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The infection of susceptible mice with Theiler's murine encephalomyelitis virus (TMEV) induces a T cell-mediated demyelinating disease. This system has been studied as a relevant infection model for multiple sclerosis (MS). Therefore, defining the type of T cell responses and their functions is critically important for understanding the relevant pathogenic mechanisms. In this study, we adoptively transferred naive VP2-specific TCR-Tg CD4+ T cells into syngeneic susceptible SJL mice and monitored the development of the disease and the activation and proliferation of CD4+ T cells during the early stages of viral infection. The preexisting VP2-specific naive CD4+ T cells promoted the pathogenesis of the disease in a dose-dependent manner. The transferred VP2-specific CD4+ T cells proliferated rapidly in the CNS starting at 2-3 dpi. High levels of FoxP3+CD4+ T cells were found in the CNS early in viral infection (3 dpi) and persisted throughout the infection. Activated VP2-specific FoxP3+CD4+ T cells inhibited the production of IFN-γ, but not IL-17, via the same VP2-specific CD4+ T cells without interfering in proliferation. Thus, the early presence of regulatory T cells in the CNS with viral infection may favor the induction of pathogenic Th17 cells over protective Th1 cells in susceptible mice, thereby establishing the pathogenesis of virus-induced demyelinating disease.
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Linfócitos T CD4-Positivos/imunologia , Infecções por Cardiovirus/imunologia , Infecções por Cardiovirus/virologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/virologia , Theilovirus/fisiologia , Transferência Adotiva , Animais , Proliferação de Células , Sistema Nervoso Central/patologia , Citocinas/biossíntese , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/virologia , Fatores de Transcrição Forkhead/metabolismo , Interferon gama/metabolismo , Interleucina-17/biossíntese , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/metabolismo , Especificidade da EspécieRESUMO
BACKGROUND: Chronic infection with Theiler's murine encephalomyelitis virus (TMEV) in susceptible SJL/J mice induces an immune-mediated demyelinating disease and has extensively been used as a relevant infectious model for multiple sclerosis (MS). Infection of the host with many other viruses also leads to acute or chronic inflammatory diseases in the central nervous system (CNS). Levels of viral load in the host often play a critical role in the pathogenesis of virus-induced diseases. Thus, the inhibition of viral replication in the host against a broad spectrum of similar viruses is critically important for preventing the viral pathogenicity. METHODS: P2/P3-expressing transgenic (B6 X SJL)F1 founders were generated and bred onto the C57BL/6 and SJL/J backgrounds. Differences in the development of demyelinating disease were compared. Viral persistence, cytokine production, and immune responses in the CNS of infected control and P2/P3-Tg mice were analyzed after infection using quantitative PCR, ELISA, and flow cytometry. Various cell types from the control and P2/P3-Tg mice, as well as cells transfected in vitro with the P2 and/or P3 regions, were also analyzed for viral replication and innate cytokine production. RESULTS: P2/P3-transgenic (P2/P3-Tg) mice carrying the viral non-structural protein genes displayed significantly reduced virus-specific T cell responses in the CNS against both the structural and non-structural proteins. Consequently, viral loads in the CNS were greater in the Tg mice during the chronic infection. However, P2/P3-Tg SJL mice exhibited reduced disease incidence and less severe clinical symptoms than did their non-transgenic littermates. Interestingly, P2/P3-Tg mice showed low viral loads in the CNS at a very early period after infection (1-3 days) with TMEV and related EMCV but not unrelated VSV. Cells from P2/P3-Tg mice and cells transfected with the P2 and/or P3 regions in vitro yielded also lower viral replication but higher IFN-α/ß production. CONCLUSIONS: This study demonstrates that the expression of viral non-structural genes in mice inhibits initial viral replication and suppresses sustaining pathogenic anti-viral immune responses to broad viral determinants. It appears that the elevation of innate immune cytokines produced in the cells expressing the non-structural viral genes upon viral infection is responsible for the inhibitions. The inhibition is partially virus-specific as it is more efficient for a related virus compared to an unrelated virus, suggesting a role for the similarity in the viral genome structures. Therefore, the expression of viral non-structural genes may serve as a useful new method to prevent a broadly virus-specific pathogenesis in the hosts.
