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Objective:To explore the early predictors for clinical cure by sequential combined interferon therapy in nucleos(t)ide analogues (NAs) experienced patients with chronic hepatitis B(CHB).Methods:CHB patients received NAs treatment≥one year with hepatitis B surface antigen (HBsAg) ≤1 500 IU/mL, hepatitis B e antigen (HBeAg) negative and hepatitis B virus (HBV) DNA <100 IU/mL in the Third Affiliated Hospital of Sun Yat-sen University from June 2016 to September 2019 were included. According to the different treatment regimens, the patients were divided into interferon alone for 48 weeks group (group A), interferon combined with NAs for 12 weeks and continued NAs treatment for 48 weeks group (group B), interferon combined with NAs for 48 weeks group (group C). Basic data such as age and gender of patients were collected. HBsAg, hepatitis B surface antibody (anti-HBs) and alanine aminotransferase (ALT) were monitored at week 4, 8, 12, 24, 36 and 48. The decline of HBsAg from baseline, and the rates of clinical cure at 48 weeks were analyzed. The independent sample t test, chi-square test and rank sum test were used for statistical analysis. Logistic regression analysis was used to achieve the early prediction index of clinical cure at week 48. Results:A total of 1 020 CHB patients were followed up regularly for at least five time points. The rates of clinical cure at week 48 in group A, B and C were 34.6%(157/454), 32.7%(69/211) and 33.5%(119/355), respectively, with no statistical significance ( χ2=0.25, P=0.883). Patients were divided into the cured group (345 cases) and the uncured group (675 cases) according to the clinical outcomes at week 48. The age ((38±13) years old vs (43±12) years old), baseline HBsAg (131.00(359.80) IU/mL vs 437.60(531.50) IU/mL) and the proportion of male patients (81.7%(282/345) vs 89.5%(604/675)) of patients in the cured group were all lower than those of patients in the uncured group. The differences were all statistically significant ( t=6.32, Z=12.67, χ2=11.99, respectively, all P<0.050). There were 212 patients in the cured group who achieved clinical cure within 24 weeks of treatment. The rate of clinical cure at 48 weeks in patients whose HBsAg at week 4 decreased from baseline was higher than that in patients with increased HBsAg (41.6%(149/358) vs 28.2%(108/383)). The difference was statistically significant ( χ2=14.13, P<0.001). The rate of clinical cure at week 48 in patients with HBsAg at week 12 decreased ≤34.03% of baseline was only 6.9%(13/188). Multivariate logistic regression analysis showed that age (odds ratio ( OR)=0.962, 95% confidence interval ( CI) 0.936 to 0.989, P=0.006), HBsAg level at week 24 ( OR=0.950, 95% CI 0.934 to 0.966, P<0.001) and anti-HBs level at week 24 ( OR=1.012, 95% CI 1.005 to 1.019, P=0.001) were early predictors for clinical cure at week 48 of treatment in NAs experienced CHB patients. Conclusions:Clinical cure of NAs experienced CHB patients received sequential combined interferon therapy mostly occurs in the early stage (within 24 weeks). Age, HBsAg level at week 24, and anti-HBs level at week 24 are early predictors for clinical cure of 48-week sequential combined interferon treatment.
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Objective@#To investigate the key factor(s) of hepatitis B virus X protein (HBx) promoting B7-H6 gene activation.@*Methods@#The DNA fragments of the B7-H6 promoter were amplified from the human genomic DNA using polymerase chain reaction(PCR). Products of PCR were digested by KpnI and HindⅢ, and inserted into luciferase reporter vector (pGL3-Basic). The correctness of the recombinant plasmid pGL3-B7-H6 was confirmed by sequencing. Human hepatoma cell line HepG2 were co-transfected with pGL3-B7-H6 and the eukaryotic expression vectors (pCMV-HBs、pCMV-HBc and pCMV-HBx), and the relative luciferase activity was detected.The different dose of HBx expression plasmids were transfected into the HepG2 cells, and the expression of B7-H6 protein were determined by Western blot.@*Results@#A period of 2.2 Kb of B7-H6 promoter region were successfully cloned into pGL3-Basic, which was confirmed by DNA sequencing. The relative luciferase activity was significantly higher in the cells transfected with pGL3-B7-H6 than that in the cells transfected with the empty vector pGL3-Basic (5.24±1.25 vs. 1.12±0.31, P=0.005). The relative luciferase activity in HepG2 cells co-transfected with pGL3-B7-H6 and pCMV-HBx was remarkably increased compared with the control group (17.60±3.36 vs. 6.73±1.36, P=0.001). Western blot further demonstrated that HBx protein can significantly enhance B7-H6 protein expression.@*Conclusions@#Hepatitis B Virus X proteins enhanced B7-H6 promoter activity and promoted B7-H6 protein expression.
