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1.
Chin Med J (Engl) ; 134(14): 1701-1708, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34133353

RESUMO

BACKGROUND: The basis of individualized treatment should be individualized mortality risk predictive information. The present study aimed to develop an online individual mortality risk predictive tool for acute-on-chronic liver failure (ACLF) patients based on a random survival forest (RSF) algorithm. METHODS: The current study retrospectively enrolled ACLF patients from the Department of Infectious Diseases of The First People's Hospital of Foshan, Shunde Hospital of Southern Medical University, and Jiangmen Central Hospital. Two hundred seventy-six consecutive ACLF patients were included in the present study as a model cohort (n = 276). Then the current study constructed a validation cohort by drawing patients from the model dataset based on the resampling method (n = 276). The RSF algorithm was used to develop an individual prognostic model for ACLF patients. The Brier score was used to evaluate the diagnostic accuracy of prognostic models. The weighted mean rank estimation method was used to compare the differences between the areas under the time-dependent ROC curves (AUROCs) of prognostic models. RESULTS: Multivariate Cox regression identified hepatic encephalopathy (HE), age, serum sodium level, acute kidney injury (AKI), red cell distribution width (RDW), and international normalization index (INR) as independent risk factors for ACLF patients. A simplified RSF model was developed based on these previous risk factors. The AUROCs for predicting 3-, 6-, and 12-month mortality were 0.916, 0.916, and 0.905 for the RSF model and 0.872, 0.866, and 0.848 for the Cox model in the model cohort, respectively. The Brier scores were 0.119, 0.119, and 0.128 for the RSF model and 0.138, 0.146, and 0.156 for the Cox model, respectively. The nonparametric comparison suggested that the RSF model was superior to the Cox model for predicting the prognosis of ACLF patients. CONCLUSIONS: The current study developed a novel online individual mortality risk predictive tool that could predict individual mortality risk predictive curves for individual patients. Additionally, the current online individual mortality risk predictive tool could further provide predicted mortality percentages and 95% confidence intervals at user-defined time points.


Assuntos
Insuficiência Hepática Crônica Agudizada , Humanos , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Estudos Retrospectivos
2.
Clin Cancer Res ; 27(13): 3772-3783, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33947693

RESUMO

PURPOSE: Intratumoral hepatitis B virus (HBV) integrations and mutations are related to hepatocellular carcinoma (HCC) progression. Circulating cell-free DNA (cfDNA) has shown itself as a powerful noninvasive biomarker for cancer. However, the HBV integration and mutation landscape on cfDNA remains unclear. EXPERIMENTAL DESIGN: A cSMART (Circulating Single-Molecule Amplification and Resequencing Technology)-based method (SIM) was developed to simultaneously investigate HBV integration and mutation landscapes on cfDNA with HBV-specific primers covering the whole HBV genome. Patients with HCC (n = 481) and liver cirrhosis (LC; n = 517) were recruited in the study. RESULTS: A total of 6,861 integration breakpoints including TERT and KMT2B were discovered in HCC cfDNA, more than in LC. The concentration of circulating tumor DNA (ctDNA) was positively correlated with the detection rate of these integration hotspots and total HBV integration events in cfDNA. To track the origin of HBV integrations in cfDNA, whole-genome sequencing (WGS) was performed on their paired tumor tissues. The paired comparison of WGS data from tumor tissues and SIM data from cfDNA confirmed most recurrent integration events in cfDNA originated from tumor tissue. The mutational landscape across the whole HBV genome was first generated for both HBV genotype C and B. A region from nt1100 to nt1500 containing multiple HCC risk mutation sites (OR > 1) was identified as a potential HCC-related mutational hot zone. CONCLUSIONS: Our study provides an in-depth delineation of HBV integration/mutation landscapes at cfDNA level and did a comparative analysis with their paired tissues. These findings shed light on the possibilities of noninvasive detection of virus insertion/mutation.