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Doenças Desmielinizantes/genética , Doenças Desmielinizantes/metabolismo , Regulação Viral da Expressão Gênica , Theilovirus/genética , Theilovirus/metabolismo , Replicação Viral/fisiologia , Animais , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Linfócitos T/fisiologiaRESUMO
UNLABELLED: Intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelinating disease in susceptible SJL/J mice but not in resistant C57BL/6 mice. Previous studies have indicated that the major histocompatibility complex (MHC) genes play the most prominent role in the development of TMEV-induced demyelinating disease. In this study, we used C57BL/6.S (B6.S) congenic mice, which carry H-2(s) MHC genes instead of H-2(b) MHC genes in conjunction with the C57BL/6 (B6) background genes. Our data show that virus-infected B6.S mice are free from disease and have significantly lower viral loads than susceptible SJL mice, particularly in the spinal cord. A strong protective Th1-type T helper response with virtually no pathogenic Th17 response was detected in B6.S mice, in contrast to the reduced Th1- and robust Th17-type responses in SJL mice. Notably, lower levels of viral infectivity in B6.S antigen-presenting cells (APCs) correlated with the disease resistance and T-cell-type response. In vitro studies using APCs from B6.S and SJL mice show that TLR2, -3, -4, and -7, but not TLR9, signaling can replace viral infection and augment the effect of viral infection in the differentiation of the pathogenic Th17 cell type. Taken together, these results strongly suggest that the viral replication levels in APCs critically affect the induction of protective versus pathogenic Th cell types via the signaling of pattern recognition receptors for innate immune responses. Our current findings further imply that the levels of viral infectivity/replication and TLR-mediated signaling play critical roles in the pathogenesis of chronic viral diseases. IMPORTANCE: This study indicates that innate immune cytokines produced in antigen-presenting cells stimulating the T cell immune responses during early viral infection play a critical role in determining the susceptibility of mice to the development of demyelinating disease. The level of innate immune cytokines reflects the level of initial viral infection in the antigen-presenting cells, and the level determines the development of T cell types, which are either protective or pathogenic. The level of initial viral infection to the cells is controlled by a gene or genes that are not associated with the major histocompatibility antigen complex genes. This finding has an important implication in controlling not only chronic viral infections but also infection-induced autoimmune-like diseases, which are closely associated with the pathogenic type of T cell responses.
Assuntos
Células Apresentadoras de Antígenos/virologia , Infecções por Cardiovirus/patologia , Infecções por Cardiovirus/virologia , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/virologia , Theilovirus/isolamento & purificação , Carga Viral , Animais , Células Apresentadoras de Antígenos/imunologia , Infecções por Cardiovirus/imunologia , Doenças Desmielinizantes/imunologia , Feminino , Genes MHC Classe I , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Células Th17/imunologia , Theilovirus/imunologia , Receptores Toll-Like/imunologiaRESUMO
UNLABELLED: Interleukin-6 (IL-6) plays an important role in the development and progression of inflammatory responses, autoimmune diseases, and cancers. Many viral infections, including Theiler's murine encephalomyelitis virus (TMEV), result in the vigorous production of IL-6. However, the role of IL-6 in the development of virus-induced inflammatory responses is unclear. The infection of susceptible mice with TMEV induces the development of chronic demyelinating disease, which is considered a relevant infectious model for multiple sclerosis. In this study, we demonstrate that resistant C57BL/6 mice carrying an IL-6 transgene (IL-6 Tg) develop a TMEV-induced demyelinating disease accompanied by an increase in viral persistence and an elevated Th17 cell response in the central nervous system. Either IL-6 or IL-17 induced the expression of Bcl-2 and Bcl-xL at a high concentration. The upregulated expression of prosurvival molecules in turn inhibited target cell destruction by virus-specific CD8(+) T cells. More interestingly, IL-6 and IL-17 synergistically promoted the expression of these prosurvival molecules, preventing cellular apoptosis at a much lower (<5-fold) concentration. The signals involved in the synergy appear to include the activation of both STAT3 and NF-κB via distinct cytokine-dependent pathways. Thus, the excessive IL-6 promotes the generation of Th17 cells, and the resulting IL-6 and IL-17 synergistically promote viral persistence by protecting virus-infected cells from apoptosis and CD8(+) T cell-mediated target destruction. These results suggest that blocking both IL-6 and IL-17 functions are important considerations for therapies of chronic viral diseases, autoimmune diseases, and cancers. IMPORTANCE: This study indicates that an excessive level of IL-6 cytokine produced following viral infection promotes the development of IL-17-producing pathogenic helper T cells. We demonstrate here for the first time that IL-6 together with IL-17 synergistically enhances the expression of survival molecules to hinder critical host defense mechanisms removing virus-infected cells. This finding has an important implication in controlling not only chronic viral infections but also autoimmune diseases and cancers, which are associated with prolonged cell survival.
