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Objective To investigate the possible influence of long-term antiviral therapy with entecavir on renal function in patients with chronic hepatitis B (CHB) and the sensitive indicators for early identification of renal injury. Methods A cross-sectional real-world study was conducted for the clinical data of 125 CHB patients treated with entecavir for more than 1 year (treatment group) and 44 patients with chronic HBV infection who did not receive antiviral therapy (control group), including the changes in serum creatinine (SCr), estimated glomerular filtration rate (eGFR), and the levels of urinary α1 microglobulin (α1-MG), β2 microglobulin (β2-MG), and N-acetyl-β-D-glucosaminidase (NAG). The chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. The independent-samples t test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups. The Logistic regression analysis was used to investigate independent influencing factors for abnormal urinary α1-MG, β2-MG, and NAG in the treatment group. Results There were no significant differences in SCr and eGFR between the treatment group and the control group ( t =0.999 and -1.259, P > 0.05), and both indices were within the normal range in these two groups. The treatment group had significantly higher abnormal rates of urinary α1-MG and β2-MG than the control group (47.2%/42.4% vs 13.6%/13.6%, χ 2 =15.693 and 12.567, both P 2×upper limit of normal (18.4%/21.6% vs 2.3%/4.5%, both P 0.05) and the proportion of patients with urinary NAG > 2×upper limit of normal (8.8% vs 6.8%, P > 0.05). Compared with the control group, the treatment group had a significantly higher proportion of patients with abnormalities in two or more indicators for renal tubular injury (33.6% vs 11.4%, χ 2 =8.519, P 0.05). Conclusion Long-term treatment of CHB with entecavir may be associated with the risk of renal tubular dysfunction, and abnormalities in more than two indicators for renal injury may help to identify renal tubular dysfunction in patients, so as to adjust related treatment in time.
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Objective To investigate liver inflammation and fibrosis in patients with chronic HBV infection with a low viral load. Methods Among the HBsAg-positive patients who attended Ganzhou Fifth People's Hospital from April 2019 to June 2022, 41 patients with 20 IU/mL 200-2 000 IU/mL and 4 (26.67%) had an HBV DNA level of 20-200 IU/mL; the patients with G2 liver inflammation accounted for 73.33% (11/15), and those with S2 liver fibrosis accounted for 46.67% (7/15); the patients with ALT ≤30 U/L accounted for 46.67% (7/15); the patients aged ≥30 years accounted for 86.66% (13/15); the patients with LSM > 17 kPa accounted for 6.67% (1/15), those with an LSM value of 12.4-17 kPa accounted for 46.67% (7/15), and those with an LSM value of 9.4-12.4 kPa accounted for 33.33% (5/15). Conclusion Patients with chronic HBV infection and low-level viremia have a relatively high risk of progression of inflammation and fibrosis. ALT level cannot be used as a basis for antiviral therapy in HBV-infected people with a low viral load. LSM based on transient elastography can be used as a noninvasive test to screen for CHB patients with a low viral load, and antiviral therapy should be considered when HBV-infected patients with a low viral load have an age of > 30 years and an LSM value of > 9.4 kPa persistently.
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Objective To investigate the difference in the prognosis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) caused by hepatitis recurrence after withdrawal of nucleos(t)ide analogues (NUC) and possible causes in HBeAg-positive versus HBeAg-negative chronic hepatitis B (CHB) patients. Methods A total of 108 CHB patients with HBV-ACLF caused by withdrawal of NUC who were admitted to The First Affiliated Hospital of Nanchang University from January 2017 to December 2018 were enrolled, and according to HBeAg status, these patients were divided into HBeAg-positive group with 57 patients and HBeAg-negative group with 51 patients. The two groups were compared in terms of sex, age, clinical manifestation, signs, levels of total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, prothrombin time, activated partial thromboplastin time, prothrombin time/international normalized ratio, and HBV DNA quantification on admission, complications (including hepatic encephalopathy, hepatorenal syndrome, and spontaneous bacterial peritonitis), and prognosis of HBV-ACLF. In addition, 48 CHB patients with continuous NUC antiviral therapy for > 2 years and HBV DNA < 20 IU/mL were enrolled, and the serum level of HBV pgRNA was measured to investigate the possible causes of the difference in the prognosis of HBV-ACLF between the patients with different HBeAg statuses. The two-independent-samples t test was used for comparison of normally distributed continuous data between two groups, and the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data. Results For the 108 patients with HBV-ACLF caused by drug withdrawal and recurrence, the HBeAg-positive group had an improvement rate of 49.1% and the HBeAg-negative group had an improvement rate of 74.5%. The HBeAg-negative group had a significantly higher improvement rate than the HBeAg-positive group ( χ 2 =2.811, P =0.006). The HBeAg-positive group had a significantly higher level of HBV DNA than the HBeAg-negative group on admission ( t =-3.138, P =0.002). For the 48 CHB patients who achieved virologic response after long-term antiviral therapy, the HBeAg-positive group had a significantly higher HBV pgRNA load than the HBeAg-negative group ( H =2.814, P =0.049). Conclusion Compared with the HBeAg-positive CHB patients, HBeAg-negative CHB patients have a significantly better improvement rate of HBV-ACLF caused by hepatitis recurrence after withdrawal of NUC antiviral therapy. The difference in baseline HBV pgRNA level may be associated with the difference in the prognosis of HBV-ACLF in patients with different HBeAg statuses.