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Objective To study the modification effect of age on the association between body mass index and the risk of hypertension.Methods People age ≥ 18 years old were selected by clusters,from a rural area of Henan province.In total,20 194 people were recruited at baseline during 2007 and 2008,and the follow-up study was completed from 2013 to 2014.Logistic regression model was used to assess the risk of incident hypertension by baseline BMI and age-specific BMI.Results During the 6-year follow-up period,1 950 hypertensive persons were detected,including 784 men and 1 166 women,with cumulative incidence rates as 19.96％,20.51％,and 19.61％,respectively.Compared with those whose BMI＜22 kg/m2,the RRs of hypertension were 1.09 (0.93-1.27),1.17 (1.01-1.37),1.34 (1.14-1.58) and 1.31 (1.09-1.56) for participants with BMI as 22-,24-,26-and ≥28 kg/m2,respectively.In young and middle-aged populations,the risk of hypertension gradually increased with the rise of BMI (trend P＜0.05).However,in the elderly,the increasing trend on the risk of hypertension risk was not as significantly obvious (trend P＞0.05).Conclusion The effect of BMI on the incidence of hypertension seemed to depend on age.Our findings suggested that a weight reduction program would be more effective on young or middle-aged populations,to prevent the development of hypertension.
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Objective To study the modification effect of age on the association between body mass index and the risk of hypertension.Methods People age ≥ 18 years old were selected by clusters,from a rural area of Henan province.In total,20 194 people were recruited at baseline during 2007 and 2008,and the follow-up study was completed from 2013 to 2014.Logistic regression model was used to assess the risk of incident hypertension by baseline BMI and age-specific BMI.Results During the 6-year follow-up period,1 950 hypertensive persons were detected,including 784 men and 1 166 women,with cumulative incidence rates as 19.96％,20.51％,and 19.61％,respectively.Compared with those whose BMI＜22 kg/m2,the RRs of hypertension were 1.09 (0.93-1.27),1.17 (1.01-1.37),1.34 (1.14-1.58) and 1.31 (1.09-1.56) for participants with BMI as 22-,24-,26-and ≥28 kg/m2,respectively.In young and middle-aged populations,the risk of hypertension gradually increased with the rise of BMI (trend P＜0.05).However,in the elderly,the increasing trend on the risk of hypertension risk was not as significantly obvious (trend P＞0.05).Conclusion The effect of BMI on the incidence of hypertension seemed to depend on age.Our findings suggested that a weight reduction program would be more effective on young or middle-aged populations,to prevent the development of hypertension.