3.
Health Qual Life Outcomes ; 19(1): 140, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962617

RESUMO

BACKGROUND: Health Related Quality of Life (HRQL) is a multi-dimensional construct that can comprehensively evaluate the patient's health status, including physical, emotional, mental and social well-being. In this study, we aimed to evaluate the impact of non-alcoholic fatty liver disease (NAFLD) on HRQL in a Chinese population. METHODS: In this national multicenter cross-sectional survey, patients with NAFLD were enrolled. Chronic Liver Disease Questionnaire (CLDQ)-NAFLD was used to qualify HRQL. Univariate and multivariate analysis were used to identify independent risk factors of HRQL. RESULTS: A total of 5181 patients with NAFLD from 90 centers were enrolled in this study (mean age, 43.8 ± 13.3 years; male, 65.8%). The overall CLDQ score was 5.66 ± 0.89. Multivariate logistic regression analysis showed that body mass index (BMI: HR, 1.642; 95% CI, 1.330-2.026), alanine transaminase (ALT: HR, 1.006; 95% CI, 1.001-1.011), triglyceride (HR, 1.184; 95% CI, 1.074-1.305), disease severity (HR, 3.203; 95% CI, 1.418-7.232) and cardiovascular disease (HR, 4.305; 95% CI, 2.074-8.939) were independent risk factors for overall CLDQ score. In the logistic analyses of individual domain, BMI and triglyceride were independent risk factors of all domains. ALT, disease severity, diabetes, depression and cardiovascular disease were influencing factors for the CLDQ score of several domains. CONCLUSIONS: This national multicenter cross-sectional survey in China indicated that the HRQL in patients with NAFLD was impaired. HRQL was found to be significantly associated with sociodemographic and clinical factors. Attention should be paid to the optimally managing care of patients with NAFLD to improve their HRQL.


Assuntos
Grupo com Ancestrais do Continente Asiático/psicologia , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Nível de Saúde , Hepatopatia Gordurosa não Alcoólica/psicologia , Qualidade de Vida/psicologia , Índice de Gravidade de Doença , Inquéritos e Questionários/normas , Adolescente , Adulto , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
4.
Biomed Res Int ; 2016: 3524842, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27144164

RESUMO

The complement is thought to be involved in the pathogenesis of multiple liver disorders. However, its role in patients with HBV related acute-on-chronic liver failure (HBV-ACLF) remains unclear. Serum levels of the third and fourth complement components (C3, C4) and complement function (CH50) were examined in this prospective, observational study. Associations between their expression and disease activity were analyzed. Survival was analyzed by Kaplan-Meier curves. Predictors of clinical outcome were determined by Cox regression analysis. C3, C4, and CH50 levels were significantly lower in HBV-ACLF patients compared to controls. C3, C4, and CH50 levels were negatively correlated with Tbil levels but positively associated with PTA levels. C3 levels were negatively associated with MELD-Na. C3 levels were significantly lower in HBV-ACLF patients who died compared to patients who survived. In a median hospital stay of 39 days, mortality occurred in 41 patients with a progressive increase based on C3 grade (P = 0.008). The actuarial probability of developing mortality was significantly higher in patients with low C3 grade compared to those with high C3 grade (P < 0.001). Multivariate Cox regression analysis showed that C3 levels were an independent predictor of mortality. Complement played a pathogenic role in HBV-ACLF patients and C3 was an independent predictor of mortality.


Assuntos
Complemento C3/metabolismo , Doença Hepática Terminal , Hepatite B , Falência Hepática Aguda , Adulto , Complemento C4/metabolismo , Ensaio de Atividade Hemolítica de Complemento/métodos , Doença Hepática Terminal/sangue , Doença Hepática Terminal/etiologia , Doença Hepática Terminal/mortalidade , Feminino , Hepatite B/sangue , Hepatite B/complicações , Hepatite B/mortalidade , Humanos , Falência Hepática Aguda/sangue , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/mortalidade , Masculino , Estudos Prospectivos , Fatores de Risco
5.
Hepat Mon ; 14(7): e19370, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25147572

RESUMO

BACKGROUND: The pathogenesis of HBV-related acute-on-chronic liver failure (HBV-ACLF) is mainly based on a heightened immune-inflammatory reaction; however, the intimate underlying mechanism remains unclear. OBJECTIVES: The aim of the study was to explore potential key immune molecular targets that could serve as early predictive markers for HBV-ACLF. PATIENTS AND METHODS: Twenty-seven patients with acute exacerbation of chronic hepatitis B (CHB) (defined by: alanine transaminase ≥ 20 ULN, total bilirubin ≥ 5 ULN, 40% < prothrombin time activity ≤ 60%) and without cirrhosis were divided into 18 cases which did not progress to HBV-ACLF (defined by: prothrombin time activity < 40% and development within four weeks of hepatic encephalopathy and/or ascites) and nine cases that developed HBV-ACLF. Nine healthy people defined the normal control group (NC). Interleukin-1ß (IL-1ß), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, TNF-α and IFN-γ protein levels were assayed by Cytometric Bead Array (CBA) in blood plasma. The ELISA method was applied to confirm IL-10 detection using the CBA method. RESULTS: IL-4, IL-12p70 and IFN-γ were undetectable; IL-1ß, IL-6, IL-8, IL-10 and TNF-α levels were significantly higher than in NC. Moreover, cytokines reached the highest levels in acute exacerbation of CHB, with the exception of IL-2 and IL-8. When comparing the HBV-ACLF patients prior to and at the time of ACLF diagnosis, IL-10 was the only cytokine that exhibited a significant decrease (P = 0.008). IL-10 concentrations were positively correlated to ALT levels (r = 0.711, P < 0.001). CONCLUSIONS: The assessment of plasma IL-10 levels in chronic hepatitis B acute exacerbation may provide an early predictive marker for progression to HBV-ACLF.

