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BACKGROUND: In the United States, a few studies have evaluated geographic variation of severe asthma at the subnational level. OBJECTIVE: To assess state-level geographic variation in the prevalence and characteristics of severe persistent asthma in the United States. METHODS: Patients aged above or equal to 12 years with severe persistent asthma were identified using nationally representative data from IQVIA open-source Medical/Pharmacy Claims and PharMetrics Plus databases (January 2019-December 2020). The index date was defined as the patient's earliest qualifying date for a severe asthma diagnosis. Baseline characteristics were measured during the 12-month pre-index period. Outcomes including exacerbation occurrence, asthma control, and medication use were measured during the 12-month post-index period and compared across states using census-level projections. RESULTS: A total of 2,092,799 patients with asthma were identified; 496,750 (23.7%) met criteria for severe persistent asthma and all inclusion criteria. Mean age was 50.5 years; 68.4% were females. The prevalence of severe persistent asthma varied across states, ranging from 19.6% (New Mexico) to 31.9% (Alaska). Among patients with severe persistent asthma, 40.9% had more than or equal to 1 exacerbation, ranging from 34.2% (Vermont) to 45.6% (Louisiana); 21.1% had uncontrolled disease, ranging from 16.5% (Vermont) to 24.0% (Arizona). Among patients with exacerbations, 13.7% had exacerbation-related emergency department visits or hospitalizations, ranging from 7.0% (North Carolina) to 17.7% (Nevada). Among patients with severe uncontrolled asthma, 15.6% used biologics post-index, ranging from 2.2% (Hawaii) to 27.9% (Mississippi). CONCLUSION: There is significant variability in severe persistent asthma prevalence and disease burden across US states. Reasons for geographic variation may include differences in socioeconomic/environmental factors or asthma management.
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Asma , Índice de Gravidade de Doença , Humanos , Asma/epidemiologia , Estados Unidos/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Prevalência , Adolescente , Criança , Efeitos Psicossociais da Doença , Idoso , Adulto JovemRESUMO
Chronic kidney disease (CKD) is a serious public health problem. Due to a high variability in the speed of CKD progression to end-stage renal disease (ESRD) and the critical involvement of Wnt/ß-catenin signaling in CKD, we investigated the role of the Wnt antagonist Dickkopf-1 (DKK1) in CKD progression. Our data revealed that patients with CKD stages 4-5 had higher DKK1 levels in their serum and renal tissues than the control subjects. In an 8-year follow-up, the serum DKK1-high group in the enrolled CKD patients showed a faster progression to ESRD than the serum DKK1-low group. Using a rat model of 5/6 nephrectomy (Nx)-induced CKD, we consistently detected elevated serum levels and renal production of DKK1 in 5/6 Nx rats compared to sham-operated rats. Importantly, the knockdown of the DKK1 levels in the 5/6 Nx rats markedly attenuated the CKD-associated phenotypes. Mechanistically, we demonstrated that the treatment of mouse mesangial cells with recombinant DKK1 protein induced not only the production of multiple fibrogenic proteins, but also the expression of endogenous DKK1. Collectively, our findings suggest that DKK1 acts as a profibrotic mediator in CKD, and elevated levels of serum DKK1 may be an independent predictor of faster disease progression to ESRD in patients with advanced CKD.