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Apoptose , Evasão da Resposta Imune , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Linfócitos T Citotóxicos/imunologia , Theilovirus/imunologia , Theilovirus/fisiologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Infection with Theiler's murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) of susceptible mice results in an immune-mediated demyelinating disease which is considered a relevant viral model of human multiple sclerosis. We previously demonstrated that the expression of positive costimulatory molecules (CD40, CD80, and CD86) is higher on the microglia of TMEV-resistant C57BL/6 (B6) mice than the microglia of TMEV-susceptible SJL/J (SJL) mice. In this study, we analyzed the expression levels of the negative costimulatory molecules PD-1 and PDL-1 in the CNS of TMEV-infected SJL mice and B6 mice. Our results indicated that TMEV infection induces the expression of both PD-1 and PDL-1 on microglia and macrophages in the CNS but not in the periphery. The expression of PD-1 only on CNS-infiltrating macrophages and not on resident microglia was considerably higher (>4-fold) in TMEV-infected SJL mice than TMEV-infected B6 mice. We further demonstrated that interleukn-6 (IL-6) is necessary to induce the maximal expression of PDL-1 but not PD-1 after TMEV infection using IL-6-deficient mice and IL-6-transgenic mice in conjunction with recombinant IL-6. In addition, cells from type I interferon (IFN) receptor knockout mice failed to upregulate PD-1 and PDL-1 expression after TMEV infection in vitro, indicating that type I IFN signaling is associated with the upregulation. However, other IFN signaling may also participate in the upregulation. Taken together, these results strongly suggest that the expression of PD-1 and PDL-1 in the CNS is primarily upregulated following TMEV infection via type I IFN signaling and the maximal expression of PDL-1 additionally requires IL-6 signaling.
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Antígeno B7-H1/metabolismo , Infecções por Cardiovirus/virologia , Sistema Nervoso Central/virologia , Interleucina-6/imunologia , Microglia/virologia , Receptor de Morte Celular Programada 1/metabolismo , Theilovirus/imunologia , Animais , Infecções por Cardiovirus/imunologia , Feminino , Macrófagos/virologia , Camundongos , Camundongos Knockout , Camundongos TransgênicosRESUMO
The importance of aesthetics in children has increased over time. Therefore, this multicenter randomized clinical trial aimed to analyze and compare three-dimensional (3D)-printed resin crowns (RCs) as a potential alternative to stainless-steel crowns (SSCs) for restoring primary molars with extensive carious lesions. According to the null hypothesis, no statistically significant difference was observed in restoration failure between RC and SSC groups. A total of 56 primary molars after pulp treatment at two dental hospitals were included. After pulp treatment, the teeth were randomly divided into two groups: SSCs (n = 28) and RCs (n = 28). At 1 week and 3, 6 and 12 months, the Quigley-Hein plaque index (QHI), gingival index (GI), occlusal wear, and survival rate were assessed by examination, radiography and alginate impressions. No significant difference in QHI was observed between the two groups. However, the GI at 12 months and occlusal wear in the RC group were significantly higher than those in the SSC group (p < 0.05). The survival rates were 100% in the SSC group and 82.1% in the RC group (p = 0.047). Cracks and discoloration were also observed in the RCs. Within the limitations of this study, 3D-printed RCs are aesthetically superior to SSCs and clinically easy to repair. However, if clinical effectiveness and safety are improved, RCs could potentially become a viable aesthetic alternative in the future.
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Coroas , Dente Molar , Impressão Tridimensional , Aço Inoxidável , Dente Decíduo , Humanos , Feminino , Masculino , Criança , Cárie Dentária/terapia , Restauração Dentária Permanente/métodos , Pré-Escolar , Planejamento de Prótese Dentária , Índice Periodontal , Falha de Restauração DentáriaRESUMO
Auxetic metamaterials are a unique class of materials or structures with a negative Poisson's ratio and a wide array of functionalities. However, their inherent porosity presents challenges in practical applications. Filling the inherent perforations while preserving their unique auxeticity is difficult because it demands the seamless integration of components that have highly distinct mechanical characteristics. Here we introduce a seamless auxetic substrate film capable of achieving a negative Poisson's ratio of -1, the theoretical limit of isotropic materials. This breakthrough is realized by incorporating a highly rigid auxetic structure reinforced by glass-fabric, with surface-flattening soft elastomers. We effectively optimize the mechanical properties of these components by systematic experimental and theoretical investigations into the effects of relative differences in the moduli of the constituents. Using the developed auxetic film we demonstrate an image distortion-free display having 25 PPI resolution of micro-LEDs that is capable of 25% stretching without performance degradation.
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Passive radiative cooling represents a transformative approach to achieving sustainable cooling on Earth without relying on energy consumption. In this research, the optical characteristics of five readily accessible metal-organic frameworks (MOFs): ZIF-67(Co), MOF-74(Ni), HKUST-1(Cu), MOF-801(Zr), and UiO-66(Zr) are meticulously explored. The objective is to identify the pivotal factors that influence their ability to facilitate radiative cooling. Through an in-depth analysis encompassing spectroscopic features, surface texture, and porosity, it is found that the MOFs' cooling efficacy is largely influenced by their optical bandgaps and functional groups, although other factors like chemical composition and structural characteristics remain to be considered. Notably, UiO-66(Zr) emerged as the standout performer, boasting an impressive solar reflectance of 91% and a mid-infrared emissivity of 96.8%. Remarkably, a fabric treated with UiO-66(Zr) achieved a substantial sub-ambient cooling effect, lowering temperatures by up to 5 °C and delivering a cooling power of 26 W m-2 at 300 K. The findings underscore the vast potential of MOFs in offering new opportunities to advance passive radiative cooling technologies, paving the way for their extensive application in this field.