6.
Liver Int ; 34(2): 266-73, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23890319

RESUMO

BACKGROUND: Interleukin-6/IL-12 family cytokines play a key role in inflammatory diseases via their effects on the differentiation or regulation of T helper cells. AIMS: The aim of this study was to determine the role of interleukin-27 (IL-27) and its association with helper T cells in hepatitis B virus (HBV)-infected patients. METHODS: Samples were assessed from 51 HBV-infected patients [28 chronic hepatitis B (CHB) subjects and 23 acute-on-chronic liver failure (ACLF) subjects] and 18 normal controls (NC). Serum IL-27 levels were examined by enzyme-linked immunosorbent assay. Circulating helper T cells were determined using flow cytometry and associations between IL-27 expression and helper T cells were analysed. RESULTS: Serum IL-27 levels rose in HBV-infected patients (502.88 ± 23.35 pg/ml) compared to (NC, 277.14 ± 23.96 pg/ml, P < 0.0001). Furthermore, it significantly increased in patients with ACLF (587.90 ± 33.08 pg/ml) when compared with CHB (433.04 ± 26.57 pg/ml, P = 0.001). However, no statistically significant differences were observed between IL-27 and the presence of HBeAg. High levels of IL-27 then positively correlated with Tbil levels (r = 0.401, P = 0.004), but negatively associated with prothrombin time activity levels (r = -0.496, P < 0.001), and a slightly negative correlation trend with HBV-DNA loads (r = -0.228, P = 0.107) existed in these HBV-infected subjects. Additionally, frequency of circulating interleukin-17-producing CD4(+) T cells (Th17 cells) increased in HBV-infected patients (ACLF, mean, 5.39%; CHB, median, 3.12%) as compared to NC subjects (median, 2.22%, P < 0.0001). Moreover, correlation analysis showed that serum IL-27 level was positively associated with circulating Th17 cells (r = 0.342, P = 0.036). CONCLUSION: These results provided evidence that IL-27 was positively correlated with Th17 cells commitment, and may exerted a proinflammatory effect in the development of liver injury in HBV-infected patients.


Assuntos
Biomarcadores/sangue , Hepatite B Crônica/imunologia , Interleucina-27/sangue , Falência Hepática Aguda/imunologia , Células Th17/imunologia , China , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Hepatite B Crônica/sangue , Hepatite B Crônica/complicações , Humanos , Falência Hepática Aguda/sangue , Falência Hepática Aguda/etiologia , Projetos Piloto , Tempo de Protrombina
7.
J Gastroenterol Hepatol ; 28(3): 513-21, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23215950

RESUMO

BACKGROUND AND AIM: Although regulatory T cells (Treg) and interleukin-17-producing CD4 T cells (Th17) have been demonstrated to play opposing roles in inflammation-associated diseases, their frequency and balance in different stages of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) remain unknown. METHODS: Fourteen patients with HBV-associated ACLF were studied and defined into different stages according to disease activity. Circulating Th17 cells and Treg cells were analyzed by flow cytometry, and the cytokines were quantitated by enzyme-linked immunosorbent assay. Results were correlated with temporal changes in viral load, disease progression and compared with 30 chronic hepatitis B (CHB) subjects and 18 healthy subjects. RESULTS: We showed a significantly higher frequency of circulating Th17 cells in the remission stage of ACLF when compared with the progression stage, the CHB group, or normal controls. However, the frequency of circulating Treg cells was significantly lower in the remission stage of ACLF when compared with the progression stage or the CHB group. The increase in Th17 cells and concomitant decrease in Treg cells created an imbalance in the remission stage of ACLF patients, which negatively correlated with disease progression. In addition, we showed that ACLF patients in the remission stage had an altered profile of cytokines that regulated the induction of Th17 cells and Treg cells. CONCLUSIONS: ACLF patients in the remission stage had an imbalance of Th17 to Treg cells, which could be used as a prognostic marker to predict disease progression. This imbalance could play a role in the immunopathogenesis of HBV-related ACLF.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Hepatite B Crônica/complicações , Interleucina-17/sangue , Falência Hepática/imunologia , Linfócitos T Reguladores/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Progressão da Doença , Doença Hepática Terminal/imunologia , Doença Hepática Terminal/virologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Falência Hepática/virologia , Falência Hepática Aguda/imunologia , Falência Hepática Aguda/virologia , Masculino , Pessoa de Meia-Idade , Carga Viral , Adulto Jovem
8.
PLoS One ; 7(8): e43408, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22927965