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Objective:To investigate the predictive value of serum soluble urokinase-type plasminogen activator receptor (suPAR) combined with alpha-fetoprotein (AFP) and model for end-stage liver disease (MELD) score in short-term prognosis assessment of patients with chronic hepatitis B (CHB) related acute-on-chronic liver failure (ACLF).Methods:From January 2018 to May 2020, 66 patients with CHB related ACLF from Fuzhou First People′s Hospital were enrolled. After 90 days of follow-up, the patients with CHB related ACLF were divided into death group and survival group according to the outcome. Meanwhile, 30 patients with CHB were enrolled by simple random sampling method. The differences of serum suPAR in patients with CHB related ACLF and patients with CHB were analyzed. The values of suPAR, AFP and MELD score were compared between death group and survival group in patients with CHB related ACLF. The predictive value of suPAR, AFP, MELD score, Child-Turcotte Pugh score (CTP score) and suPAR combined with AFP and MELD score in the short-term prognosis of patients with CHB related ACLF were analyzed by area under the receiver operator characteristic curve (AUROC). Data were analyzed by two independent sample t test or non-parametric test. Results:The serum suPAR level of patients with CHB related ACLF was (9.6±0.8) ln ng/L, which was higher than that of patients with CHB ((8.0±0.3) ln ng/L). The difference was statistically significant ( t=14.533, P<0.01). The suPAR and MELD score of patients with CHB related ACLF in the death group were (9.9±0.7) ln ng/L and 29.6 (7.1) points, respectively, which were higher than those in the survival group ((9.4±0.7) ln ng/L and 21.0 (5.0) points, respectively). The AFP level in the death group was 45.9 (108.1) μg/L, which was lower than that in the survival group (209.3 (187.1) μg/L). There were significant differences in suPAR ( t=2.895, P=0.005), MELD score ( Z=4.708, P<0.01) and AFP ( Z=3.051, P<0.01) between the death group and the survival group. AUROC of suPAR (0.741, P=0.001), AFP (0.724, P=0.002) and MELD score (0.885, P<0.01) had predictive value for death in patients with CHB related ACLF. The sensitivities of suPAR, AFP, MELD score, CTP score and suPAR combined with AFP and MELD score were 84.6%, 73.1%, 88.5%, 96.2% and 84.6%, respectively, and the specificities were 75.0%, 72.5%, 70.0%, 52.5% and 92.5%, respectively. The AUROC of suPAR combined with AFP and MELD score was 0.871 ( P<0.01), which was higher than that of CTP score (0.793, P<0.01). Conclusions:Serum suPAR is increased in patients with CHB related ACLF. SuPAR combined with AFP and MELD score could apply in the prognostic value for patients with CHB related ACLF.
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Objective:To investigate the expression levels of interferon-α receptor (IFNAR), interferon-stimulated gene factor 3(ISGF3), double-stranded RNA-activated protein kinase(PKR) and ribonuclease L (RNase L) in patients with chronic hepatitis B (CHB) treated with interferon.Methods:From July 2014 to June 2017, 41 treatment naive CHB patients were enrolled in the Department of Infectious Diseases, First Affiliated Hospital of Nanchang University. Eighteen patients were treated with polyethylene glycol interferon α-2b, and 23 patients were treated with conventional interferon. The mRNA and protein expression levels of IFNAR1, IFNAR2, ISGF3, PKR and RNase L in peripheral blood mononuclear cells (PBMC) were detected by reverse transcription polymerase chain reaction and Western blot, respectively. The differences of these molecular expression levels in PBMC between the effective and ineffective groups were compared. The data were analyzed by t test. Results:After 24 weeks of treatment, 25 cases were effective, while 16 cases were ineffective. At four weeks of treatment, the mRNA expression levels of IFNAR1, IFNAR2 and PKR in PBMC of the effective group were 0.748±0.129, 1.169±0.125 and 1.047±0.091, respectively, which were all higher than those in the ineffective group (0.591±0.021, 0.689±0.059 and 0.791±0.033, respectively). The differences were statistically significant ( t=-4.304, 16.482 and -5.346, respectively, all P<0.01). The mRNA expressions of ISGF3 and RNase L in PBMC of the effective group were 0.739±0.159 and 0.780±0.140, respectively, while those in the ineffective group were 0.690±0.035 and 0.733±0.122, respectively, which were not significantly different ( t=-0.160 and -1.443, respectively, both P>0.05). The mRNA expression levels of IFNAR1, IFNAR2, ISGF3, PKR and RNase L at baseline, week eight, 12 and 24 of treatment in the effective group were all higher than those in the ineffective group (all P<0.01). The protein expression levels of IFNAR1, IFNAR2, ISGF3, PKR and RNase L in the effective group were all higher than those in the ineffective group (all P<0.01). Conclusion:After interferon treatment, the mRNA and protein expression levels of IFNAR1, IFNAR2, ISGF3, PKR and RNase L in PBMC of CHB patients are all increased, especially IFNAR2 and PKR levels increase in the early stage of treatment (four weeks).