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Theiler's virus-induced demyelinating disease has been extensively investigated as a model for persistent viral infection and multiple sclerosis (MS). However, the role of CD8(+) T cells in the development of disease remains unclear. To assess the role of virus-specific CD8(+) T cells in the pathogenesis of demyelinating disease, a single amino acid substitution was introduced into the predominant viral epitope (VP3 from residues 159 to 166 [VP3(159-166)]) and/or a subdominant viral epitope (VP3(173-181)) of susceptible SJL/J mice by site-directed mutagenesis. The resulting variant viruses (N160V, P179A, and N160V/P179A) failed to induce CD8(+) T cell responses to the respective epitopes. Surprisingly, mice infected with N160V or N160V/P179A virus, which lacks CD8(+) T cells against VP3(159-166), did not develop demyelinating disease, in contrast to wild-type virus or P179A virus lacking VP3(173-181)-specific CD8(+) T cells. Our findings clearly show that the presence of VP3(159-166)-specific CD8(+) T cells, rather than viral persistence itself, is strongly correlated with disease development. VP3(173-181)-specific CD8(+) T cells in the central nervous system (CNS) of these virus-infected mice expressed higher levels of transforming growth factor ß, forkhead box P3, interleukin-22 (IL-22), and IL-17 mRNA but caused minimal cytotoxicity compared to that caused by VP3(159-166)-specific CD8(+) T cells. VP3(159-166)-specific CD8(+) T cells exhibited high functional avidity for gamma interferon production, whereas VP3(173-181)-specific CD8(+) T cells showed low avidity. To our knowledge, this is the first report indicating that the induction of the IL-17-producing CD8(+) T cell type is largely epitope specific and that this specificity apparently plays a differential role in the pathogenicity of virus-induced demyelinating disease. These results strongly advocate for the careful consideration of CD8(+) T cell-mediated intervention of virus-induced inflammatory diseases.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos/imunologia , Esclerose Múltipla/imunologia , Viroses/imunologia , Animais , Linhagem Celular , Cricetinae , Modelos Animais de Doenças , Camundongos , Esclerose Múltipla/virologia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Replicação ViralRESUMO
Positive airway pressure (PAP) is an important treatment tool for patients with moderate and severe obstructive sleep apnea (OSA), and adherence to PAP significantly affects treatment outcomes. Disease severity, adverse effects, and psychosocial factors are known to predict medication adherence. Cephalometric parameters have been reported to positively correlate with upper airway collapse. However, research on the correlation between these cephalometric parameters and PAP adherence remains insufficient. This study aimed to identify this relationship. This study included 185 patients with OSA who were prescribed PAP. Polysomnography (PSG) was performed to diagnose OSA, and paranasal sinus computed tomography (PNS CT) was performed to check for comorbidities of the upper airway. In addition, cephalometric parameters such as the hyoid-posterior nasal spine (H-PNS), posterior nasal spine-mandibular plane (PNS-MP), and hyoid-mandibular plane (H-MP) were measured in the midsagittal and axial CT views. Adherence was evaluated 3-12 months after the PAP prescription. A total of 136 patients were PAP-adherent, and 49 were nonadherent. There were more males in the adherent group and a higher average height in the adherent group. The PSG results showed that the apnea-hypopnea index (AHI), respiratory disturbance index (RDI), oxygen desaturation index (ODI), arousal index (AI), rapid eye movement (REM) AHI, and supine AHI were significantly higher, and the lowest oxygen saturation was lower in the adherent group. In the analysis of covariance (ANCOVA) model adjusted for sex and height, among the cephalometric parameters, H-MP was significantly longer in the adherent group (p = 0.027), and H-PNS showed a longer tendency (p = 0.074). In the logistic regression analysis model, the odds ratio (OR) and 95% confidence intervals (95% CI) of adherence and severe OSA in the third tertile compared to the first tertile of H-MP were 2.93 (1.25-6.86) and 4.00 (1.87-8.56). In the case of H-PNS, they were 2.58 (1.14-5.81) and 4.86 (2.24-10.54), respectively. This study concluded that an inferiorly placed hyoid bone in adult patients is associated with PAP adherence and disease severity.