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<p><b>OBJECTIVE</b>To determine the immune repertoires of peripheral CD4+T cell receptor (TCR) Vb CDR3 in primary biliary cirrhosis (PBC) and analyze TCR diversity and preferred usage at sequence-level resolution.</p><p><b>METHODS</b>ARM-PCR and high-throughput sequencing were used to obtain millions of TCR Vb CDR3 sequences from peripheral CD4+T cells isolated from 7 patients with PBC and healthy volunteers. All sequencing data were analyzed, together with corresponding clinical information, by bioinformatic software. The Mann-Whitney U test was used for statistical analysis.</p><p><b>RESULTS</b>The PBC patients showed a lower level of diversity among the peripheral CD4+TCR Vb CDR3 than the healthy volunteers, and patients with higher level progression of the disease showed a greater lack of diversity. In addition, 4 specific preferred-usage amino acid sequences were discovered for the PBC patients: ASSFTGGPVEQY, ASSLISSGNNEQF, ATSRDTLAGGPGDTQY, and SASLEGNTEAF; these sequences were also found in higher frequencies in patients with later stages of PBC.</p><p><b>CONCLUSIONS</b>Decreased TCR Vb CDR3 diversities and specific preferred usage of TCR CDR3 sequences in peripheral CD4+T lymphocytes in PBC suggest that clonal expansion of a large number of CD4+T cells may be an important factor for PBC progression. These data provide a better understanding about the general characteristics of CD4+T cells in PBC patients and related to pathogenesis of the disease, and may provide useful insights into potential targets for immunotherapy.</p>
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Humans , Amino Acid Sequence , CD4-Positive T-Lymphocytes , High-Throughput Nucleotide Sequencing , Liver Cirrhosis, Biliary , Polymerase Chain Reaction , Receptors, Antigen, T-CellABSTRACT
Objective To explore the efficacy of sequential or combined amphotericin B (AmB) and fluconazole (FCZ) therapy on a 5 flucytosine based regimen in non-acquired immunodeficiency syndrome (AIDS)-related cryptococcal meningitis.Methods A tatal of 117 cases of non-AIDS-related cryptococcal meningitis treated with 5-flurocytosine-based regimens were retrospectively divided into five groups:AmBgroup (n=38),FCZ group (n=25),FCZ and AmB sequential group (n=18),AmB and FCZ sequential group (n=15),AmB and FCZ combination group (n=21).The number in cerebrospinal fluid (CSF) of the five groups were compared.Statistical analyses included t test,oneway analysis of variance,K-independent samples test and chi-square test.Results Intracranial pressure of AmB group,FCZ group,FCZ and AmB sequential group,AmB and FCZ sequential group,AmBandFCZ combination group were (208.6±75.1),(191.5±94.5),(185.0±76.3),(201.9±69.7) and (223.1±89.3) mm H2O (1 mm H2O=0.0098 kPa),respectively,and the differences were not statistically significant (F=0.611,P =0.656).Median cryptococcus counts in CSF of the five groups were 0,10,0,3 and 0/mL,respectively,with no statistical significance (x2 =7.638,P-0.090).CSF protein levels of the five groups were 0.55,0.69,0.67,0.53 and 0.96 g/L,respectively,with no significant differences among groups (F=7.063,P=0.133).The cure rates of the five groups were 55.3％ (21/38),32.0％ (8/25),9/18,6/15 and 47.6％ (10/21),respectively;progression rates or mortality of the five groups were 28.9％ (11/38),44.4％ (11/25),5/18,4/15and 23.8％ (5/21),respectively; and the differences among cure rates (x2 =3.638,P=0.457) and progression rates or mortality (x2-2.785,P =0.604) were not statistically significant.Conclusion FCZ or AmB alone,sequential or combined therapy were all effective in the treatment of cryptococcal meningitis.
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ObjectiveTo investigate the therapeutic effects of patients with non-acquired immunodeficiency syndrome ( AIDS )-related cryptococcal meningitis treated with fluconazole and flucytosine.MethodsA retrospective study was conducted including 52 cases of non-AIDS-related cryptococcal meningitis,which were divided into two groups:the amphotericin B combined with flucytosine group (n =32) and the fluconazole combined with flucytosine group (n =20 ). The comparison between groups was done by t test and chi-square test.ResultsThe intracranial pressure of the amphotericin B combined with flucytosine group and the fluconazole combined with flucytosine group were (221.9±76.2) and (213.4±99.2) mm H2O,respectively (t=0.302,P＞0.05) ; the cryptococcus counts in the cerebrospinal fluid (CSF) were (351 ± 1180) and (508 ± 943)/mL,respectively (t=- 0.473,P＞0.05) ; the CSF protein levels were (0.754 ± 0.726) and (0.649 ±0.308) g/L,respectively (t=0.578,P＞0.05) ; the CSF white blood cell (WBC) counts were (16±25) × 106/L and (28±32) × 106/L,respectively (t=-1.348,P＞0.05).The cured rates were 59.38％ (19/32) and 35.00％ (7/20),respectively in the amphotericin B combined with flucytosine group and the fluconazole combined with flucytosine group,and the improved rates were 6.25％(2/32)and 25.00％ (5/20),respectively,the uncured or mortality rates were 34.38％ (11/32) and 40.00％ (8/20),respectively,and the difference were not significant of cured rates (x2 =2.925,P＞0.05) and uncured or mortality rates (x2 =0.168,P＞0.05) between two groups.ConclusionFluconazole combined with flucytosine also has a good effect on the treatment of cryptococcal meningitis.
