on IFN-7 expression in chronic hepatitis B. Method The authors recruited 30 patients with UBeAg-positive chronic hepatitis B (CHB), 30 HBeAg-negative CHB patients, and 30 healthy blood donors. Pyrosequeneing was used to determine the methylation status at CpG site -55 in the IFN-γ gene promoter following bisulfite treatment of DNA in peripheral blood mononuclear cells (PBMCs). The expression of IFN-γ was analyzed by real-time RT-PCR and ELISA. HBV DNA in PBMCs was detected by nested PCR. Results The methylation level at CpG site -55 in the IFN-γ gene promoter was significantly increased, resulting in subsequent down-regulation of the expression of this cytoldne in CHB. The methylation level at CpG site -55 was significantly higher in HBeAg-positive patients than in HBeAg-negative ones (P<0.01) and was also significantly higher in PBMCs from HBV DNA-positive patients than from HBV DNA-negative ones (P<0.01) ; the methylation level at CpG site -55 was positively correlated with the amount of HBV DNA in serum (P<0.01). Oonclusion IFN-γ gene expression appears to be regulated by methylation of the IFN-γ gene promoter in CHB; the methylation level at CpG site -55 is associated with HBV infection.

Primary study on mechanism of collagen synthesis inhibition in cultured human fetal hepatocytes pretreated by salvia miltiorrhiza bunge / 西安交通大学学报·英文版

Objective: The effects of salvia miltiorrhiza bunge (SMB) on collagen synthesis in the human fetal hepatocytes culture were studied. Methods: The collagen synthesis of hepatocytes were stimulated by the addition of carbon tetrachloride (CCl4) to the culture medium, the concentration of type procollagen (PC) in the culture medium and the hydroxyproline (Hyp) in hepatocytes were determined, as well as the activity of se-dependent glutathione peroxidase (Se-GSH-Px) and the concentration of malondiadehyde (MDA) in the culture medium. Results: A significant decrease in PC, Hyp and MDA production, and the significant increase in Se-GSH-Px activity were observed in the cultures pretreated with 1 g L-1 SMB for 4 hours compared with the untreated cultures. Analysis of the Se-GSH-Px/MDA ratio in SMB pretreated group showed more marked increase compared to that of the untreated group (P<0.01). There was a significant negative correlation between the ratio of Se-GSH-Px/MDA and the concentration of PC in SMB pretreated group (r = -0.9017, P<0.01). Conclusion: Our results indicate that SMB may suppress the collagen synthesis of cultured human fetal hepatocytes stimulated by CCl4, and its mechanism may be related to the increase in Se-GSH-Px/MDA ratio and the enhancement of hepatocytes antioxidation capability.