Background: An easily accessible and valid surrogate marker for interventional stroke trials is needed. Objective: To investigate the usefulness of various S100B serum measures to predict long-term outcome and infarct...Background: An easily accessible and valid surrogate marker for interventional stroke trials is needed. Objective: To investigate the usefulness of various S100B serum measures to predict long-term outcome and infarct volume in patients with acute stroke. Design: Inception cohort study. Setting: Tertiary care university hospital. Patients: Thirty-nine patients (mean±SD age, 69.1±11.5 years) with acute nonlacunar middle cerebral artery infarction presenting less than 6 hours after symptom onset. Main Outcome Measures: Functional outcome 6 months after stroke (modified Rankin scale score) and final infarct volume on day 7 by means of standardized volumetry of brain images. Serum S100B level was determined at hospital admission and 24, 48, 72, 96, 120, and 144 hours after symptom onset. Results: Single S100B measures obtained 48 and 72 hours after stroke onset demonstrated the highest Spearman rank correlations with modified Rankin scale scores (p=0.68 and p=0.67, respectively; P < .001) and infarct volume (p=0.95 and p=0.94, respectively; P < .001). A 48-hour S100B value of 0.37 μg/L or less revealed a sensitivity of 0.87 and a specificity of 0.78 in predicting an independent functional outcome. In a multivariate model, S100B emerged as an outcome predictor that was independent of age, sex, stroke severity, etiology, lesion side, and risk factors. Conclusions: Single S100B values obtained 48 and 72 hours after stroke onset provide the highest predictive values with respect to functional outcome and infarct volume in nonlacunar middle cerebral artery infarction. More complex measures of the S100B kinetic (ie, area under the curve or peak value) were not superior. Therefore, these single S100B measures appear to be useful surrogate end points in acute interventional stroke trials.展开更多
Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epit...Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epitopes. In the chronic phase of infection, HCV-specific CD8+ T cell responses are usually weak, narrowly focused and display often functional defects regarding cytotoxicity, cytokine production, and proliferative capacity. In the last few years, different mechanisms which might contribute to the failure of HCV-specific CD8+ T cells in chronic infection have been identified, including insufficient CD4+ help, deficient CD8+ T cell differentiation, viral escape mutations, suppression by viral factors, inhibitory cytokines, inhibitory ligands, and regulatory T cells. In addition, host genetic factors such as the host’s human leukocyte antigen (HLA) background may play an important role in the efficiency of the HCV- specific CD8+ T cell response and thus outcome of infection. The growing understanding of the mechanisms contributing to T cell failure and persistence of HCV infection will contribute to the development of successful immunotherapeutical and -prophylactical strategies.展开更多
Virus-specific CD8+T cell responses play an important role in the natural course of infection;however,the impact of certain CD8+T cell responses in determining clinical outcome has not been fully defined.A well-define...Virus-specific CD8+T cell responses play an important role in the natural course of infection;however,the impact of certain CD8+T cell responses in determining clinical outcome has not been fully defined.A well-defined cohort of women inoculated with HCV from a single source showed that HLAB27 has a strong association with spontaneous clearance.The immunological basis for this association is unknown.However,the finding is especially significant because HLA-B27 has also been shown to have a protective role in HIV infection.We report the identification of an HLA-B27 restricted hepatitis C virus(HCV)specific CD8+T cell epitope that is recognized in the majority of recovered HLA-B27 positive women.In chronically HCV-infected individuals,analysis of the corresponding viral sequence showed a strong association between sequence variations within this epitope and expression of HLA-B27,indicating allele-specific selection pressure at the population level.Functional analysis in 3 chronically HCV-infected patients showed that the emerging variant viral epitopes represent escape mutations.In conclusion,our results suggest a dominant role of HLA-B27 in mediating spontaneous viral clearance as well as viral evolution in HCV infection and mechanistically link both associations to a dominant novel CD8+T cell epitope.These results support the central role of virus-specific CD8+T cells and the genetically determined restriction of the virus-specific T cell repertoire in HCV infection.展开更多