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Objective To understand the clinical features of hepatitis B virus(HBV)/hepatitis C virus(HCV)coinfected patients with different virological profiles.Methods The clinical data of 186 patients with HBV/HCV coinfection from May 1999 to May 2010 in the Third Affiliated Hospital of Sun Yat-Sen University were analyzed retrospectively.The demographic data,epidemiological data,laboratory results and pathological index were analyzed.The statistical analysis was done using t test and chi square test.Results A total of 186 patients were divided into 4 groups:66(35.5%)in HBV DNA(-)/HCV RNA(-)group,8(4.3%)in HBV DNA(+)/HCV RNA(+)group,68(36.6%)in HBV DNA(+)/HCV RNA(-)group and 44(23.7%)in HBV DNA(-)/HCV RNA(+) group.The gender composition,complication incidence,transmission among drug users,alanine aminotransferase(ALT)level,total bilirubin(TBil)level,prothrombin activity(PTA)and hapatitis B e antigen(HBeAg)negative rate were all significantly different among four groups(F or x2=11.578,8.451,11.738,2.669,5.102,4.254 and 18.413,respectively;all P0.05).The HBeAg negative rate in HBV DNA(-)patients was 85.5%,which was higher than that in HBV DNA(+)patients(59.2%)(x2=16.393,P<0.05).Conclusions HBV DNA(+/-)/HCV RNA(-)profile were major components in HBV/HCV confection.HBV DNA level is related to disease progression and prognosis,but not relate to disease severity.Liver function damage and disease severity are aggravated with HCV RNA level decreases.HBV DNA level is related to HBeAg negative rate,while HCV RNA level is not related to HBeAg seroconversion rate.
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Objective To evaluate the efficacy of entecavir treatment on hepatitis B patients with acute-on-chronic liver failure. Methods Eighty-four hepatitis B patients with acute-on-chronic liver failure were treated with entecavir 0.5 mg daily and Other routine drugs. Another 99 hepatitis B patients with acute-on-chronic liver failure were treated with only routine drugs as control. The survival, liver functions, hepatitis B virus (HBV) DNA level, prothrombin time (PT) were observed. The survival rates of patients with early, middle or late stage of liver failure were analyzed. The comparison of rates were done using chi-square test. The numeration data were compared by t test. The survival rates were compared using Kaplan-Meier method. Results Among patients with early stage of acute-on-chronic liver failure, the survival rate in treatment group was 63.3% (31/49), which was significantly higher than that in control group (39.7%, 23/58) (χ2=5.923, P=0.015). Among patients with middle stage of acute-on-chronic liver failure, the surviral rate in treatment group was 63.0% (17/27), which was significantly higher than that in control group (35.1%, 13/37) (χ2=4.854, P=0.028). Among patients with late stage of acute-on-chronic liver failure, four out of eight cases survived in treatment group, while one out of four cases survived in control group. In patients with serum total hilirubin (TBil) level > 342 μmol/L, the survival rate was 56.0% in treatment group, which was significantly higher than that in control group (26.8%) (χ2=9.351,P=0.002). At week 4 of the treatment, the HBV DNA reduction in treatment group was 3. 95 lg copy/mL, which was higher than that in control group (1.78 lg copy/mL) (t=5.847, P=0.001). Conclusions Entecavir treatment could improve the survival rate of hepatitis B patients with early or middle stage of acute-on-chronic liver failure. And the further study with larger population is needed in patients with late stage of liver failure. In addition, entecavir therapy could also improve the survival rate of patients with TBil >342 μmol/L.
