Expert consensus on antiviral therapy of COVID-19 / 中华临床感染病杂志

COVID-19 is caused by a novel coronavirus-severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which has being spreading around the world, posing a serious threat to human health and lives. Neutralizing antibodies and small molecule inhibitors for virus replication cycle are the main antiviral treatment for novel coronavirus recommended in China. To further promote the rational use of antiviral therapy in clinical practice, the National Center for Infectious Diseases (Beijing Ditan Hospital Capital Medical University and the First Affiliated Hospital, Zhejiang University School of Medicine) invited experts in fields of infectious diseases, respiratory and intensive care to develop an Expert Consensus on Antiviral Therapy of COVID-19 based on the Diagnosis and Treatment Guideline for COVID-19 ( trial version 10) and experiences in the diagnosis and treatment of COVID-19 in China. The consensus is concise, practical and highly operable, hopefully it would improve the understanding of antiviral therapy for clinicians and provide suggestions for standardized medication in treatment of COVID-19.

Clinical features of 99 cases of brucellosis in Henan Province / 中华地方病学杂志

Objective To analyze the clinical data of brucellosis,and to provide references for brucellosis therapy.Methods The patients definitely diagnosed brucellosis at the First Affiliated Hospital of Zhengzhou University from January 2013 to June 2016 were assessed,data of clinical features,laboratory examination,treatment and prognosis were analyzed.Results Of all 99 cases,the mean age was (46.7 ± 15.7) years old,83 cases had a history of closely contacted with sheep,2 cases with pig and 1 case with cattle.The occupational distribution of patients included 90 farmers,1 veterinarian,2 cooks,6 children and students.All patients had clinical manifestations such as fever,fatigue,and sweating.There were 18 patients with back and joint pain,13 cases had abnormal manifestation on magnetic resonance imaging (MRI).Blood culture was positive in 54 (71.05％,54/76) and serum test tube agglutination test was positive in 61 (98.39％,61/62).Eighty-one patients received doxycycline combined with rifampicin treatment,six months laters,all patients were cured.Conclusions Sheep are the main sources of infection for brucellosis.Fatigue,sweaty and fever are the most common symptoms,and osteoarticular is the most frequently involved.Serum agglutination test and blood culture are important tests for diagnosis of brucellosis.Doxycycline combined with rifampicin was the most common used antibiotics regimen.Early,combined,regular,full-course antibiotic treatment has a better prognosis.

A report of 4 cases of myeloperoxidase antin eutrophil cytoplasmic antibody associated hypertrophic pachymeningitis with literature review / 中华风湿病学杂志

Objective To investigate the clinical features of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) associated hypertrophic pachymeningitis (HP).Methods Clinical data of 4 casesdiagnosed with MPO-ANCA vasculitis complicated with HP in our hospital were analyzed retrospectively and the related literaturewere reviewed.Results Four male patients with an age range from 44 to 66 years were diagnosed with ANCA-associated HP.The main clinical manifestations included headache and withvarious degree ofmultiple cranial paralysis.During active phase of the disease,all patients showed perinuclear(p)-ANCA positive,elevated levels of inflammatory biomarkers and titers of MPO-ANCA,whereas renal function,cytoplasmic (c)-ANCA and protease 3 (PR3)-ANCA were negative.Contrast-enhanced cranial magnetic resonance imaging (MRI) scan showed obviously thickened dura mater and sinusitis or mass in paranasal sinus.Four patients were sensitive to glucocorticoid.Three patients had a relapse during glucocorticoid tapering and were undercontrol when the dosage of glucocorticoid was increased and immunosuppressive agents were added.Levels of inflammatory biomarkers,titers of MPO-ANCA and p-ANCA recovered to normal,and the dural thickness on MRI was reduced in the remission stage.Conclusion MPO-ANCA associated HP is a type of central nervous system involvement in ANCA associated vasculitis (AAV).It involves the upper respiratory tract more frequently,and less frequently progresses to systemic AAV.This should be taken into consideration when middle-aged and elderly patients presented with headache and multiple cranial neuropathies.Enhanced MRI is the preferred examination for diagnosis,and dural biopsy should be done when necessary.