RESUMO

AIMS: Bone marrow-derived mesenchymal stem cells (BMSCs) can reduce liver fibrosis. Apart from the paracrine mechanism by which the antifibrotic effects of BMSCs inhibit activated hepatic stellate cells (HSCs), the effects of direct interplay and juxtacrine signaling between the two cell types are poorly understood. The purpose of this study was to explore the underlying mechanisms by which BMSCs modulate the function of activated HSCs. METHODS: We used BMSCs directly and indirectly co-culture system with HSCs to evaluate the anti-fibrosis effect of BMSCs. Cell proliferation and activation were examined in the presence of BMSCs and HGF. c-met was knockdown in HSCs to evaluate the effect of HGF secreted by BMSCs. The TLR4 and Myeloid differentiation primary response gene 88(MyD88) mRNA levels and the NF-kB pathway activation were determined by real-time PCR and western blotting analyses. The effect of BMSCs on HSCs activation was investigated in vitro in either MyD88 silencing or overexpression in HSCs. Liver fibrosis in rats fed CCl(4) with and without BMSCs supplementation was compared. Histopathological examinations and serum biochemical tests were compared between the two groups. RESULTS: BMSCs remarkably inhibited the proliferation and activation of HSCs by interfering with LPS-TLR4 pathway through a cell-cell contact mode that was partially mediated by HGF secretion. The NF-kB pathway is involved in HSCs activation inhibition by BMSCs. MyD88 over expression reduced the BMSC inhibition of NF-kB luciferase activation. BMSCs protected liver fibrosis in vivo. CONCLUSION: BMSCs modulate HSCs in vitro via TLR4/MyD88/NF-kB signaling pathway through cell-cell contact and secreting HGF. BMSCs have therapeutic effects on cirrhosis rats. Our results provide new insights into the treatment of hepatic fibrosis with BMSCs.


Assuntos
Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/efeitos dos fármacos , Fator de Crescimento de Hepatócito/farmacologia , Células-Tronco Mesenquimais/citologia , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Células da Medula Óssea/citologia , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Lipopolissacarídeos/farmacologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Fator 88 de Diferenciação Mieloide/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
9.
Artigo em Chinês | MEDLINE | ID: mdl-21186536

RESUMO

OBJECTIVE: To observe the efficacy and safety of PEG-interferon alpha-2a (PEG-IFNalpha-2a) treatment on lamivudine (LAM)-resistant chronic hepatitis B (CHB) patients. METHODS: Eighty-one patients with lamivudine-resistant HBeAg (+) chronic hepatitis B patients were enrolled and divided into PEG-IFNalpha-2a treatment group (40 cases) and adefovir dipivoxil (ADV) control group (41 cases). Two groups were combined with LAM in the first 12 weeks(w). The ALT normalization rate, the HBV DNA and HBeAg negative rate, and the HBeAg seroconversion rate were observed in 12 W, 24 W, 48 W. RESULTS: The ALT normalization rate in 12 W, 24 W of PEG-IFNalpha-2a group was 62.5% and 80.0%. And it was higher than that of ADV group. The HBeAg negative rate and HBeAg seroconversion rate in 48 W of PEG-IFNalpha-2a group were 60% and 57.5% , which were higher than that of ADV group. The difference was statistically significant (P < 0.05). CONCLUSION: PEG-IFNalpha-2a treatment of lamivudine-resistant HBeAg (+) chronic hepatitis B is superior to ADV, and its security is well.