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Objective@#To explore the efficacy of glucocorticoid (GC) therapy on hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF), and the effectiveness and safety of voriconazole (VCZ) in preventing pulmonary Aspergillus infection in HBV-ACLF patients treated with GC.@*Methods@#Two hundred and thirty-two patients with HBV-ACLF were enrolled from January 2016 to December 2018 in the First Affiliated Hospital of Nanchang University. They were divided into non-GC group (104 cases), GC group (74 cases), and GC+ VCZ group (54 cases). The observation period was four months. The baseline liver function, the incidence of pulmonary Aspergillus infection, the survival rate during observation period, and the incidence of complications were compared among the three groups. The adverse reactions of VCZ were observed to identify the best dose for prevention. Quantitative data were analyzed by analysis of variance or rank sum test. Count data were analyzed by chi-square test or Fisher exact test.@*Results@#The baseline liver functions were not significantly different among the three groups (all P>0.05). The incidence of pulmonary Aspergillus infection in the GC group (22.97%(17/74)) was both higher than that in the non-GC group (5.77%(6/104)) and GC+ VCZ group (1.85%(1/54)), the differences were both statistically signifrcant (χ2=11.373 and 9.843, respectively, both P<0.01). The overall mortality rate of HBV-ACLF patients with pulmonary Aspergillus infection was 79.2%(19/24). The survival rate in non-GC group (37.5%(39/104)) showed no statistical difference with that in GC group (39.19%(29/74), χ2=0.052, P=0.819). The survival rate of GC+ VCZ group (66.67%(36/54)) was significantly higher than that in GC group and non-GC group (χ2 =12.126 and 9.431, respectively, both P<0.01). The blood concentrations of VCZ were randomly measured in 16 patients from the GC+ VCZ group, and the range was 0.82-5.38 mg/L, with no evident adverse reactions.@*Conclusions@#The GC treatment is effective in HBV-ACLF patients in early stage. The VCZ treatment effectively reduces the incidence of pulmonary Aspergillus infection in HBV-ACLF patients receiving GC treatment and increases the survival rate. Oral VCZ (200 mg/d) treatment has a stable blood concentration in HBV-ACLF patients, with rare adverse reactions and good safety.
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Objective To explore the efficacy of glucocorticoid (GC) therapy on hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF),and the effectiveness and safety of voriconazole (VCZ) in preventing pulmonary Aspergillus infection in HBV-ACLF patients treated with GC.Methods Two hundred and thirty-two patients with HBV-ACLF were enrolled from January 2016 to December 2018 in the First Affiliated Hospital of Nanchang University.They were divided into non-GC group (104 cases),GC group (74 cases),and GC + VCZ group (54 cases).The observation period was four months.The baseline liver function,the incidence of pulmonary Aspergillus infection,the survival rate during observation period,and the incidence of complications were compared among the three groups.The adverse reactions of VCZ were observed to identify the best dose for prevention.Quantitative data were analyzed by analysis of variance or rank sum test.Count data were analyzed by chi-square test or Fisher exact test.Results The baseline liver functions were not significantly different among the three groups (all P＞ 0.05).The incidence of pulmonary Aspergillus infection in the GC group (22.97％ (17/74)) was both higher than that in the non-GC group (5.77％ (6/104)) and GC + VCZ group (1.85％ (1/54)),the differences were both statistically signifrcant (x2=11.373 and 9.843,respectively,both P＜0.01).The overall mortality rate of HBV-ACLF patients with pulmonary Aspergillus infection was 79.2％ (19/24).The survival rate in non-GC group (37.5％ (39/104)) showed no statistical difference with that in GC group (39.19％ (29/74),x2=0.052,P =0.819).The survival rate of GC + VCZ group (66.67％ (36/54)) was significantly higher than that in GC group and non-GC group (x2 =12.126 and 9.431,respectively,both P ＜0.01).The blood concentrations of VCZ were randomly measured in 16 patients from the GC + VCZ group,and the range was 0.82-5.38 mg/L,with no evident adverse reactions.Conclusions The GC treatment is effective in HBV-ACLF patients in early stage.The VCZ treatment effectively reduces the incidence of pulmonary Aspergillus infection in HBV-ACLF patients receiving GC treatment and increases the survival rate.Oral VCZ (200 mg/d) treatment has a stable blood concentration in HBV-ACLF patients,with rare adverse reactions and good safety.