Whether antiviral therapy can reduce the incidence of hepatocellular carcinoma in patients with chronic HCV infection / 临床肝胆病杂志

In 2010,studies found that achievement of sustained virologic response after treatment in patients with chronic HCV infection meant cure;the overall cure rate of interferon combined with ribavirin around the world was about 60％,and the result of real-world study in China was 71.1％.In 2013,the US took the lead in launching the direct-acting antiviral agents (DAAs) for HCV,and the cure rate was increased to almost 100％.However,recent studies have found that the incidence of hepatocellular carcinoma (HCC) tends to increase after the application of DAAs,and there are still controversies over whether DAAs are the major cause of this phenomenon.In our opinion,this phenomenon is caused by the fact that the indications for DAAs cover more end-stage hepatitis C patients who are intrinsically the high-risk population of HCC;however,it cannot be excluded that DAAs may lead to the change in the body's antitumor immune status.Studies are needed in the future to examine this issue at the molecular level.

Risk factors for occurrence of post-sustained virologic response hepatocellular carcinoma in chronic hepatitis C ;patients / 中华传染病杂志

Objective To investigate the risk factors and predictive model for the occurrence of post-sustained virologic response (SVR)hepatocellular carcinoma in chronic hepatitis C (CHC)patients. Methods A total of 203 CHC patients hospitalized at the First Affiliated Hospital of Zhengzhou University from January 2006 to December 2014 who received antiviral therapy and achieved SVR were collected,including 11 post-SVR HCC cases.Risk factors for post-SVR HCC were estimated by Cox′s proportional hazards regression model.Cutoff value predicting risk of post-SVR HCC was determined by receiver operating characteristic curve.Results In Cox′s model,the risk of post-SVR HCC increased by 9.4-fold in patients with initial diagnosis as compensated cirrhosis compared to those with initial diagnosis as CHC.Increase in post-SVR albumin by per 1 g/L was associated with reduced risk by 20% for the occurrence of post-SVR HCC.Cut-off value of post-SVR albumin for the prediction of HCC was determined as ≤ 36.0 g/L with an area under the curve (AUC)of 0.809.A predictive model for post-SVR HCC was created based on initial diagnosis as compensated cirrhosis and post-SVR albumin ≤36.0 g/L with an AUC of 0.871 .The sensitivity,specificity and negative predictive value of the model were 0. 818,0.896 and 0.989,respectively.Conclusions Initial diagnosis as compensated cirrhosis combines with post-SVR albumin ≤36.0 g/L are risk factors for post-SVR HCC with ideal prediction value for the occurrence of post-SVR HCC in CHC patients.

Dynamic changes of PD-1 expression on CD4 + and CD8 + T cells in patients with HBeAg-positive chronic hepatitis B treated with telbivudine / 中华临床感染病杂志

Objective To investigate the expression of PD-1 on CD4 +and CD8 + T cells in patients with HBeAg-positive chronic hepatitis B(CHB)treated with telbivudine.Methods Fifty-six HBeAg-positive CHB patients admitted in the First Affiliated Hospital of Zhengzhou University during January 201 3 and June 201 4 were enrolled in this study.The expression of PD-1 on CD4 +and CD8 + T cells was detected with flow cytometry at baseline,24,48 and 72 wks after telbivudine treatment.The relationship of PD-1 expression with alanine aminotransferase (ALT)level,HBeAg seroconversion and HBV DNA loads was analyzed.t test and completely random variance analysis were used to analyze the data.Results The PD-1 expression on CD4 + and CD8 + T cells at baseline was higher in patients with low ALT levels compared to those with high ALT levels(t =1 2.20 and 9.69,both P <0.01 ),while higher levels of PD-1 expression was also observed in patients with high HBV DNA load (≥5 lgIU /mL)compared to those with low HBV DNA load (t =4.39 and 4.85,both P <0.01 ).PD-1 levels on CD4 + and CD8 + T cells presented a declining trend after telbivudine treatment(F =6.98 and 8.97,both P <0.01 ),PD-1 expression in patients with HBeAg seroconversion showed lower levels compared with baseline values (t =1 8.45 and 1 8.01 ,both P <0.01 ). Conclusion In HBeAg-positive CHB patients,the expression of PD-1 on CD4 + and CD8 + T lymphocytes shows a decreasing trend during the treatment with telbivudine,indicating that antiviral therapy may alleviate the immunosuppression in these patients.

