RESUMO
BACKGROUND: There is a need for new tools for monitoring of the response to TB treatment. Such tools may allow for tailored treatment regimens, and stratify patients initiating TB treatment into different risk groups. We evaluated combinations between previously published host biomarkers and new candidates, as tools for monitoring TB treatment response, and prediction of relapse. METHODS: Serum samples were collected at multiple time points, from patients initiating TB treatment at research sites situated in South Africa (ActionTB study), Brazil and Uganda (TBRU study). Using a multiplex immunoassay platform, we evaluated the concentrations of selected host inflammatory biomarkers in sera obtained from clinically cured patients with and without subsequent relapse within 2 years of TB treatment completion. RESULTS: A total of 130 TB patients, 30 (23%) of whom had confirmed relapse were included in the study. The median time to relapse was 9.7 months in the ActionTB study (n = 12 patients who relapsed), and 5 months (n = 18 patients who relapsed) in the TBRU study. Serum concentrations of several host biomarkers changed during TB treatment with IL-6, IP-10, IL-22 and complement C3 showing potential individually, in predicting relapse. A six-marker signature comprising of TTP, BMI, sICAM-1, IL-22, IL-1ß and complement C3, predicted relapse, prior to the onset of TB treatment with 89% sensitivity and 94% specificity. Furthermore, a 3-marker signature (Apo-CIII, IP-10 and sIL-6R) predicted relapse in samples collected at the end of TB treatment with sensitivity of 71% and specificity of 74%. A previously identified baseline relapse prediction signature (TTP, BMI, TNF-ß, sIL-6R, IL-12p40 and IP-10) also showed potential in the current study. CONCLUSION: Serum host inflammatory biomarkers may be useful in predicting relapse in TB patients prior to the initiation of treatment. Our findings have implications for tailored patient management and require prospective evaluation in larger studies.
Assuntos
Antituberculosos , Biomarcadores , Recidiva , Tuberculose Pulmonar , Humanos , Biomarcadores/sangue , Masculino , Feminino , Adulto , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/diagnóstico , Uganda , África do Sul , Antituberculosos/uso terapêutico , Pessoa de Meia-Idade , Brasil , Adulto Jovem , Quimiocina CXCL10/sangue , Interleucinas/sangue , Citocinas/sangue , Complemento C3/análiseRESUMO
Before the colonial period, California harboured more language variation than all of Europe, and linguistic and archaeological analyses have led to many hypotheses to explain this diversity1. We report genome-wide data from 79 ancient individuals from California and 40 ancient individuals from Northern Mexico dating to 7,400-200 years before present (BP). Our analyses document long-term genetic continuity between people living on the Northern Channel Islands of California and the adjacent Santa Barbara mainland coast from 7,400 years BP to modern Chumash groups represented by individuals who lived around 200 years BP. The distinctive genetic lineages that characterize present-day and ancient people from Northwest Mexico increased in frequency in Southern and Central California by 5,200 years BP, providing evidence for northward migrations that are candidates for spreading Uto-Aztecan languages before the dispersal of maize agriculture from Mexico2-4. Individuals from Baja California share more alleles with the earliest individual from Central California in the dataset than with later individuals from Central California, potentially reflecting an earlier linguistic substrate, whose impact on local ancestry was diluted by later migrations from inland regions1,5. After 1,600 years BP, ancient individuals from the Channel Islands lived in communities with effective sizes similar to those in pre-agricultural Caribbean and Patagonia, and smaller than those on the California mainland and in sampled regions of Mexico.
Assuntos
Variação Genética , Povos Indígenas , Humanos , Agricultura/história , California/etnologia , Região do Caribe/etnologia , Etnicidade/genética , Etnicidade/história , Europa (Continente)/etnologia , Variação Genética/genética , História do Século XV , História do Século XVI , História do Século XVII , História do Século XVIII , História do Século XIX , História Antiga , História Medieval , Migração Humana/história , Povos Indígenas/genética , Povos Indígenas/história , Ilhas , Idioma/história , México/etnologia , Zea mays , Genoma Humano/genética , Genômica , AlelosRESUMO
The T-box transcription factor T-bet is regarded as a "master regulator" of CD4+ Th1 differentiation and IFN-γ production. However, in multiple models of infection, T-bet appears less critical for CD8+ T cell expansion and effector function. Here, we show that following vaccination with a replication-deficient strain of Toxoplasma gondii, CD8+ T cell expression of T-bet is required for optimal expansion of parasite-specific effector CD8+ T cells. Analysis of the early events associated with T cell activation reveals that the α chain of LFA1, CD11a, is a target of T-bet, and T-bet is necessary for CD8+ T cell upregulation of this integrin, which influences the initial priming of CD8+ effector T cells. We propose that the early expression of T-bet represents a T cell-intrinsic factor that optimizes T-DC interactions necessary to generate effector responses.