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Falência Renal Crônica , Insuficiência Renal Crônica , Ratos , Camundongos , Animais , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Rim/metabolismo , Falência Renal Crônica/genética , Falência Renal Crônica/metabolismo , Via de Sinalização Wnt/genéticaRESUMO
Diabetes-induced chronic kidney disease leads to mortality and morbidity and thus poses a great health burden worldwide. Krüppel-like factor 10 (KLF10), a zinc finger-containing transcription factor, regulates numerous cellular functions, such as proliferation, differentiation, and apoptosis. In this study, we explored the effects of KLF10 on diabetes-induced renal disease by using a KLF10 knockout mice model. Knockout of KLF10 obviously diminished diabetes-induced tumor growth factor-ß (TGF-ß), fibronectin, and type IV collagen expression, as evidenced by immunohistochemical staining. KLF10 knockout also repressed the expression of Dickkopf-1 (DKK-1) and phosphorylated ß-catenin in diabetic mice, as evidenced by immunohistochemical staining and Western blot analysis. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) revealed that significantly decreased type IV collagen, fibronectin, and DKK-1 existed in KLF10 knockout diabetic mice compared with control diabetic mice. Moreover, knockout of KLF10 reduced the renal fibrosis, as shown by Masson's Trichrome analysis. Overall, the results indicate that depletion of KLF10 ameliorated diabetic renal fibrosis via the downregulation of DKK-1 expression and inhibited TGF-ß1 and phosphorylated ß-catenin expression. Our findings suggest that KLF10 may be a promising therapeutic choice for the treatment of diabetes-induced renal fibrosis.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Fatores de Transcrição Kruppel-Like , Animais , Colágeno Tipo IV/metabolismo , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Regulação para Baixo , Fatores de Transcrição de Resposta de Crescimento Precoce/genética , Fatores de Transcrição de Resposta de Crescimento Precoce/metabolismo , Feminino , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos , Camundongos Knockout , Fator de Crescimento Transformador beta1/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Diabetic nephropathy is a complication of diabetes that leads to end-stage kidney disease and is a major health burden worldwide. Prenylflavonoid compounds extracted from Macaranga tanarius (MTE) exhibit anti-inflammation, anti-oxidant, and anti-bacterial properties. However, the effects of these compounds on diabetic nephropathy remain unclear. The effects of MTE on diabetic nephropathy were investigated in vitro by using mouse renal mesangial cells and in vivo by using a db/db knockout mouse model. No overt alteration in proliferation was observed in mouse renal mesangial cells treated with 0-1 µg/mL MTE. Western blot analysis indicated that MTE dose-dependently attenuated the expression of fibronectin, α-smooth muscle actin, and collagen IV. Administration of MTE ameliorated renal albumin loss in db/db mice. Immunohistochemical staining revealed that MTE mitigated diabetes-induced fibronectin and collagen IV expression. Periodic acid-Schiff (PAS) and trichrome staining also showed that administration of MTE reduced the renal fibrosis phenomenon. MTE significantly ameliorated diabetes-induced nephropathy.
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INTRODUCTION: The aim of this work is to evaluate baricitinib safety with respect to venous thromboembolism (VTE), major adverse cardiovascular events (MACE), and serious infection relative to tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA). METHODS: Patients with RA from 14 real-world data sources (three disease registries, eight commercial and three government health insurance claims databases) in the United States (n = 9), Europe (n = 3), and Japan (n = 2) were analyzed using a new user active comparator design. Propensity score matching (1:1) controlled for potential confounding. Meta-analysis of incidence rate ratios (IRR) and incidence rate differences (IRD) for each outcome, from each data source was executed using modified Poisson regression and Cochran-Mantel-Haenszel analysis. RESULTS: Of 9013 eligible baricitinib-treated patients, 7606 were propensity score-matched with TNFi-treated patients, contributing 5879 and 6512 person-years of baricitinib and TNFi exposure, respectively. Across data sources, 97 patients (56 baricitinib) experienced VTE during follow-up, 93 experienced MACE (54 baricitinib), and 321 experienced serious infection (176 baricitinib). Overall IRRs comparing baricitinib with TNFi treatment were 1.51 (95% CI 1.10, 2.08) for VTE, 1.54 (95% CI 0.93, 2.54) for MACE, and 1.36 (95% CI 0.86, 2.13) for serious infection. IRDs for VTE, MACE, and serious infection, respectively, were 0.26 (95% CI -0.04, 0.57), 0.22 (95% CI -0.07, 0.52), and 0.57 (95% CI -0.07, 1.21) per 100 person-years greater for baricitinib than TNFi. CONCLUSIONS: Overall results suggest increased risk of VTE with baricitinib versus TNFi, with consistent point estimates from the two largest data sources. A numerically greater risk was observed for MACE and serious infection when comparing baricitinib versus TNFi, with different point estimates from the two largest data sources. Findings from this study and their impact on clinical practice should be considered in context of limitations and other evidence regarding the safety and efficacy of baricitinib and other Janus kinase inhibitors. TRIAL REGISTRATION: EU PAS Register ( http://encepp.eu ), identifier #32271.