Dynamic changes of regulatory T cells and their inhibitory molecules during antiviral treatment in patients with chronic hepatitis C / 中华传染病杂志

Objective To investigate the dynamic changes of regulatory T cells (Treg ) and the surface expression of programmed death (PD)‐1 and the level of transforming growth factor (TGF )‐βduring antiviral treatment in patients with chronic hepatitis C (CHC) .Methods Eighty‐six CHC patients referred to the First Affiliated Hospital of Zhengzhou University from October 2012 to October 2013 were included ,and all of them were administered with pegylated interferon α‐2a and ribavirin .Thirty healthy controls were enrolled .The percentage of Treg cells ,PD‐1 expression and TGF‐β level were analyzed by flow cytometry at baseline and at time of achieving rapid virological response (RVR ) , early viral virological (EVR ) , end‐of‐treatment virological response (ETVR ) and sustained virological response (SVR) ,or not achieving SVR .Comparison between two groups was analyzed by t test .Results Among 86 CHC patients ,the proportions of RVR ,EVR ,ETVR ,and SVR at week 24 of follow‐up were 29 cases ,67 cases ,79 cases and 67 cases ,respectively .Percentage of Treg cells in CHC patients was much higher than that in healthy controls (10 .31 ± 5 .61 vs 2 .18 ± 0 .65 ,t = 2 .28 , P< 0 .05) .During antiviral therapy ,percentages of Treg cells declined ,not only in CHC patients with HCV genotype 1b (at baseline , RVR ,EVR ,and ETVR :14 .44 ± 3 .78 ,11 .01 ± 1 .79 ,8 .24 ± 2 .98 ,and 5 .36 ± 1 .47 ,respectively ) ,but also in those infected with HCV genotype 2a (at baseline ,RVR ,EVR ,and ETVR :12 .34 ± 2 .82 ,8 .99 ± 1 .68 ,7 .53 ± 2 .96 ,and 4 .79 ± 1 .23 ,respectively ) .Expressions of PD‐1 and TGF‐β also decreased .At baseline ,the expressions of PD‐1 in patients with SVR and without SVR were 29 .11 ± 14 .65 and 37 .73 ± 11 .65 ,respectively (t = 2 .15 , P = 0 .04) ,and the levels of TGF‐β were 41 .20 ± 18 .96 and 56 .75 ± 14 .42 ,respectively (t= 2 .66 ,P< 0 .01) .At week 24 ,the expressions of PD‐1 in patients with SVR and without SVR were 10 .36 ± 4 .81 and 36 .46 ± 10 .52 ,respectively (t= 13 .95 ,P< 0 .01) ,and the levels of TGF‐β were 10 .06 ± 4 .64 and 45 .23 ± 17 .85 , respectively ( t = 11 .85 , P < 0 .01 ) . Conclusions Percentages of Treg cells and expressions of PD‐1 and TGF‐β decrease during antiviral treatment in CHC patients .Thus ,it could be of assist to predict the treatment response by monitoring these parameters .