Assuntos
Antivirais/uso terapêutico , DNA Viral/análise , Farmacorresistência Viral/genética , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Lamivudina/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , DNA Viral/efeitos dos fármacos , Farmacorresistência Viral/efeitos dos fármacos , Feminino , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/virologia , Humanos , Interferon alfa-2 , Interferons/imunologia , Interferons/farmacologia , Masculino , Pessoa de Meia-Idade , Mutação , Organofosfonatos/uso terapêutico , Proteínas Recombinantes , Resultado do Tratamento , Conduta Expectante
11.
Zhonghua Gan Zang Bing Za Zhi ; 14(3): 205-9, 2006 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-16556417

RESUMO

OBJECTIVE: To study the clinical efficacy of three kinds of hybrid bioartificial liver support systems (HBLSS) in treating chronic severe hepatitis. METHODS: A bioartificial liver support system (BAL), comprising porcine hepatocytes and fiber tube style bioreactor, was constructed. Then three kinds of HBLSS were constructed: Molecular absorbent recirculating system (MARS) plus BAL; slow plasma exchange (SPE) plus continuous hemodiafiltration (CHDF) and BAL; and SPE plus hemoperfusion (HP) and BAL. One hundred-twenty patients in middle or late stages of chronic severe hepatitis were enrolled in this study. They were randomly divided into 6 groups: H1 group was treated with BAL+MARS, H2 with BAL+SPE+CHDF and H3 with BAL+SPE+HP (as treatment groups); C1 group was treated with MARS, C2 with SPE+CHDF and C3 with SPE+HP (as control groups). The changes in the clinical symptoms, in the hepatic encephalopathy stages, and in the serum total bilirubin (TBIL), the serum albumin (ALB), the prothrombin activities (PTA), endotoxin, ammonia, creatinine and a-fetal protein (AFP) were all observed before the treatment, right after it and 72 hours later. The improving and curing rates and the rates of side effect occurrences in each group were observed. RESULTS: In all 6 groups, the patients' clinical symptoms ameliorated; their TBIL, endotoxin and ammonia levels decreased (P<0.05), and their PTA and AFP levels lowered significantly (P<0.05). But in the H1, H2 and H3 groups they were more distinctive than in the control groups. In H1 and H2 groups creatinine and ammonia levels were decreased more significantly than in the H3 group (P<0.05). The improving and curing rates of each group were 65 % (13/20), 60% (12/20), 45% (9/20), 45% (9/20), 40% (8/20) and 20% (4/20) respectively. No serious side effects were observed during the treatment. CONCLUSION: In treating middle and late stage chronic severe hepatitis, the measures used in H1, H2 and H3 are better than those in C1, C2 and C3. Furthermore, H1 and H2 treatments can ameliorate hepatic and renal functions, prevent the development of multiple organ dysfunction syndrome, and are better than those used in H3.


Assuntos
Hepatite Viral Humana/terapia , Falência Hepática Aguda/terapia , Fígado Artificial , Fígado/citologia , Adulto , Idoso , Animais , Reatores Biológicos , Estado Terminal , Feminino , Hemodiafiltração , Encefalopatia Hepática/sangue , Encefalopatia Hepática/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Troca Plasmática , Suínos
12.
J Gastroenterol ; 38(9): 861-4, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14564632

RESUMO

BACKGROUND: We aimed to determine a discriminant function for prognosis in chronic severe hepatitis B (CSHB), by discriminant analysis of prognostic indexes and probability of death. METHODS: In 205 patients with chronic severe hepatitis B (101 patients in the survival group and 104 patients in the death group), we carried out discriminant analysis of serum total bilirubin, prothrombin activity, white blood cells, creatinine, maximum depth of ascites, hepatic encephalopathy, singultus, and digestive tract hemorrhage. RESULTS: The discriminant function was V=0.00043 x total bilirubin (microM) - 0.025 x prothrombin activity (%) + 0.056 x white blood cells (10(9)/l) + 0.00284 x creatinine (microM) + 0.0014 x maximum depth of ascites (mm) + 0.724 x hepatic encephalopathy score + 0.078 x singultus score + 0.457 x digestive tract hemorrhage score - 2.488. The correctness of the function for predicting death in the death group was 92.3%, and that for predicting survival in the survival group was 96.0%. When the V values were -infinity, -4.595, -2.197, -1.386, -0.405, 0.405, 1.386, 2.197, 2.944, 4.595, and infinity, a posterior probabilities of death were 0%, 5%, 10%, 20%, 40%, 60%, 80%, 90%, 95%, 99%, and 100%, respectively. CONCLUSIONS: The discriminant function is an objective, convenient, and practical method to assess the prognosis of chronic severe hepatitis B.


Assuntos
Análise Discriminante , Hepatite B Crônica/mortalidade , Probabilidade , Prognóstico , Hepatite B Crônica/diagnóstico , Humanos , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Análise de Sobrevida
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