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INTRODUCTION: High-grade pneumonitis is a severe and potentially life-threatening adverse event associated with concurrent chemoradiation (cCRT) in patients with non-small cell lung cancer (NSCLC). The aim of this study was to summarize and quantify the incidence of severe (grade 3-5) cCRT-induced pneumonitis in unresectable stage III NSCLC patients. METHODS: A systematic literature review and meta-analysis were performed in accordance with PRISMA guidelines. Published literature was searched for randomized controlled trials (RCTs), observational studies, and non-randomized trials from 2014 to April 2020. The primary outcome of interest was incidence of grade 3-5 pneumonitis. RESULTS: Included were 17 studies for the review and 11 for the meta-analysis (1,788 participants); all studies examined radiation-related pneumonitis (RP). The pooled incidence of cCRT-induced grade 3-5 RP in unresectable stage III NSCLC patients was estimated to be 3.62% [95% confidence interval (CI): 1.65-6.21] in RCTs, 5.98% [95% CI: 2.26-12.91] in observational studies, and 7.85% [95% CI: 4.08-13.10] in observational studies using platinum-based doublet chemotherapies. CONCLUSION: These results suggest the incidence of severe and fatal RP in patients with unresectable stage III NSCLC treated with cCRT ranges from 3.62% to 7.85%, with incidence varying by study design and chemotherapy regimen. Estimates of RP incidence were higher in the real-world setting compared to RCTs. These results can be used to contextualize the baseline risk of cCRT-induced pneumonitis in unresectable stage III NSCLC to better understand the adverse event of pneumonitis associated with novel immunotherapy treatments indicated for concomitant use with this modality.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonia , Pneumonite por Radiação , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Pneumonite por Radiação/diagnóstico , Pneumonite por Radiação/epidemiologia , Pneumonite por Radiação/etiologia , Pneumonia/etiologia , Pneumonia/induzido quimicamenteRESUMO
Recognition of viral antigenic peptides bound to major histocompatibility complex class I molecules (MHCI) by TCR is critical for initiating the responses of CD8(+) T cells that ultimately lead to elimination of virus-infected cells. This antigen recognition is enhanced by the CD8 coreceptor through its interaction with the peptide-MHCI complexes (pMHCI). Mouse CD8alphabeta can form two different complexes with pMHCI via either the CD8alpha- or CD8beta-dominated interaction. To understand the functional significance of these complexes in vivo, we generated Tg mice carrying a variant CD8alphabeta (CD8alpha(m3)beta) capable of forming only the CD8beta-dominated CD8alphabeta/pMHCI complex. These mice show sub-optimal thymic differentiation with reduced populations of CD8(+) single-positive thymocytes. Tg CD8(+) T cells exhibit a compromised developmental capacity when competing with CD8(+) T cells from B6 mice in mixed bone marrow chimera experiments. However, once these CD8(+) T cells have emigrated to the peripheral lymphoid organs, they exhibit normal effector function against viral infection. Our observations indicate that, in addition to the CD8 activity conferred by CD8beta-dominated CD8alphabeta/pMHCI complexes, full thymocyte differentiation requires additional coreceptor activities conferred by CD8alphaalpha and/or CD8alphabeta with CD8alpha-dominated CD8/pMHCI complexes.
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Antígenos CD8/imunologia , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/imunologia , Separação Celular , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe I/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Timo/citologia , Timo/imunologiaRESUMO
PURPOSE: The primary objectives were to describe weight changes following initiation of lurasidone versus other antipsychotics and estimate the risk of clinically relevant (≥7%) weight changes. PATIENTS AND METHODS: This retrospective, longitudinal comparative cohort study was based on electronic medical records (EMRs) of United States (US) adult patients with schizophrenia who were prescribed lurasidone or other antipsychotics as monotherapy between 1 April 2013 and 30 June 2019. RESULTS: Overall, the study included 15,323 patients with a diagnosis of schizophrenia; 6.1% of patients received lurasidone, 60.4% received antipsychotics associated with a medium-high risk of weight gain (clozapine, olanzapine, quetiapine, risperidone, paliperidone) and 33.5% received antipsychotics with a low risk of weight gain (aripiprazole, first-generation antipsychotics, ziprasidone). Lurasidone was associated with the smallest proportion of patients experiencing clinically relevant weight gain and the greatest proportion of patients with clinically relevant weight loss. The risk of clinically relevant weight gain was numerically higher with all antipsychotics versus lurasidone and was statistically significant for olanzapine (hazard ratio [HR]=1.541; 95% confidence interval [CI]=1.121; 2.119; p=0.0078) versus lurasidone. The likelihood of ≥7% weight loss was significantly greater with lurasidone versus all antipsychotics (p<0.05), except ziprasidone. CONCLUSION: This real-world study suggests that lurasidone has a lower risk of clinically relevant weight gain and a higher likelihood of clinically relevant weight loss than other commonly used antipsychotics.