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BACKGROUND: Theiler's virus infection induces chronic demyelinating disease in mice and has been investigated as an infectious model for multiple sclerosis (MS). IL-1 plays an important role in the pathogenesis of both the autoimmune disease model (EAE) and this viral model for MS. However, IL-1 is known to play an important protective role against certain viral infections. Therefore, it is unclear whether IL-1-mediated signaling plays a protective or pathogenic role in the development of TMEV-induced demyelinating disease. METHODS: Female C57BL/6 mice and B6.129S7-Il1r1tm1Imx/J mice (IL-1R KO) were infected with Theiler's murine encephalomyelitis virus (1 x 106 PFU). Differences in the development of demyelinating disease and changes in the histopathology were compared. Viral persistence, cytokine production, and immune responses in the CNS of infected mice were analyzed using quantitative PCR, ELISA, and flow cytometry. RESULTS: Administration of IL-1ß, thereby rending resistant B6 mice susceptible to TMEV-induced demyelinating disease, induced a high level of Th17 response. Interestingly, infection of TMEV into IL-1R-deficient resistant C57BL/6 (B6) mice also induced TMEV-induced demyelinating disease. High viral persistence was found in the late stage of viral infection in IL-1R-deficient mice, although there were few differences in the initial anti-viral immune responses and viral persistent levels between the WT B6 and IL-1R-deficiecent mice. The initial type I IFN responses and the expression of PDL-1 and Tim-3 were higher in the CNS of TMEV-infected IL-1R-deficient mice, leading to deficiencies in T cell function that permit viral persistence. CONCLUSIONS: These results suggest that the presence of high IL-1 level exerts the pathogenic role by elevating pathogenic Th17 responses, whereas the lack of IL-1 signals promotes viral persistence in the spinal cord due to insufficient T cell activation by elevating the production of inhibitory cytokines and regulatory molecules. Therefore, the balance of IL-1 signaling appears to be extremely important for the protection from TMEV-induced demyelinating disease, and either too much or too little signaling promotes the development of disease.
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Doenças Desmielinizantes/virologia , Interleucina-1beta/fisiologia , Poliomielite/virologia , Transdução de Sinais/imunologia , Animais , Doenças Desmielinizantes/etiologia , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/etiologia , Esclerose Múltipla/patologia , Esclerose Múltipla/virologia , Poliomielite/etiologia , Poliomielite/patologia , Theilovirus/crescimento & desenvolvimento , Theilovirus/imunologiaRESUMO
Infection of the central nervous system (CNS) with Theiler's murine encephalomyelitis virus (TMEV) induces an immune-mediated demyelinating disease in susceptible mouse strains such as SJL/J (H-2(s)) but not in strains such as C57BL/6 (H-2(b)). In addition, it has been shown that (C57BL/6 × SJL/J)F1 mice (F1 mice), which carry both resistant and susceptible MHC haplotypes (H-2(b/s)), are resistant to both viral persistence and TMEV-induced demyelinating disease. In this study, we further analyzed the immune responses underlying the resistance of F1 mice. Our study shows that the resistance of F1 mice is associated with a higher level of the initial virus-specific H-2(b)-restricted CD8(+) T cell responses than of the H-2(s)-restricted CD8(+) T cell responses. In contrast, pathogenic Th17 responses to viral epitopes are lower in F1 mice than in susceptible SJL/J mice. Dominant effects of resistant genes expressed in antigen-presenting cells of F1 mice on regulation of viral replication and induction of protective T cell responses appear to play a crucial role in disease resistance. Although the F1 mice are resistant to disease, the level of viral RNA in the CNS was intermediate between those of SJL/J and C57BL/6 mice, indicating the presence of a threshold of viral expression for pathogenesis.
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Infecções por Cardiovirus/imunologia , Imunidade Inata/imunologia , Linfócitos T/imunologia , Theilovirus/imunologia , Animais , Infecções por Cardiovirus/genética , Cruzamentos Genéticos , Camundongos , Camundongos Endogâmicos C57BL , Especificidade da EspécieRESUMO
BACKGROUND: Suppression of hepatitis B virus (HBV) DNA is more potent, and occurrence of resistant strain is rare with entecavir than lamivudine, but whether these merits result in a more favourable outcome in HBV-related decompensated cirrhosis patients is unclear. AIMS: To compare virologic response, changes in liver function, clinical course and predictive factors for early mortality after treatment between patients treated with lamivudine and those with entecavir in HBV-related decompensated cirrhosis patients. METHODS: HBV-related decompensated cirrhosis patients [Child-Turcotte-Pugh (CTP) score ≥ 7] treated with either lamivudine or entecavir were enrolled. Serum HBV DNA levels, CTP score and Model for End-stage Liver Disease (MELD) score were monitored every 3 months. RESULTS: Eighty-six patients were enrolled; mean age was 54 ± 11 years, and 63 (73.3%) patients were men; 41 (47.7%) and 45 (52.3%) patients were assigned to the lamivudine group and entecavir group respectively. Although suppression of serum HBV DNA level was more potent in the entecavir group, CTP or MELD scores during the course of treatment did not differ between the two groups. Similarly, 6-month survival rates did not differ between the two groups (95.1 vs 93.2%, P = 0.684). Baseline CTP score and MELD score at 3 months of treatment were significantly associated with 6-month mortality. The 6- and 12-month mortality rates for patients with baseline CTP score ≥ 11 and MELD score ≥ 17.5 after 3 months of treatment were 42.9 and 61.9% respectively. CONCLUSIONS: Although HBV DNA suppression was more potent in the entecavir group than the lamivudine group, early mortality rates did not differ between the two groups. The baseline CTP score and MELD score 3 months after initiating antiviral treatment were significant predictors of early mortality.