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Objective To assess the efficacy and safety of 100 mg or 200 mg yimitasvir phosphate combined with sofosbuvir in patients with non-cirrhotic chronic hepatitis C virus ( HCV) genotype 1 infection who were treatment-na?ve or had a virologic failure to prior interferon-based treatment.Methods A multicenter, randomized, open-label, phase 2 clinical trial was conducted.The patients were randomly assigned to yimitasvir phosphate 100 mg+sofosbuvir 400 mg group (Group 100 mg) and yimitasvir phosphate 200 mg+sofosbuvir 400 mg group ( Group 200 mg) in a 1∶1 ratio with the stratified factors of " treatment-naive" or"treatment-experienced" for 12 weeks and followed up for 24 weeks after the end of treatment.During the clinical trial, HCV RNA was tested in all patients.Resistance of virus in patients who didn′t achieved sustained virological response (SVR) was monitored.Safety and tolerability were assessed by monitoring adverse events , physical examination , laboratory examination, electrocardiogram, and vital signs during the study.The primary end point was SVR12 after the end of therapy.Descriptive statistics were used for categorical variables and eight descriptive statistics were used for continuous variables.Descriptive statistics were used and summarized according to HCV genotypes and treatment groups.Safety data were presented using descriptive statistics and summarized according to treatment groups.Results A total of 174 subjects were screened from July 31, 2017 to September 26, 2018.One hundred and twenty-nine patients were successfully enrolled and received treatment , and 127 completed the study.There were 64 patients and 65 patients assigned to Group 100 mg and Group 200 mg, respectively.Among the 129 patients who underwent randomization and were treated , 18.6% were treatment-experienced and: 100%were HCV genotype 1b infection.The total SVR rate was 98.4%(127／129), with 98.4%(63／64, 95%confidence interval [CI]: 91.60%-99.96%) in the Group 100 mg, and 98.50%(64／65, 95%CI: 91.72%-99.96%) in the Group 200 mg.There was no significant difference between the two groups (χ2 ＝0.000 2, P＝0.989 2).The SVR rates in treatment-naive group and treatment-experienced group were 98.10%(95%CI: 93.29%-99.77%) and 100.00%(24／24, 95%CI: 85.75%-100.00%), respectively.Virological failure during treatment ( including breakthrough , rebound and poor efficacy) and relapse after treatment did not occur during the trial.By Sanger sequencing , 11.6%(15／129) patients had baseline NS5A Y93H／Y or Y93H resistance-associated substitutions ( RAS), 1.6%( 2／129) patients had baseline NS5A L31M RAS.No mutation was observed in NS5B S282 at baseline.There was no S282 mutation in HCV NS5B.A total of 100 (77.5%) subjects had adverse events.No adverse events ≥Grade 3 or severe adverse events related to the study treatment.No patient prematurely discontinued study treatment owing to an adverse event.No life-threatening adverse event was reported.Conclusion Twelve weeks of yimitasvir phosphate 100 mg or 200 mg combined with sofosbuvir 400 mg daily is a highly effective and safe regimen for patients without cirrhosis with HCV genotype 1b infection who had not been treated previously or had a virologic failure to prior interferon-based treatment.
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Objective@#To investigate the clinical effect and safety of long-acting pegylated interferon-α-2b (Peg-IFN-α-2b) (Y shape, 40 kD) injection (180 μg/week) in the treatment of HBeAg-positive chronic hepatitis B (CHB) patients, with standard-dose Peg-IFN-α-2a as positive control.@*Methods@#This study was a multicenter, randomized, open-label, and positive-controlled phase III clinical trial. Eligible HBeAg-positive CHB patients were screened out and randomized to Peg-IFN-α-2b (Y shape, 40 kD) trial group and Peg-IFN-α-2a control group at a ratio of 2:1. The course of treatment was 48 weeks and the patients were followed up for 24 weeks after drug withdrawal. Plasma samples were collected at screening, baseline, and 12, 24, 36, 48, 60, and 72 weeks for centralized detection. COBAS® Ampliprep/COBAS® TaqMan® HBV Test was used to measure HBV DNA level by quantitative real-time PCR. Electrochemiluminescence immunoassay with Elecsys kit was used to measure HBV markers (HBsAg, anti-HBs, HBeAg, anti-HBe). Adverse events were recorded in detail. The primary outcome measure was HBeAg seroconversion rate after the 24-week follow-up, and non-inferiority was also tested. The difference in HBeAg seroconversion rate after treatment between the trial group and the control group and two-sided confidence interval (CI) were calculated, and non-inferiority was demonstrated if the lower limit of 95% CI was > -10%. The t-test, chi-square test, or rank sum test was used according to the types and features of data.@*Results@#A total of 855 HBeAg-positive CHB patients were enrolled and 820 of them received treatment (538 in the trial group and 282 in the control group). The data of the full analysis set showed that HBeAg seroconversion rate at week 72 was 27.32% in the trial group and 22.70% in the control group with a rate difference of 4.63% (95% CI -1.54% to 10.80%, P = 0.1493). The data of the per-protocol set showed that HBeAg seroconversion rate at week 72 was 30.75% in the trial group and 27.14% in the control group with a rate difference of 3.61% (95% CI -3.87% to 11.09%, P = 0.3436). 95% CI met the non-inferiority criteria, and the trial group was non-inferior to the control group. The two groups had similar incidence rates of adverse events, serious adverse events, and common adverse events.@*Conclusion@#In Peg-IFN-α regimen for HBeAg-positive CHB patients, the new drug Peg-IFN-α-2b (Y shape, 40 kD) has comparable effect and safety to the control drug Peg-IFN-α-2a.