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The asymmetric disposition of T cell receptor (TCR) Cbeta and Calpha ectodomains creates a cavity with a side-wall formed by the rigid Cbeta FG loop. To investigate the significance of this conserved structure, we generated loop deletion (betaDeltaFG) and betawt transgenic (tg) mice using the TCR beta subunit of the N15 CTL. N15betawt and N15betaDeltaFG H-2(b) animals have comparable numbers of thymocytes in S phase and manifest developmental progression through the CD4(-)CD8(-) double-negative (DN) compartment. N15betaDeltaFG facilitates transition from DN to CD4(+)8(+) double-positive (DP) thymocytes in recombinase activating gene (RAG)-2(-/-) mice, showing that pre-TCR function remains. N15betaDeltaFG animals possess approximately twofold more CD8(+) single-positive (SP) thymocytes and lymph node T cells, consistent with enhanced positive selection. As an altered Valpha repertoire observed in N15betaDeltaFG mice may confound the deletion's effect, we crossed N15alphabeta TCR tg RAG-2(-/-) with N15betaDeltaFG tg RAG-2(-/-) H-2(b) mice to generate N15alphabeta RAG-2(-/-) and N15alphabeta.betaDeltaFG RAG-2(-/-) littermates. N15alphabeta.betaDeltaFG RAG-2(-/-) mice show an 8-10-fold increase in DP thymocytes due to reduced negative selection, as evidenced by diminished constitutive and cognate peptide-induced apoptosis. Compared with N15alphabeta, N15alphabeta.betaDeltaFG T cells respond poorly to cognate antigens and weak agonists. Thus, the Cbeta FG loop facilitates negative selection of thymocytes and activation of T cells.
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Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Timo/citologia , Sequência de Aminoácidos , Animais , Apoptose , Bovinos , Divisão Celular , Linhagem da Célula , Citocinas/metabolismo , Cães , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Linfonodos/citologia , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Dados de Sequência Molecular , Conformação Proteica , Coelhos , Ratos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Homologia de Sequência de Aminoácidos , Linfócitos T/metabolismo , Timo/imunologiaRESUMO
BACKGROUND: Hepatotoxicity is the most severe adverse effect of anti-tuberculosis therapy. Isoniazid's metabolite hydrazine is a mitochondrial complex II inhibitor. We hypothesized that mitochondrial DNA variants are risk factors for drug-induced liver injury (DILI) due to isoniazid, rifampicin or pyrazinamide. METHODS: We obtained peripheral blood from tuberculosis (TB) patients before anti-TB therapy. A total of 38 patients developed DILI due to anti-TB drugs. We selected 38 patients with TB but without DILI as controls. Next-generation sequencing detected point mutations in the mitochondrial DNA genome. DILI was defined as ALT ≥5 times the upper limit of normal (ULN), or ALT ≥3 times the ULN with total bilirubin ≥2 times the ULN. RESULTS: In 38 patients with DILI, the causative drug was isoniazid in eight, rifampicin in 14 and pyrazinamide in 16. Patients with isoniazid-induced liver injury had more variants in complex I's NADH subunit 5 and 1 genes, more nonsynonymous mutations in NADH subunit 5, and a higher ratio of nonsynonymous to total substitutions. Patients with rifampicin- or pyrazinamide-induced liver injury had no association with mitochondrial DNA variants. CONCLUSIONS: Variants in complex I's subunit 1 and 5 genes might affect respiratory chain function and predispose isoniazid-induced liver injury when exposed to hydrazine, a metabolite of isoniazid and a complex II inhibitor.