文摘Background: An easily accessible and valid surrogate marker for interventional stroke trials is needed. Objective: To investigate the usefulness of various S100B serum measures to predict long-term outcome and infarct volume in patients with acute stroke. Design: Inception cohort study. Setting: Tertiary care university hospital. Patients: Thirty-nine patients (mean±SD age, 69.1±11.5 years) with acute nonlacunar middle cerebral artery infarction presenting less than 6 hours after symptom onset. Main Outcome Measures: Functional outcome 6 months after stroke (modified Rankin scale score) and final infarct volume on day 7 by means of standardized volumetry of brain images. Serum S100B level was determined at hospital admission and 24, 48, 72, 96, 120, and 144 hours after symptom onset. Results: Single S100B measures obtained 48 and 72 hours after stroke onset demonstrated the highest Spearman rank correlations with modified Rankin scale scores (p=0.68 and p=0.67, respectively; P < .001) and infarct volume (p=0.95 and p=0.94, respectively; P < .001). A 48-hour S100B value of 0.37 μg/L or less revealed a sensitivity of 0.87 and a specificity of 0.78 in predicting an independent functional outcome. In a multivariate model, S100B emerged as an outcome predictor that was independent of age, sex, stroke severity, etiology, lesion side, and risk factors. Conclusions: Single S100B values obtained 48 and 72 hours after stroke onset provide the highest predictive values with respect to functional outcome and infarct volume in nonlacunar middle cerebral artery infarction. More complex measures of the S100B kinetic (ie, area under the curve or peak value) were not superior. Therefore, these single S100B measures appear to be useful surrogate end points in acute interventional stroke trials.
基金the Deutsche Forschungsgemeinschaft (Emmy Noether Programm, SFB 610)the Wilhelm Sander Stiftung, and the Bundesministerium fuer Wissenschaft und Forschung (Start-up fonds Kompetenznetz Hepatitis)
文摘Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epitopes. In the chronic phase of infection, HCV-specific CD8+ T cell responses are usually weak, narrowly focused and display often functional defects regarding cytotoxicity, cytokine production, and proliferative capacity. In the last few years, different mechanisms which might contribute to the failure of HCV-specific CD8+ T cells in chronic infection have been identified, including insufficient CD4+ help, deficient CD8+ T cell differentiation, viral escape mutations, suppression by viral factors, inhibitory cytokines, inhibitory ligands, and regulatory T cells. In addition, host genetic factors such as the host’s human leukocyte antigen (HLA) background may play an important role in the efficiency of the HCV- specific CD8+ T cell response and thus outcome of infection. The growing understanding of the mechanisms contributing to T cell failure and persistence of HCV infection will contribute to the development of successful immunotherapeutical and -prophylactical strategies.
文摘Virus-specific CD8+T cell responses play an important role in the natural course of infection;however,the impact of certain CD8+T cell responses in determining clinical outcome has not been fully defined.A well-defined cohort of women inoculated with HCV from a single source showed that HLAB27 has a strong association with spontaneous clearance.The immunological basis for this association is unknown.However,the finding is especially significant because HLA-B27 has also been shown to have a protective role in HIV infection.We report the identification of an HLA-B27 restricted hepatitis C virus(HCV)specific CD8+T cell epitope that is recognized in the majority of recovered HLA-B27 positive women.In chronically HCV-infected individuals,analysis of the corresponding viral sequence showed a strong association between sequence variations within this epitope and expression of HLA-B27,indicating allele-specific selection pressure at the population level.Functional analysis in 3 chronically HCV-infected patients showed that the emerging variant viral epitopes represent escape mutations.In conclusion,our results suggest a dominant role of HLA-B27 in mediating spontaneous viral clearance as well as viral evolution in HCV infection and mechanistically link both associations to a dominant novel CD8+T cell epitope.These results support the central role of virus-specific CD8+T cells and the genetically determined restriction of the virus-specific T cell repertoire in HCV infection.