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Objective@#To investigate the efficacy and safety of the new investigational drug pegylated interferon α-2b (Peg-IFN-α-2b) (Y shape, 40 kD) injection (180 µg/week) combined with ribavirin in the treatment of patients with genotype 1/6 chronic hepatitis C (CHC), with standard-dose Peg-IFN-α-2a combined with ribavirin as a positive control.@*Methods@#A multicenter, randomized, open-label, and positive-controlled phase III clinical trial was performed. Eligible patients with genotype 1/6 CHC were screened out and randomly divided into Peg-IFN-α-2b(Y shape, 40kD) group and Peg-IFN-α-2a group at a ratio of 2:1. The patients in both groups were given oral ribavirin for 48 weeks in addition and then followed up for 24 weeks after drug withdrawal. Abbott Real Time HCV Genotype II was used to determine HCV genotype, and Cobas TaqMan quantitative real-time PCR was used to measure HCV RNA level at 0, 4, 12, 24, 48, and 72 weeks. Adverse events were recorded in detail. The primary efficacy endpoint was sustained virological response (SVR), and a non-inferiority test was also performed.@*Results@#A total of 561 patients with genotype 1/6 CHC were enrolled, among whom 529 received treatment; 90.9% of these patients had genotype 1 CHC. The data of the full analysis set showed that SVR rate was 69.80% (95% CI 65.00%-74.60%) in the trial group and 74.16% (95% CI 67.73%-80.59%) in the control group (P = 0.297 0). The data of the per protocol set (PPS) showed that SVR rate was 80.63% (95% CI 76.04%-85.23%) in the trial group and 81.33% (95% CI 75.10%-87.57%) in the control group (P = 0.849 8), and the 95% CI of rate difference conformed to the non-inferiority standard. The analysis of the PPS population showed that of all subjects, 47.9% achieved rapid virologic response, with a positive predictive value of 93.8%. The incidence rate of adverse events was 96.30% in the trial group and 94.94% in the control group, and the incidence rate of serious adverse events was 5.13% in the trail group and 5.06% in the control group.@*Conclusion@#In the regimen of Peg-IFN-α combined with ribavirin for the treatment of genotype 1/6 CHC, the new investigational drug Peg-IFN-α-2b(Y shape, 40 kD) has comparable clinical effect and safety to the control drug Peg-IFN-α-2a.
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Acute-on-chronic liver failure (ACLF) is the most common type of liver failure in China, and it has complicated clinical manifestations and high mortality. When the patients experience ACLF complicated by acute kidney injury (AKI), they tend to have a prolonged length of hospital stay and a high risk of multiple organ failure, which always suggests poor prognosis. This article briefly describes the advances in the definition, causative factors, prognostic evaluation, diagnostic markers, and treatment of ACLF complicated by AKI. It is pointed out that early identification, diagnosis, and intervention of AKI helps to reverse kidney injury and avoid the development of severe AKI.
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Objective To understand the epidemiological characteristics and clinical features of Zika virus disease,and to improve its prophylaxis and treatment.Methods The first case with imported Zika virus disease in China was retrospectively reported and analyzed.The literature of Zika virus infection in human was reviewed.Results This patient was the first case with imported Zika virus disease in China who presented with typical clinical characteristics and had clear epidemiological history.All the contacts were test negative for Zika virus nucleic acid.Literature retrieval showed evidence of Zika virus propagation in more than 40 countries in Africa,Asia,and Americas.The majority of patients presented with mild symptoms and the main prevention measures included mosquito control and improved awareness of personal protection.Conclusions Human infected with Zika virus often shows recessive infection.Only a small part develop disease and have generally good prognosis with supportive treatment.
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Objective To study the impact of tumor necrosis factor-α (TNF-α) and its antagonist on the expressions of intestinal mucosa claudin-1,Zonula Occludens-1 (ZO-1) and myosin light chain kinase (MLCK) in rat models of acute liver failure.Methods Fifty four healthy male SpragueDawley (SD) rats were randomly divided into normal control group,model group and intervention group according to a random number table.Rats in normal control (n=6) group were intraperitoneally injected with 0.9％ saline (12 mL/kg).Rats in model group (n=24) and intervention group (n=24) were intraperitoneally injected with a full dose of D-galactosamine (D-GalN) at a dose of 1 200 mg/kg to establish model of acute liver failure,while rats in intervention group were intraperitoneally injected with TNF-α antagonists (rhTNFR∶Fc) at a dose of 12.5 mg/kg before 24 hours given D-GalN.At each time point of hour 8,24,48 and 72,six rats in both model group and the intervention group were sacrificed,respectively,while the normal control group were all anesthetized and sacrificed at 72 h.Models were repeated five times.Serum liver function was detected by biochemical method,and serum TNF-α level was detected by enzyme-linked immunosorbent assay (ELISA).Hematoxylin-eosin (HE) stained sections of liver and terminal ileum were examined under an optical microscope for pathological changes;and protein expression of the terminal ileum Claudin-1,ZO-1 protein and MLCK were determined by immunohistochemistry and Western blot.Means among groups were compared with t test.Results Acute liver failure was successfully induced in the D-GalN injected rats.In the model group,alanine aminotransferase (ALT) began to decline,total bilirubin continued to rise,and enzyme-jaundice separation developed at hour 72.But total bilirubin in intervention group at hour 72 was decreased.Light microscope showed that at hour 72,villus lodged at terminal ileum in the model group with part of villus tip failing off in the model group.Villus mucosa and submucosa interstitial were edema and infiltrated with numerous neutrophils.The terminal ileum kept integrate in the intervention group,and villus mucosa and submucosa were mild edema and only infiltrated with a small amount of neutrophil.Expressions of tumor necrosis necrosis factor (TNF)-α in rats of model group and intervention group were gradually increased and peaked at hour 24 ([239.83 ± 15.81] and [182.71± 17.08] ng/L,respectively),which were significantly higher than that of the control group ([24.19±3.57] ng/L,t=22.68and 15.73,respectively;both P＜0.01).Expression of serumTNF-α in the intervention group was significantly lower than that of model group (t=4.58,P＜0.01).Expressions of Claudin-1 and ZO-1 in model group decreased gradually at an early stage and reached the lowest level at hour 24 (0.355 ± 0.068 and 0.387 ± 0.091,respectively),which were both significantly lower than that of control group (1.640±0.188 and 1.015±0.150,respectively;t=12.87 and 7.14,respectively;both P＜0.01).In the intervention group,expressions of Claudin-1 and ZO-1 also decreased to the lowest level at hour 24 (1.051 ± 0.370 and 0.642 ± 0.082,respectivley),which were both significantly lower than that of control group (t =2.84 and 4.36,respectively;both P＜0.05),but significantly higher than model group with stastically difference (t =3.70 and 4.15,respectively;both P＜0.01).MLCK protein levels in the model and intervention group were gradually increased,which peaked at hour 24 (1.298±0.194 and 1.033 ± 0.073,respectively),significantly higher than the control group (0.460±0.069,t=8.16 and 11.44,both P＜0.01);and MLCK in the intervention group was lower than that in the model group with statistically difference (t=2.56,P＜0.05).Conclusions Expression of serum TNF-α in rat model of acute liver failure increases,which leads to decreased expression of Claudin-1 and ZO-1,and increased expression of MLCK,makes cell shrunk and cell gap increased.TNF-α antagonist could significantly reduce the inflammation and liver cell apoptosis,improve liver function by inhibiting MLCK expression and preventing decrease of Claudin-1 and ZO-1 proteins.