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OBJECTIVE: To determine whether the Patient-Centered Medical Home (PCMH) transformation reduces hospital and ED utilization, and whether the effect is specific to chronic conditions targeted for management by the PCMH in our setting. DATA SOURCES AND STUDY SETTING: All patients aged 18 years and older in 2,218 primary care practices participating in a statewide PCMH incentive program sponsored by Blue Cross Blue Shield of Michigan (BCBSM) in 2009-2012. STUDY DESIGN: Quantitative observational study, jointly modeling PCMH-targeted versus other hospital admissions and ED visits on PCMH score, patient, and practice characteristics in a hierarchical multivariate model using the generalized gamma distribution. DATA COLLECTION: Claims data and PCMH scores held by BCBSM. PRINCIPAL FINDINGS: Both hospital and ED utilization were reduced proportionately to PCMH score. Hospital utilization was reduced by 13.9 percent for PCMH-targeted conditions versus only 3.8 percent for other conditions (p = .003), and ED utilization by 11.2 percent versus 3.7 percent (p = .010). Hospital PMPM cost was reduced by 17.2 percent for PCMH-targeted conditions versus only 3.1 percent for other conditions (p < .001), and ED PMPM cost by 9.4 percent versus 3.6 percent (p < .001). CONCLUSIONS: PCMH transformation reduces hospital and ED use, and the majority of the effect is specific to PCMH-targeted conditions.
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Doença Crônica/terapia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Assistência Centrada no Paciente/organização & administração , Assistência Centrada no Paciente/estatística & dados numéricos , Planos de Seguro Blue Cross Blue Shield , Humanos , Revisão da Utilização de Seguros , Michigan , Atenção Primária à Saúde , Qualidade da Assistência à Saúde , Características de Residência , Fatores de Risco , Fatores SexuaisRESUMO
BACKGROUND AND PURPOSE: Certain alternatively spliced exons of CD44 gene have been associated with specific functions. However, these functions may have come from inclusion of a central array of alternatively spliced exons, rather than a single one. The goals of this study were to analyze all of the variant exons included by alternative splicing, the entire population of CD44 mRNA transcripts, and the prognostic implications of CD44 mRNA and protein isoforms expressed by non-small cell lung cancer (NSCLC). METHODS: Using a polymerase chain reaction protocol with short reaction times, we amplified, sequenced and quantified CD44 mRNA transcripts from 52 samples of NSCLC to determine the splicing patterns of alternatively included exons and the proportion of each CD44 mRNA transcript. The expression of CD44 standard form and variant isoforms CD44v3 and CD44v6 were also analyzed by immunohistochemistry (IHC). RESULTS: Normal lung and NSCLC expressed CD44 mRNA transcripts containing variant exons v10, v8-10, v6-10, v3-10 and v2-10. In squamous cell carcinoma, the expression rates of these mRNA transcripts were equal to or higher than those of the normal lung, and the splicing pattern was not associated with disease progression. In adenocarcinoma, the expression rates of CD44v6-10, v3-10 and v2-10 mRNA were lower than in normal lung. The down-regulation of CD44v6-10, CD44v3-10 mRNA and CD44v6 protein paralleled the progression of adenocarcinoma. Recurrence of adenocarcinoma was associated with negative expression of CD44v6-10 or CD44v3-10 mRNA, and with low-level expression of CD44v6 or CD44v3 by IHC. Negative expression of CD44v6-10 mRNA and reduced expression of CD44 v6 protein were associated with a shorter disease-free and overall survival in the univariate but not the multivariate analysis. CONCLUSION: Our data suggest that CD44 splicing pattern is associated with disease progression in adenocarcinoma.