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Antivirais/uso terapêutico , Guanina/análogos & derivados , Vírus da Hepatite B/genética , Hepatite B/complicações , Lamivudina/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Adulto , Idoso , Guanina/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Pessoa de Meia-Idade , Análise Multivariada , República da Coreia , ViremiaRESUMO
Prior research has shown that the total amount of white matter ischemia had no significant correlation with cognitive deficits. We compared the association of white matter hyperintensities (WMHs) of total as well as cholinergic pathways with clinical dementia severity and investigated whether cholinergic ischemic burden had an independent predictive value with respect to cognitive decline in subcortical vascular cognitive impairment (SVCI). Forty-eight patients underwent detailed neuropsychological tests and brain magnetic resonance imaging. Quantification of WMH in the total white matter and in cholinergic pathways was achieved using the visual Scheltens scale and Cholinergic Pathway HyperIntensity Scale (CHIPS), respectively. We explored the association between WMH scores and clinical dementia rating scale (CDR). To assess the relation between WMH and cognitive scores, multiple linear regression analysis was used. The CHIPS score was higher in subcortical vascular dementia compared to subcortical vascular MCI, while this difference was not found with the total TMHs (TWMH) score. The TWMH score had a positive correlation with CHIPS, however only CHIPS scores positively correlated with sum of box scores of CDR scale (CDR SB; ρ = .474, P = .001). Higher CHIPS scores were associated with lower performance on the semantic word fluency test (ß = -.447, P = .036), whereas the TWMH scores had no independent predictive value with respect to cognitive impairment, after controlling for CHIPS score. Our data confirmed the association of ischemic damage within cholinergic pathways with dementia severity, independent of TWMH in SVCI. In addition, this cholinergic deficit is clinically relevant to cognitive deterioration, especially with frontal dysfunction.
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Isquemia Encefálica/psicologia , Neurônios Colinérgicos/patologia , Transtornos Cognitivos/patologia , Cognição , Demência Vascular/psicologia , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Isquemia Encefálica/patologia , Transtornos Cognitivos/psicologia , Demência Vascular/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: We have previously shown that toll-like receptor 3 (TLR3)-mediated signaling plays an important role in the induction of innate cytokine responses to Theiler's murine encephalomyelitis virus (TMEV) infection. In addition, cytokine levels produced after TMEV infection are significantly higher in the glial cells of susceptible SJL mice compared to those of resistant C57BL/6 mice. However, it is not known whether TLR3-mediated signaling plays a protective or pathogenic role in the development of demyelinating disease. METHODS: SJL/J and B6;129S-Tlr3tm1Flv/J (TLR3KO-B6) mice, and TLR3KO-SJL mice that TLR3KO-B6 mice were backcrossed to SJL/J mice for 6 generations were infected with Theiler's murine encephalomyelitis virus (2 × 105 PFU) with or without treatment with 50 µg of poly IC. Cytokine production and immune responses in the CNS and periphery of infected mice were analyzed. RESULTS: We investigated the role of TLR3-mediated signaling in the protection and pathogenesis of TMEV-induced demyelinating disease. TLR3KO-B6 mice did not develop demyelinating disease although they displayed elevated viral loads in the CNS. However, TLR3KO-SJL mice displayed increased viral loads and cellular infiltration in the CNS, accompanied by exacerbated development of demyelinating disease, compared to the normal littermate mice. Late, but not early, anti-viral CD4+ and CD8+ T cell responses in the CNS were compromised in TLR3KO-SJL mice. However, activation of TLR3 with poly IC prior to viral infection also exacerbated disease development, whereas such activation after viral infection restrained disease development. Activation of TLR3 signaling prior to viral infection hindered the induction of protective IFN-γ-producing CD4+ and CD8+ T cell populations. In contrast, activation of these signals after viral infection improved the induction of IFN-γ-producing CD4+ and CD8+ T cells. In addition, poly IC-pretreated mice displayed elevated PDL-1 and regulatory FoxP3+ CD4+ T cells in the CNS, while poly IC-post-treated mice expressed reduced levels of PDL-1 and FoxP3+ CD4+ T cells. CONCLUSIONS: These results suggest that TLR3-mediated signaling during viral infection protects against demyelinating disease by reducing the viral load and modulating immune responses. In contrast, premature activation of TLR3 signal transduction prior to viral infection leads to pathogenesis via over-activation of the pathogenic immune response.