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Objective To investigate the incidence and risk factors of acute kidney injury (AKI)in hepatitis B virus (HBV)related acute-on-chronic liver failure (ACLF)patients,and to explore the impact of AKI on the prognosis of ACLF.Methods The medical records of 227 patients who were diagnosed with HBV-related ACLF at the Department of Infectious Diseases in the First Affiliated Hospital of Nanchang University from January 2015 to August 2016 were retrospectively reviewed.Patients were divided into AKI group and non-AKI group based on the AKI criteria published by International Club of Ascites in 2015 .Demographic and clinical data were compared between groups.The AKI incidence and its impact on patients’prognosis were analyzed.The comparison of continuous variables was done by t test or rank-sum test.The comparison of categorical variables was done byχ2 test or Fisher exact test.AKI risk factors were analyzed by using logistic regression.Results There were 66 (29.1 %)cases were diagnosed with AKI among 227 ACLF patients,among which,45 patients (68.2%)were stage Ⅰ,14 (21 .2%) were stage Ⅱ and 7 (10.6%)were stage Ⅲ.Age,cirrhosis,concentrations of total bilirubin and albumin,international normalized ratio (INR),percentage of neutrophils,MELD scores and spontaneous peritonitis rate (SBP)were all statistically different between AKI group and non-AKI group (all P <0.05).The binary logistic regression analysis revealed that only INR (OR=3.132,P =0.001 )and SBP (OR=4.204,P =0.001 )were the independent risk factors of AKI.The optimal cut-off value for INR was 2.025 with AUROC of 0.609 (P =0.01),sensitivity of 59.1 % and specificity of 62.1 %.The 30-day mortality of AKI group was significantly higher than non-AKI group (χ2= 18.324,P < 0.01). Conclusions AKI is relatively common in patients with ACLF.The risk factors of AKI are INR and SBP. AKI has significant impact on the short-term survival rate of ACLF.Therefore,physicians should pay attention to patients with INR of ACLF at admissions and SBP during the management so as to prevent the occurrence of AKI and to reduce the fatality of ACLF.
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Objective To explore the potential mechanism of severe liver injury shortly after withdrawal of antiviral therapy in chronic hepatitis B (CHB) patients.Methods Forty-nine patients with chronic hepatitis B virus (HBV) infection from the Department of Infectious Diseases of the First Affiliated Hospital of Nanchang University and 8 healthy volunteers from August 2014 to March 2015 were included in this study.All of them were human leukocyte antigen (HLA)-A2-positive.CHB patients were classified into three groups,including 15 cases in immune-tolerance group,20 cases in sustained antiviral treatment group,and 14 cases in recurrence of drug withdrawal group.The frequency of peripheral HLA-A0201-restricted hepatitis B core antigen (HBcAg)18-27 pentamer complex specific CD8+ T cells in CHB patients was analyzed by flow cytometry.Enzyme linked immunospot assay(ELISPOT) was used to detect interferon-gamma (IFN-γ) and tumor necrosis factor-α (TNF-α) secretions of HBcAg18-27-specific CD8+ T cells.The experimental data were analyzed using non-parametric U tests.Results In healthy control group,immune-tolerance group,sustained antiviral treatment group and recurrence of drug withdrawal group,the frequencies of HBcAg-specific CD8+T cells were (0.17 ± 0.16) ％,(1.46±0.72)％,(3.24± 1.60)％ and (4.67±2.43)％,respectively.Compared with healthy control group,the difference were all statistically significant in the three groups (Z=-3.583,-4.018 and-3.823,respectively;all P＜0.01).The frequencies of HBcAg-specific CD8+T cells in immune tolerance group or recurrence of drug withdrawal group were both significantly different from that in sustained antiviral therapy group (Z=-3.400 and-2.030,respectively;both P＜0.05).The difference between immune-tolerance group and recurrence of drug withdrawal group was also significant (Z =-3.230,P＜0.01).The secretion levels of IFN-γ of HBcAg-specific CD8+T cells in healthy control group,immune-tolerance group,sustained antiviral treatment group and recurrence of drug withdrawal group were2 (0-6),16 (2-53),106 (14-254) and 156 (28-395) spot forming cell (SFC)/106 peripheral blood mononuclear cell (PBMC),respectively.The differences between healthy control group and immune-tolerance group,sustained antiviral treatment group or recurrence of drug withdrawal group were all statistically significant (Z=-3.585,-4.069 and-3.824,respectively;all P＜0.01).The IFN-γ level of HBcAg-specific CD8+ T cells in recurrence of drug withdrawal group was significantly higher than that in sustained antiviral therapy group (Z=-2.205,P=0.027),and that in sustained antiviral therapy group was significantly higher than that in immune-tolerance group (Z=-4.700,P＜ 0.01).The TNF-α levels secreted by HBcAg-specific CD8+ T cells in each group were 2 (0-5),16 (2-32),112 (15-283),and 195 (55-537) SFC/106PBMC,respectively.The differences between healthy control group and immune-tolerance group,sustained antiviral treament group or recurrence of drug withdrawal group were all statistically significant (Z=-3.619,-4.069 and-3.824,respectively;all P＜0.01).The TNF-α level secreted by HBcAg-specific CD8+T cells in recurrence of drug withdrawal group was significantly higher than that in sustained antiviral therapy group (Z=-2.449,P=0.014),and that in sustained antiviral therapy group was significantly higher than that in immune-tolerance group (Z=-4.350,P＜0.01).Conclusions The changes of frequency and immune function of HBcAg-specific CD8+T cells in CHB patients may be one of the reasons causing severe liver damage after irregular withdrawal of nucleoside analogues.
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Objective To analyze the characteristics and significance of matrix metalloproteinase-9 (MMP-9) expression in the pathophysiological processes of tuberculous meningitis in mice.Methods Sixteen mice were intracerebroventricularly injected with H37RV suspension as the model group.Meanwhile,the other 16 mice were injected with 0.9％ sodium chloride solution as the control group.Thirty days later,all mice were decapitated and the brain tissue were respectively used to for Mycobacterium tuberculosis (M.tuberculosis) incubation,pathological changes observation,MMP-9 activity detection by zymography,blood-brain-barrier permeability and moisture content detection,and immunofluorescence stain of MMP-9,glial fibrillary acidic protein (GFAP) and integrin αM (OX-42).The t test was used to compare the differences between the two groups.Results Every experimental mouse was injected with (1.271±0.111) × 106 colony-forming units (cfu) M.tuberculosis.Thirty days later,the amount of M.tuberculosis in brain tissue homogenates was (4.900± 1.407) × 104 cfu/mL,and the hematoxylin and eosin staining showed dilatation of subarachnoid and ventricular and infiltration of a large number of inflammatory cells.The cumulative absorbance (A) of MMP-9 bands of brain tissue was 47 821 ± 19 932 in the model group and 10 082 ± 3 544 in the control group.The difference was statistically significant (t =3.728,P=0.010).The evans blue (EB) content of brain tissue was (11.8 ± 3.6) μg/g in model group and (4.7 ±3.4) μg/g in control group.The difference was statistically significant (t=2.887,P=0.028).The moisture of brain tissue was 0.849±0.035 in model group and 0.775±0.037 in control group.The difference was statistically significant (t=2.925,P=0.026).The immunofluorescence staining showed that the infected brain tissue expressed high degrees of MMP-9,GFAP and OX-42.And MMP-9 was overlapped with both GFAP and OX-42 obviously.Conclusions The activity of MMP-9 is significantly enhanced in brain tissue of mice suffering from tuberculous meningitis and participates in blood-brain barrier damage,tissue edema and inflammatory cells exudation.Microglia cells-astrocytes network is involved in the secretion of MMP-9.