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Adenocarcinoma/genética , Processamento Alternativo , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores de Hialuronatos/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Éxons , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/análise , Imuno-Histoquímica , Pulmão/química , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Mensageiro/análiseRESUMO
OBJECTIVES: We aimed to describe and contrast the targeting methods and engagement outcomes for health plan-delivered disease management with those of a provider-delivered care management program. STUDY DESIGN: Health plan epidemiologists partnered with university health services researchers to conduct a quasi-experimental, mixed-methods study of a 2-year pilot. We used semi-structured interviews to assess the characteristics of program-targeting strategies, and calculated target and engagement rates from clinical encounter data. METHODS: Five physician organizations (POs) with 51 participating practices implemented care management. Health plan member lists were sent monthly to the practices to accept patients, and then the practices sent back data reports regarding targeting and engagement in care management. Among patients accepted by the POs, we compared those who were targeted and engaged by POs with those who met health plan targeting criteria. RESULTS: The health plan's targeting process combined claims algorithms and employer group preferences to identify candidates for disease management; on the other hand, several different factors influenced PO practices' targeting approaches, including clinical and personal knowledge of the patients, health assessment information, and availability of disease-relevant programs. Practices targeted a higher percentage of patients for care management than the health plan (38% vs 16%), where only 7% of these patients met the targeting criteria of both. Practices engaged a higher percentage of their targeted patients than the health plan (50% vs 13%). CONCLUSIONS: The health plan's claims-driven targeting approach and the clinically based strategies of practices both provide advantages; an optimal model may be to combine the strengths of each approach to maximize benefits in care management.
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Gerenciamento Clínico , Programas de Assistência Gerenciada/organização & administração , Relações Médico-Paciente , Atenção Primária à Saúde/organização & administração , Feminino , Humanos , Revisão da Utilização de Seguros , Masculino , Pessoa de Meia-Idade , Médicos , Fatores SocioeconômicosRESUMO
Women have a higher risk of drug-induced hepatotoxicity during antituberculosis treatment (HATT) than men. We hypothesized that single nucleotide polymorphism (SNP) genotype and derived haplotype of pregnane X receptor (PXR) gene, which could regulate the expression of phase I enzyme cytochrome P450 (CYP) 3A4, had a sex-specific influence on the risk of HATT. Six SNPs of the PXR gene were sequenced. Genotypes and haplotypes of the PXR SNPs, and other potential risk factors for HATT were compared between pulmonary TB patients with and those without HATT. HATT was defined as an increase in serum transaminase level >3 times the upper limit of normal (ULN) with symptoms, or >5 times ULN without symptoms. We performed the study in a derivation and a validation cohort. Among the 355 patients with pulmonary TB in the derivation cohort, 70 (19.7%) developed HATT. Logistic regression analysis revealed the risk of HATT increased in female genotype AA at rs2461823 (OR: 6.87 [2.55-18.52]) and decreased in female genotype AA at rs7643645 (OR: 0.14 [0.02-1.02]) of PXR gene. Haplotype analysis showed that female h001101 (OR: 2.30 [1.22-4.32]) and female h000110 (OR: 2.25 [1.08-4.69]) haplotype were associated with increased HATT risk. The identified predictors were also significantly associated with female HATT risk among the 182 patients in the validation cohort. Two PXR SNP genotypes and 2 haplotypes influenced the risk of HATT only in females. The PXR SNP showed a sex-specific impact that contributed to an increased HATT risk in females.
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Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/genética , Citocromo P-450 CYP3A/biossíntese , Receptores de Esteroides/genética , Adulto , Idoso , Antituberculosos/uso terapêutico , Arilamina N-Acetiltransferase/genética , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptor de Pregnano X , Fatores Sexuais , Tuberculose/tratamento farmacológicoRESUMO
The objective of this study was to investigate the effects of Polygonum multflorum (PM) Thunb. on the learning and memory ability in one and seven-month-old male senescence accelerated mice (SAMP8). The mice were fed with two different diets for 18 weeks; they were casein dietary group (control group) and casein diet supplemented with PM extracts. Active shuttle avoidance test was performed to determine the learning and memory ability of the mice while the spongy degeneration and the lipofuscin, malondialdehyde, and total thiol levels of the brain were measured to evaluate the extent of the brain degeneration and oxidative status. Results of active shuttle avoidance test showed the mice fed with the PM extracts had significantly better learning and memory ability than the control group. The spongy degeneration and the lipofuscin and malondialdehyde concentrations of the mice in the PM groups were significantly lower than the control in both age groups, whereas the total thiol levels were higher but not significantly different. It was concluded that the supplement of the PM extracts could improve the learning and memory ability and reduce the brain pathological changes in mice. This might be due to the antioxidant phytochemicals of the PM extracts.