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Objective To investigate the level of serum macrophage migration inhibitory factor (MIF) and its correlation with serum precollagen Ⅲ peptide (PⅢP) and tissue inhibitor of metalloproteinase (TIMP)-1 in patients with chronic hepatitis B (CHB) and hepatitis B virus (HBV)-related cirrhosis. Methods Forty-four CHB patients (hepatitis B group), 44 patients with HBV-related cirrhosis (cirrhosis group) and 30 healthy controls (control group) were enrolled in this study. The venous blood was collected and MIF level was detected by enzyme-linked immunosorbent assay (ELISA). Correlations between MIF and PⅢP, TIMP-1 were analyzed in observed groups. Comparison between groups was done using t test. The correlations between MIF level and alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), plasma thromboplastin antecedent (PTA), PⅢP and TIMP-1 were analyzed by rectilinear correlation. Results The levels of serum MIF, PⅢP and TIMP-1 in CHB group and cirrhosis group were all significantly higher than those in control group (t=12.87,5.28, 10.98,t=11.22,14.84,11.17;all P<0.05), while there were no significant differences between CHB group and cirrhosis group (t= -1.05,1.52,--2.07;all P>0.05). There was no correlation between MIF level and ALT, AST, TBil and PTA. MIF level in CHB patients with hepatitis B e antigen (HBeAg) positive and high viral load were both higher than that in patients with HBeAg negative and low viral load. MIF level was both positively correlated with PⅢP level in CHB group and cirrhosis group (r=0. 603, P<0.05 and r=0. 415, P<0. 05, respectively). MIF level was also positively correlated with TIMP-1 level in CHB group (r=0. 458, P<0.05), while not correlated in cirrhosis group (r=0. 210, P>0.05). Levels of PⅢP and T1MP-1 were both correlated in CHB group and cirrhosis group (r=0. 849, P< 0.05 and r=0. 424, P<0.05, respectively). Conclusions The levels of serum MIF are significantly increased both in patients with CHB and cirrhosis. The early production of MIF might be related with viral replication, but not with liver function. MIF participates in formations of hepatitis, liver fibrosis and cirrhosis, which could reflect the degree of liver cirrhosis.
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Objective To investigate the therapeutic effects of recombinant yeast hepatitis B virus(HBV)vaccine combined with interferon(IFN)α-1b and determine the rational dosage of HBV vaccine for the further clinical study with larger sample.Methods Two hundreds and sixteen patients with chronic hepatitis B(CHB)were enrolled in this randomized,multi-center,double-blinded and placebo-controlled clinical trial.All the subjects were not treated with antiviral drugs within 6 months and randomly divided into 90μg,60μg and placebo groups with a ratio of 1:1:1.All the patients were intramuscularly administrated with 90μg or 60μg recombinant HBV vaccine or placebo at week 0,2,6,10,14,18,22,respectively.Meanwhile,they were also treated with IFNα-1b 50μg,3 times a wcek for 24 weeks.All patients were followed up for 24 weeks after withdrawal of anti-HBV therapy.Serum HBV DNA level,HBeAg titer and liver function were monitored frequently.Interferon-γ secreting lymphoeytes were detected by Enzyme-linked immunospot(ELISPOT)in part of the patients.Results The serum HBV DNA levels were(6.03±1.79),(5.52±1.82)and(6.29±1.70)log10 copy/mL at week 24 of treatment in high dose,low dose and placebo groups,respectively (P=0.458).And the serum HBV DNA levels were(5.92±1.98),(5.49±1.99)and(6.16±1.76)log10 copy/mL at weck 24 after withdrawal of treatment,respectively(P=0.720).The rates of patients whose HBV DNA＜1×105 copy/mL in these three groups were 30.4%,39.4% and 20.8% at week 24 of treatment,respectively and there was significant difference between high dose group and low dose group(P=0.015).The rate of patients whose HBV DNA＜1×105 copy/mL at week 24 after withdrawal was highest in low dose group,but no significant differences before and after treatment in these three groups(P=0.257).The HBV DNA negative rates were 17.4%,25.4% and 6.9% in these three groups,respectively,which were significantly different(P=0.012).At week 24 of treatment and week 24 after withdrawal of treatment,the alanine aminotransferase normalization rate,HBeAg seroconversion rate were highest in low dose group,but no significant differences in these three groups.ELISPOT positive rates at week 24 of treatment and week 24 after withdrawal of treatment in high close and low dose groups were higher than that in placebo group(P＜0.05).The incidence of adverse events was similar and there was no drug related severe adverse events in each group.Conclusion Recombinant HBV vaccine maybe contribute to anti-HBV therapy and 60μg of dosage seems to be rational.