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<p><b>OBJECTIVE</b>To study the intestinal expression of defensin-5 (RD-5), soluble phospholipase A2 (sPLA2) and lysozyme in acute liver failure (ALF) using rat models, and to determine the relation of these expressions to intestinal bacterial translocation.</p><p><b>METHODS</b>Forty-eight healthy male Sprague-Dawley rats were divided into a control group (n=8) and a model group (n=40; intraperitoneal injection of 10% D-galactosamine). The model group was further divided into five subgroups according to the time lapse after model establishment (8, 16, 24, 48, and 72 hours). At the end of the experiments, homogenates of mesenteric lymph nodes, liver and spleen were cultured in agar for bacterial outgrowth.Hematoxylin-eosin stained sections of liver and terminal ileum were examined under an optical microscope to assess pathological changes. mRNA expression of RD-5, sPLA2 and lysozyme in the terminal ileum was determined by reverse transcription-polymerase reaction (RT-PCR), and protein expression of sPLA2 and lysozyme from the same anatomic location was determined by western blotting and immunohistochemistry. Means between groups were compared with one-way analysis of variance.</p><p><b>RESULTS</b>ALF was successfully induced in the D-galactosamine injected rats. No bacteria grew in the organ cultures from the control group, while 8.3%, 37.5% and 58.3% of the rats in the 24-, 48-and 72-hour model groups showed positive cultures. Despite this, the structure of the terminal ileum from the rats in the 72-hour model group was nearly intact, without obvious necrosis of mucosal epithelial cells. Expression of RD-5 and sPLA2 mRNA in the model groups gradually increased at early time points and peaked at 16 hours after induction of ALF (1.291+/-0.153 and 1.131+/-0.128), which was significantly higher than that detected in the control group (0.725+/-0.116 and 0.722+/-0.112, t=69.25, 95.71, all P<0.01). After that, the expression of RD-5 and sPLA2 mRNA progressively decreased, and by 72 hours after the induction of ALF, the expression (0.415+/-0.104 and 0.425+/-0.076) was significantly lower than that of the control group (t=31.55 and 44.98, all P<0.01). Lysozyme mRNA expression in the model group peaked at 8 hours after ALF induction (1.211+/-0.107), which was higher than that of the control group at this time point (0.853+/-0.093), and by 72 hours after ALF induction it declined to 0.704+/-0.103, which was significantly lower than that of the control group (t=9.224; all P=0.009). In addition, at 72 hours after ALF induction the protein expression of both lysozyme and sPLA2 was significantly lower in the model group (0.327+/-0.086 and 0.382+/-0.057) than in the control group (0.583+/-0.121 and 0.650+/-0.093, t=12.28 and 15.83, P=0.004 and 0.001). Similar results were obtained with immunohistochemical staining.</p><p><b>CONCLUSION</b>The function of the ileal mucosal immune barrier in the rat model of acute liver failure decreased, along with decreases in expression of RD-5, sPLA2 and lysozyme in the Paneth cells.At the same time, the rate of organ bacterial translocation increased without obvious injury to the intestinal mucosa structure.</p>
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Animals , Male , Rats , Bacterial Translocation , Defensins , Disease Models, Animal , Galactosamine , Injections, Intraperitoneal , Intestines , Liver Failure, Acute , Muramidase , Phospholipases A2 , Protein Precursors , RNA, Messenger , Rats, Sprague-DawleyABSTRACT
ObjectiveTo analyze the levels of matrix metalloproteinase 9 (MMP-9 ) in cerebrospinal fluid (CSF) of patients with central nervous system (CNS) infection caused by different pathogens.MethodsThe levels of MMP 9 in CSF were detected by enzyme linked immunosorbent assay (ELISA) in 10 patients with tuberculous meningitis in both acute phase and recovery phase,10 purulent meningitis,10 cryptococeal meningitis,10 viral encephalitis and 10 controls.The differences among the groups were compared by t test. The correlations between MMP-9 levels and the cell count,glucose, chloride, and protein in CSF were analyzed by Spearmanrank correlation.ResultsThe CSFMMP-9levelsingroupsoftuberculousmeningitis, purulentmeningitis,cryptoeoccal meningitis and viral encephalitis were (569.46±162.42),(182.79±99.06),(54.69±19.93) and (18.52±10.31) ng/mL,respectively,which were all significantly higher than that in controls (3.51± 1.53) ng/mL. There were significant differences between tuberculous meningitis group and other groups (t=2.925,3.041,3.237,3.454;P0.0340,0.0270,0.0080 and0.0001,respectively). Moreover,in tuberculous meningitis group,the MMP-9 level in acute phase was (569.46±162.42) ng/mL,which was significantly higher than that in recovry phase (294.30+89.06) ng/mL.The CSF level of MMP-9 in tuberculous meningitis group was positively correlated with CSF protein (r=0.509,P=0.044),negative correlated with CSF glucose (r=-0.451,P=0.008) and chloride (r=-0.637,P=0.007),but no correlation with CSF cell count (r=0.308,P=0.246). And there were no correlations in other groups. ConclusionsMMP-9 level in CSF increases significantly in patients with tuberculous meningitis and purulent meningitis,which can be used as a marker of CNS infection.Dynamic monitoring of thc CSF level of MMP-9 may be meaningful for the diagnosis and treatment.
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OBJECTIVE To investigate the clinical characteristics,risk factors and preventive measures for nosocomial pneumonia in patients with post-hepatitis liver cirrhosis.METHODS A prospective and retrospective study was carried out to investigate the clinical data of 495 patients with post-hepatitis liver cirrhosis in Department of Infectious Diseases during Jan 1,2005 to Dec 31,2007.RESULTS The incidence rate of the nosocomial pneumonia in post-hepatitis liver cirrhosis patients was 13.50 %.The death rate was 25.40 %,which was obviously higher than 6.8% of patients without no nosocomial infection(?2=23.77,P
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Objective To investigate the changes of plasma levels of glucagon in cirrhotic patients and its effect in the pathogenesis of portal hemodynamics.Methods Plasma levels of glueagon were measured by radioimmunoassay(RIA)in 42 patients with liver cirrhosis and 20 healthy controls.The max diameters,mean flow velocity,flow rate of the portal vein trunks(PV)and splenic veins(SV)were detected by Color Doppler Ultrasound.Results Plasma levels of glucagon in cir- rhotic patients were significantly higher than those in controls and were increased with the severity of hepatic function im- pairment as assessed by Child-Pugh grade.Patients with ascites showed signifieanthigher plasma glucagon levels than those without ascites.Plasma levels of glueagon were positively correlated with portal vein diameters,splenic vein diame- ters and splenic vein flows.Conclusion The increase of plasma glucagon levels reflects,in part,the severity of impair- ment of hepaticfunction.In addition,it may contribute to the pathogenesis of portal hypertension.