Specific expression of CPS-II in hyperammonemia-injured liver cells / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To study the CPS-II mechanism underlying the pathological process of elevated blood ammonia leading to liver injury.</p><p><b>METHODS</b>An in vitro hyperammonemia hepatocyte cell model was constructed by exposure to various concentrations of NH4Cl. The subsequent changes to cellular morphology were observed by microscopy. to cell apoptosis were determined by flow cytometry, and to mRNA and protein expression of CPS-II were examined by real-time PCR and western blotting, respectively.</p><p><b>RESULTS</b>Exposure to NH₄Cl led to dose-dependent morphological damage, apoptosis and necrosis of the hepatocytes. The apoptosis rate was significantly higher for the high-dose group than for the control (no exposure) group (24.7% ± 2.39% vs. 4.1% ± 0.78%, q =8.06, P less than 0.05). Expression of the CPS-II mRNA was significantly elevated in response to NH₄Cl exposure (vs. the control group; F=191.881, P < 0.05).The CPS-II mRNA expression level increased with increasing NH₄Cl concentration (grey values: 1.040 ± 0.045, 1.641 ± 0.123, 2.285 ± 0.167 and 3.347 ± 0.124, respectively). The CPS-II protein expression level was also significantly enhanced in response to the NH₄Cl exposures (CPS-II protein and internal GAPDH grey value ratios: 0.099 ± 0.0130, 0.143 ± 0.025, 0.161 ± 0.036 and 0.223 ± 0.042, respectively; t=3.825, 3.968 and 6.908, P less than 0.05).</p><p><b>CONCLUSION</b>CPS-II mRNA and protein expression levels become elevated with increase in the NH₄Cl concentrations, suggesting that in addition to the urea cycle, CPS-II may play an important role in the ammonia metabolism under the condition of hyperammonemia.</p>

Heparin inhibits burn-induced spleen cell apoptosis by suppressing interleukin-1 expression / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Epidermal burn injury may trigger significant apoptosis of the spleen cells, which might be caused by a burn-induced systemic inflammatory reaction. Heparin has been shown to possess anti-inflammatory properties. Interleukin 1 (IL-1) is centrally important among pro-inflammatory cytokines. We hypothesized that heparin might inhibit burn-induced apoptosis in the spleen via suppression of the IL-1 pathway.</p><p><b>METHODS</b>Burn injury was performed on IL-1 R+/+ ( IL-1 receptor wild-type mouse) and IL-1 R-/- (IL-1 receptor knock-out mouse) mice, and they were then treated with heparin, saline or IL-1 receptor antagonist IL-Ra. Apoptosis, IL-1α and IL-1β expression were assessed in the spleens and serum. Survival curve analysis was further applied to elucidate the mechanism of heparin's protective properties.</p><p><b>RESULTS</b>Burn induced significant apoptosis (sham: 3.6%± 2.1% vs. burn: 28.8%± 5.9%; P < 0.001) and remarkable expression o IL-1α and IL-1β in the mouse spleens and serum. Heparin reduced the burn-induced apoptosis in the spleens (heparin treated: 8.6%± 3.4%, P < 0.005), which could be blocked by IL-1Ra. Heparin markedly decreased both IL-1α and IL-1β expression in the spleens and serum of burned mice. IL-1 R-/- mice demonstrated considerably less apoptosis in the spleens and had a higher survival rate after burns. Heparin did not significantly decrease apoptosis in the spleen and the mortality rate in IL-1 R-/- mice after burns.</p><p><b>CONCLUSION</b>Heparin inhibits burn-induced apoptosis of the spleen cells by suppressing IL-1 expression in mice.</p>

The influence of human immunodeficiency virus co-infection with hepatitis C virus and hepatitis B virus on the efficacy of high active anti-retroviral therapy / 中华内科杂志