Assuntos
Infecções por Cardiovirus/imunologia , Doenças Desmielinizantes/imunologia , Transdução de Sinais/imunologia , Receptor 3 Toll-Like/imunologia , Animais , Infecções por Cardiovirus/metabolismo , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/virologia , Citometria de Fluxo , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Theilovirus , Receptor 3 Toll-Like/metabolismoRESUMO
Induction of antigen-specific CD8(+) T cells bearing a high-avidity T-cell receptor (TCR) is thought to be an important factor in antiviral and antitumor immune responses. However, the relationship between TCR diversity and functional avidity of epitope-specific CD8(+) T cells accumulating in the central nervous system (CNS) during viral infection is unknown. Hence, analysis of T-cell diversity at the clonal level is important to understand the fate and function of virus-specific CD8(+) T cells. In this study, we examined the Vbeta diversity and avidity of CD8(+) T cells specific to the predominant epitope (VP2(121-130)) of Theiler's murine encephalomyelitis virus. We found that Vbeta6(+) CD8(+) T cells, associated with epitope specificity, predominantly expanded in the CNS during viral infection. Further investigations of antigen-specific Vbeta6(+) CD8(+) T cells by CDR3 spectratyping and sequencing indicated that distinct T-cell clonotypes are preferentially increased in the CNS compared to the periphery. Among the epitope-specific Vbeta6(+) CD8(+) T cells, MGX-Jbeta1.1 motif-bearing cells, which could be found at a high precursor frequency in naïve mice, were expanded in the CNS and tightly associated with gamma interferon production. These T cells displayed moderate avidity for the cognate epitope rather than the high avidity normally observed in memory/effector T cells. Therefore, our findings provide new insights into the CD8(+) T-cell repertoire during immune responses to viral infection in the CNS.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Cardiovirus/imunologia , Sistema Nervoso Central , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Theilovirus/imunologia , Sequência de Aminoácidos , Animais , Linfócitos T CD8-Positivos/citologia , Sistema Nervoso Central/citologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/virologia , Epitopos/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL/imunologia , Camundongos Endogâmicos C57BL/virologia , Dados de Sequência Molecular , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Baço/citologia , Baço/imunologiaRESUMO
BACKGROUND AND AIMS: Transient elastography (TE) is useful for predicting the fibrosis stage, but it is unsatisfactory as a substitute for liver biopsy, especially in patients with chronic hepatitis B (CHB). This study was performed to establish a reliable model for predicting significant fibrosis (SF) in patients with CHB. METHODS: All CHB patients who were admitted to undergo liver biopsy were enrolled. They were randomly classified into either a training set (n = 139) or a validation set (n = 69). A model for predicting SF was established in the training set and validated in the validation set. Low and high cutoff values (COVs) were chosen for sensitivity ≥ 99% and specificity ≥ 99%, respectively. RESULTS: A total of 208 patients were enrolled. Age was 39 ± 12 years and 149 (71.6%) were men. In the training set, liver stiffness values and serum haptoglobin, apolipoprotein A1, and α2-macroglobulin levels were independent predictors of SF on multivariate analysis. These variables were used to construct a novel model, called the HALF index. The area under the receiver operating characteristics curve of the HALF index for predicting SF was significantly higher than that of TE alone (0.915 vs 0.877, P = 0.010). Using low and high COVs of the HALF index, it appears that approximately half (47.1%) of patients could avoid liver biopsy, with an associated accuracy of 99.0%. CONCLUSION: A combination of liver stiffness and serum markers identified SF with a high degree of accuracy. Approximately half of all patients with CHB could avoid liver biopsy through the utilization of the HALF index.
Assuntos
Biópsia , Indicadores Básicos de Saúde , Hepatite B Crônica/diagnóstico , Cirrose Hepática/diagnóstico , Fígado/patologia , Procedimentos Desnecessários , Adulto , Apolipoproteína A-I/sangue , Biomarcadores/sangue , Técnicas de Imagem por Elasticidade , Feminino , Haptoglobinas/metabolismo , Hepatite B Crônica/sangue , Hepatite B Crônica/complicações , Hepatite B Crônica/patologia , Humanos , Fígado/metabolismo , Fígado/virologia , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Reprodutibilidade dos Testes , República da Coreia , Sensibilidade e Especificidade , Índice de Gravidade de Doença , alfa-Macroglobulinas/análiseRESUMO
BACKGROUND AND AIMS: It remains unclear whether the currently-used normal range for serum alanine aminotransferase (ALT) levels really reflects a healthy liver. The present study was conducted to evaluate the healthy range of serum ALT in the Korean adult population and to determine the clinical significance of unhealthy levels. METHODS: We reviewed the medical records, including questionnaires and the results of laboratory and radiological tests conducted at the Health Promotion Center at Korea University Anam Hospital between March 2005 and February 2007. The records, written in questionnaire form, included baseline data, such as physical status, social behaviors, medication history, and past and present disease histories. RESULTS: The mean age of the 7403 enrolled patients was 48 years, and 49.9% of these patients were male. A healthy cohort was selected after excluding patients who showed any abnormalities of the factors that were significantly associated with the serum ALT level upon multivariate regression analysis. The upper limit of the healthy range of the serum ALT level (i.e. 95th percentile) in the healthy population was 31 IU/L for males and 23 IU/L for females. The prevalence of metabolic syndrome and insulin resistance (IR) were significantly higher in patients with an 'unhealthy' normal ALT level than in those with a healthy ALT level. CONCLUSION: In our study, the upper limit of the healthy range of the serum ALT level was 31 IU/L for males and 23 IU/L for females. An unhealthy normal ALT level was associated with a higher prevalence of metabolic syndrome and IR.