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Envelhecimento/genética , Envelhecimento/psicologia , Transtornos Cognitivos/tratamento farmacológico , Fitoterapia , Polygonum/química , Envelhecimento/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/patologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/psicologia , Dieta , Aprendizagem/efeitos dos fármacos , Peróxidos Lipídicos/metabolismo , Malondialdeído/metabolismo , Memória/efeitos dos fármacos , Camundongos , Estresse Oxidativo/fisiologia , Extratos Vegetais/uso terapêuticoRESUMO
OBJECTIVES: Hepatitis during anti-tuberculous treatment (HATT) has been an obstacle in managing patients with tuberculosis (TB). We evaluate the risk factors of HATT and the clinical implications of serum viral loads in those with concomitant hepatitis B or C viruses (HBV/HCV) infection. METHODS: We did a prospective study on patients with pulmonary tuberculosis in a medical center. HATT was defined as an increase in serum transaminase level of >3 times the upper limit of normal (ULN) with symptoms, or an increase in serum transaminase level of >5 times ULN without symptoms. RESULTS: 360 TB patients were studied. The prevalence of concomitant HBV and HCV infection was 11.7% and 6.7%, respectively. HATT developed in 68 (18.9%). Cox regression analysis revealed that severe chronic kidney disease without hemodialysis, N-acetyltransferase (NAT2) slow acetylator, high initial HBV/HCV viral load, and women in those without HBV/HCV infection were significant predictors of drug-induced HATT, whereas severe chronic kidney disease without hemodialysis and men with high initial HBV/HCV viral load were significantly associated virus-induced HATT. CONCLUSION: HBV/HCV viral load interacts with gender and, together with severe chronic kidney disease without hemodialysis and NAT2 slow acetylator, were predictors of HATT. TB patients with these characteristics need close follow-up.
Assuntos
Antituberculosos/administração & dosagem , Hepatite B/epidemiologia , Hepatite C/epidemiologia , Tuberculose/complicações , Tuberculose/tratamento farmacológico , Carga Viral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hepatite B/virologia , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Fatores de Risco , Transaminases/sangue , Adulto JovemRESUMO
Interaction of CD8 (CD8alphaalpha or CD8alphabeta) with the peptide-major histocompatibility complex (MHC) class I (pMHCI) is critical for the development and function of cytolytic T cells. Although the crystal structure of CD8alphaalpha.pMHCI complex revealed that two symmetric CD8alpha subunits interact with pMHCI asymmetrically, with one subunit engaged in more extensive interaction than the other, the details of the interaction between the CD8alphabeta heterodimer and pMHCI remained unknown. The Ig-like domains of mouse CD8alphabeta and CD8alphaalpha are similar in the size, shape, and surface electrostatic potential of their pMHCI-binding regions, suggesting that their interactions with pMHCI could be very similar. Indeed, we found that the CD8alpha variants CD8alpha(R8A) and CD8alpha(E27A), which were functionally inactive as homodimers, could form an active co-receptor with wild-type (WT) CD8beta as a CD8alpha(R8A)beta or CD8alpha(E27A)beta heterodimer. We also identified CD8beta variants that could form active receptors with WT CD8alpha but not with CD8alpha(R8A). This observation is consistent with the notion that the CD8beta subunit may replace either CD8alpha subunit in CD8alphaalpha.pMHCI complex. In addition, we showed that both anti-CD8alpha and anti-CD8beta antibodies were unable to completely block the co-receptor activity of WT CD8alphabeta. We propose that CD8alphabeta binds to pMHCI in at least two distinguishable orientations.
Assuntos
Antígenos CD8/química , Antígenos de Histocompatibilidade Classe I/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Antígenos CD8/metabolismo , Dimerização , Humanos , Camundongos , Dados de Sequência MolecularRESUMO
The TCRbeta chain constant domain contains an unusually elongated, solvent-exposed FG loop. This structural element forms one component of an alphabeta TCR cavity against which CD3epsilongamma may abut to facilitate Ag-specific signaling. Consistent with this notion, in the present study we show that N15alphabeta TCR transfectants expressing a FG loop-deleted chain (betaDeltaFG) stimulate less tyrosine protein phosphorylation than those bearing a wild-type beta-chain (betawt) upon TCR cross-linking. Furthermore, coimmunoprecipitation studies suggest a weakened association between the CD3epsilongamma heterodimer and the beta-chain in TCR complexes containing the betaDeltaFG variant. To further investigate the biologic role of the Cbeta FG loop in development, we competitively reconstituted the thymus of Ly5 congenic or RAG-2-/- mice using bone marrow cells from betawt or betaDeltaFG transgenic C57BL/6 (B6) mice. Both betawt and betaDeltaFG precursor cells generate thymocytes representative of all maturational stages. However, betaDeltaFG-expressing thymocytes dominate during subsequent development, resulting in an excess of betaDeltaFG-expressing peripheral T cells with reduced proliferative and cytokine production abilities upon TCR stimulation. Collectively, our results show that the unique Cbeta FG loop appendage primarily controls alphabeta T cell development through selection processes.