Objective To evaluate the impact of HIV co-infection with HCV or HBV on the efficacy of highly active anti-retroviral therapy (HARRT). Methods The patients were divided into three groups: HIV + HBV + HCV co-infection group ( 23 patients), HIV + HCV co-infection group ( 166 patients), and HIV-only group (178 patients). HIV RNA, HCV RNA or HBV DNA were detected by real time PCR before treatment and 1,3,6,9 and 12 monthes after treatment, meanwhile the counts of CD4+ T lymphocyte and liver function including ALT, AST and TBil were tested. Results During one-year HAART, HIV RNA of HIV-only group, HIV + HBV + HCV co-infection group and HIV + HCV co-infection group decreased significantly from (6.78 ± 1.08), (6.23 ± 1.34), (6.54 ± 1.23) lg copies/ml to (0.53 ±0.15), (0.67 ±0.16),(0.43 ±0.11 ) lg copies/ml respectively (P＜.001 ). And CD4+ T lymphocyte counts of the three groups elevated significantly from ( 197 ± 127), (184 ± 113), (213 ± 143) cells/μl to (382 ±74), (383 ±70),(378 ±76) cells/μl respectively (P ＜0.001 ). However there were no differences among the three groups in HIV RNA and CD4+ T lymphocyte counts. There were no differences in liver functions including ALT,AST and TBil among the three groups. Conclusiom HIV co-infected with HBV and/or HCV does not impact on the efficacy of HAART. What more, HAART does not impact HCV replication.

Pol-specific T lymphocyte responses in Chinese HIV-1 recombinant subtype B/C infectors at different stages of diseases / 中华微生物学和免疫学杂志

Objective To analyze the character of Pol-specific T lymphocyte responses and identify immunodominant region recognized in Chinese HIV-1 recombinant subtype B/C infectors at different stages of diseases. Methods Eleven Chinese HIV-1 recombinant subtype B/C infectors infected in 18 months, 25 which infected time more than 3 years and 10 HIV-1-seronegative healthy individuals were enrolled. HIV-1-specific T lymphocyte responses were analyzed by an IFN-γ ELISPOT assay against 249 overlapping peptides spanning HIV-1 Pol protein in the present study. Results Pol-specific T lymphocyte responses of IFN-γsecretion were identified in 8 (72.73%) out of 11 infectors infected in 18 months, the specific T lymphocytes are mainly targe-ted at six peptides which amino acid position from Pol 481 to 631 in reverse transcriptase region: Pol5581, Pol5582, Pol5587, Pol5609, Pol5610 and Pol5615. There was a negative correlation between the breadth of re-sponse and peripheral CD4+ T cell count (P=0.0212, r=-0.762) ; Responses were identified in 15 (60%) out of 25 chronic infectors, the specific T lymphocytes are mainly targeted at four peptides which amino acid po-sition from Pol 241 to 295: Pol5521, Pol5525, Pol5526, Pol5531 and another peptide: Pol5638 which amino acid position from Pol 708 to 722 in reverse transcriptase region. There was a positive correlation between the magnitude of Pol-specific IFN-γ secretion T lymphocyte responses and plasma viremia (P = 0.006 95 , r = 0.660) . None of the seronegative healthy individuals gave the positive responses. Conclusion Chinese HIV-1 recombinant subtype B/C infectors at different stages of diseases mainly recognized different re-gions of Pol.

Effects of cefodizime on the T-lymphocyte subsets of peripheral blood in mice with immunological liver injury / 西安交通大学学报(医学版)

Objective To study the regulatory effect of cefodizime on the T-lymphocyte subsets of peripheral blood in mice with immunological liver injury.Methods The mouse model of immunological liver injury was induced by Bacillus Calmette Guerin and Lipoposaccharide.The study was conducted by using completely random design.The mice with immunological liver injury were divided into thymosin group,cefodizime high-,medium-,low-dose groups,ceftriaxone group and the normal saline group.The six groups were continuously administered agents respectively for 7 days,and T-lymphocyte subsets of peripheral blood in mice were determined and contrasted with those of the normal mice treated with normal saline on the 7th day.Flow cytomytry was used to determine the effects of cefodizime on T-lymphocyte subsets of peripheral blood in mice by using immuno-fluorescence technique.Results The immunological liver injury mice were deficient because their CD3+(%),CD4+(%),CD8+(%) and the ratio of CD4+CD8+ were lower than those of the normal mice.Cefodizime effectively increased CD3+(%),CD4+(%) and the ratio of CD4+CD8+ of the mice with immunological liver injury.Conclusion Cefodizime effectively improves the immune function of the host by regulating the balance between CD4+ cell and CD8+ cell.