Assuntos
Alanina Transaminase/sangue , Povo Asiático , Ensaios Enzimáticos Clínicos/normas , Adulto , Povo Asiático/estatística & dados numéricos , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Estudos Transversais , Feminino , Humanos , Resistência à Insulina/etnologia , Modelos Logísticos , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/etnologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Valores de Referência , República da Coreia , Medição de Risco , Fatores de Risco , Fatores SexuaisRESUMO
BACKGROUND/AIMS: Several studies suggested that serum cystatin C (CysC) is more useful than serum creatinine (Cr) for the assessment of renal function in patients with liver cirrhosis. This study evaluated the clinical significance of CysC in patients with cirrhotic ascites and normal Cr level. METHODS: We enrolled patients with cirrhotic ascites and a normal serum Cr level (<1.2 mg/dL). GFR was measured by (99m)Tc-DTPA renal scan. Serum Cr, CysC, and Cr clearance (CCr) were measured on the same day. Significant renal impairment and severe renal impairment were defined as GFR <60 mL/min and GFR <30 mL/min, respectively. RESULTS: Eighty-nine patients with cirrhotic ascites were enrolled in the study (63 men and 26 women; age, 55±11 years). Forty-seven (52.8%) and 42 (47.2%) patients were in Child-Pugh grade B and C, respectively. Serum Cr and CysC levels and GFR were 0.8±0.2 mg/dL, 1.1±0.3 mg/L, and 73.4±25.5 mL/min, respectively. Significant and severe renal impairment were noted in 28 (31.5%) and 2 (2.2%) patients, respectively. GFR was well correlated with serum Cr, CysC, and e-GFR(MDRD), while it was not correlated with e-GFR(C&G). In multivariate analysis, only CysC was significantly correlated with GFR (ß, 45.620; 95% CI, 23.042-68.198; P<0.001). Serum CysC level was the only independent predictor for significant renal impairment. CONCLUSIONS: Significant renal dysfunction was not rare in patients with cirrhotic ascites, even their serum Cr level is normal. Serum CysC is a useful marker for detecting significant renal dysfunction in these patients.
Assuntos
Cistatina C/sangue , Nefropatias/diagnóstico , Cirrose Hepática/complicações , Adulto , Idoso , Área Sob a Curva , Biomarcadores/sangue , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/complicações , Nefropatias/metabolismo , Testes de Função Renal , Cirrose Hepática/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Curva ROC , Índice de Gravidade de Doença , Pentetato de Tecnécio Tc 99mRESUMO
Intracranial infection of Theiler's murine encephalomyelitis virus (TMEV) induces demyelination and a neurological disease in susceptible SJL/J (SJL) mice that resembles multiple sclerosis. While the virus is cleared from the central nervous system (CNS) of resistant C57BL/6 (B6) mice, it persists in SJL mice. To investigate the role of viral persistence and its accompanying immune responses in the development of demyelinating disease, transgenic mice expressing the P1 region of the TMEV genome (P1-Tg) were employed. Interestingly, P1-Tg mice with the B6 background showed severe reductions in both CD4(+) and CD8(+) T-cell responses to capsid epitopes, while P1-Tg mice with the SJL background displayed transient reductions following viral infection. Reduced antiviral immune responses in P1-Tg mice led to >100- to 1,000-fold increases in viral persistence at 120 days postinfection in the CNS of mice with both backgrounds. Despite the increased CNS TMEV levels in these P1-Tg mice, B6 P1-Tg mice developed neither neuropathological symptoms nor demyelinating lesions, and SJL P1-Tg mice developed significantly less severe TMEV-induced demyelinating disease. These results strongly suggest that viral persistence alone is not sufficient to induce disease and that the level of T-cell immunity to viral capsid epitopes is critical for the development of demyelinating disease in SJL mice.