Assuntos
Diferenciação Celular/imunologia , Fragmentos de Peptídeos/fisiologia , Receptores de Antígenos de Linfócitos T alfa-beta/fisiologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Animais , Complexo CD3/química , Complexo CD3/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/genética , Proliferação de Células , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fragmentos de Peptídeos/deficiência , Fragmentos de Peptídeos/genética , Fosforilação , Estrutura Terciária de Proteína/genética , Estrutura Terciária de Proteína/fisiologia , Receptores de Antígenos de Linfócitos T alfa-beta/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Deleção de Sequência , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/metabolismo , Timo/citologia , Timo/imunologia , Timo/metabolismoRESUMO
The crystal structure of a recombinant mouse single chain CD8alphabeta ectodomains at 2.4 A resolution reveals paired immunoglobulin variable region-like domains with a striking resemblance to CD8alphaalpha in size, shape, and surface electrostatic potential of complementarity-determining regions (CDR), despite <20% sequence identity between the CD8alpha and CD8beta subunits. Unlike the CD8alpha subunit(s) in the heterodimer or homodimer, the CDR1 loop of CD8beta tilts away from its corresponding CDR2 and CDR3 loops. Consistent with this observation, independent mutational studies reveal that alanine substitutions of residues in the CDR1 loop of CD8beta have no effect on CD8alphabeta coreceptor function, whereas mutations in CD8beta CDR2 and CDR3 loops abolish CD8alphabeta coreceptor activity. The implications of these findings and additional CD8alpha mutational studies for CD8alphabeta- versus CD8alphaalpha-MHCI binding are discussed.
Assuntos
Antígenos CD8/química , Antígenos CD8/genética , Modelos Moleculares , Sequência de Aminoácidos , Animais , Antígenos CD8/metabolismo , Cristalização , Análise Mutacional de DNA , Dimerização , Camundongos , Dados de Sequência Molecular , Alinhamento de Sequência , Análise de Sequência de DNA , Eletricidade EstáticaRESUMO
CD8 glycoproteins are expressed as either alphaalpha homodimers or alphabeta heterodimers on the surface of T cells. CD8alphabeta is a more efficient coreceptor than the CD8alphaalpha for peptide Ag recognition by TCR. Each CD8 subunit is composed of four structural domains, namely, Ig-like domain, stalk region, transmembrane region, and cytoplasmic domain. In an attempt to understand why CD8alphabeta is a better coreceptor than CD8alphaalpha, we engineered, expressed, and functionally tested a chimeric CD8alpha protein whose stalk region is replaced with that of CD8beta. We found that the beta stalk region enhances the coreceptor function of chimeric CD8alphaalpha to a level similar to that of CD8alphabeta. Surprisingly, the beta stalk region also restored functional activity to an inactive CD8alpha variant, carrying an Ala mutation at Arg(8) (R8A), to a level similar to that of wild-type CD8alphabeta. Using the R8A variant of CD8alpha, a panel of anti-CD8alpha Abs, and three MHC class I (MHCI) variants differing in key residues known to be involved in CD8alpha interaction, we show that the introduction of the CD8beta stalk leads to a different topology of the CD8alpha-MHCI complex without altering the overall structure of the Ig-like domain of CD8alpha or causing the MHCI to employ different residues to interact with the CD8alpha Ig domain. Our results show that the stalk region of CD8beta is capable of fine-tuning the coreceptor function of CD8 proteins as a coreceptor, possibly due to its distinct protein structure, smaller physical size and the unique glycan adducts associated with this region.