Assuntos
Ativação Linfocitária , Células T de Memória , Regulação para Cima , Ativação Transcricional , Linfócitos T CD8-PositivosRESUMO
RATIONALE: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown. OBJECTIVES: We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment. METHODS: Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase. MEASUREMENTS AND MAIN RESULTS: A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively). CONCLUSIONS: Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).
Assuntos
Antibióticos Antituberculose/administração & dosagem , Rifampina/análogos & derivados , Tuberculose Pulmonar/tratamento farmacológico , Adolescente , Adulto , África , Idoso , Antituberculosos/administração & dosagem , Ásia , Esquema de Medicação , Quimioterapia Combinada , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Rifampina/administração & dosagem , Método Simples-Cego , América do Sul , Resultado do TratamentoRESUMO
BACKGROUND: Although extrapulmonary tuberculosis (EPTB) is less frequent than Pulmonary Tuberculosis (PTB) and is a secondary target for national TB control programs, its significance has increased worldwide during the HIV epidemic. The objective of this study was to examine the epidemiology of EPTB in Brazil between 2007 and 2011. METHODS: Cross-sectional study involving all cases of TB reported to the Brazilian Notifiable Diseases Surveillance System (Sistema de Informações de Agravo de Notificação - SINAN) in Brazil between 2007 and 2011. Sociodemographic and clinical characteristics of patients with exclusively PTB and exclusively EPTB were compared. Following analysis with Pearson's chi-square test, variables with p < 0.05 were included in a hierarchical regression model. Variables with p < 0.05 in the corresponding level were kept in the model. RESULTS: A total of 427,548 cases of TB were included. Of these, 356,342 cases (83.35%; 95% confidence interval (CI) 83.23% - 83.45%) were PTB, 57,217 (13.37%; 95% CI 13.28% - 13.48%) were EPTB, 13,989 (3.27%; 95% CI 3.21% - 3.32%) were concurrent pulmonary and extrapulmonary TB. Patients with EPTB were mainly white (16.7%), and most (29.1%) patients had five to eight years of education. Among comorbidities, HIV infection was prominent (OR 2.15; 95% CI 2.09 - 2.21), although the proportion of cases awaiting test results or untested was high (39%). Ethanol use (OR 0.45; 95% CI 0.43 - 0.46), diabetes mellitus (OR 0.54; 95% CI 0.51 - 0.57) and mental illness (OR 0.88; 95% CI 0.82 - 0.95) were associated with PTB. CONCLUSIONS: Thirteen percent of patients diagnosed with TB in Brazil have only EPTB. More effective diagnostic strategies and control measures are needed to reduce the number of cases of extrapulmonary TB in Brazil.
Assuntos
Tuberculose/epidemiologia , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Comorbidade , Estudos Transversais , Feminino , Infecções por HIV/epidemiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Factors related to the development of extrapulmonary forms of tuberculosis (EPTB) are still poorly understood, particularly in high-endemic countries like Brazil. The objective of the paper is to determine host and Mycobacterium tuberculosis (MTB) strain-related factors associated with the development of EPTB in Espírito Santo state, Brazil. METHODS AND FINDINGS: We conducted a retrospective laboratory-based surveillance study of new tuberculosis (TB) cases diagnosed in Espírito Santo state, Brazil between 1998 and 2007. We genotyped 612 isolates of MTB from 606 TB patients using spoligotyping and IS6110-restriction fragment length polymorphism (RFLP) typing and compared sociodemographic and clinical characteristics of patients with pulmonary TB (PTB) and EPTB. Among 606 patients, 464 (77%) had PTB, 79 (13%) had EPTB, 51 (8%) had both, and 12 (2%) had miliary TB. The IS6110 RFLP analysis demonstrated that 250 (41%) isolates belonged to clustered RFLP patterns, 27 (11%) of which were from EPTB. We identified 73 clusters including 35 (48%) composed of 2 isolates each. By spoligotyping, 506 (83%) MTB isolates fell into known patterns and 106 (17%) fell into patterns with no family assignment; 297 (48%) isolates belonged to the Latin-American Mediterranean family. Higher school level (4-7 years OR: 0.16 95% CI 0.34-0.73 and > 8 years of education, OR 0.06 95% CI 0.009-0.50) white ethnicity (OR: 2.54 95% CI 1.03-6.25) and HIV infection (OR: 16.83 95% CI 5.23-54.18) were associated with EPTB. No specific strain lineage or percentage of clustering was associated with EPTB. CONCLUSIONS: These results demonstrate that risk factors for EPTB are related more to host than to MTB strain lineage characteristics.
Assuntos
Cidades/epidemiologia , Mycobacterium tuberculosis/fisiologia , Tuberculose/epidemiologia , Tuberculose/microbiologia , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Estudos Retrospectivos , Fatores de Risco , Especificidade da Espécie , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/microbiologia , Adulto JovemRESUMO
To assess whether rinsing with oral antiseptics before sputum collection would reduce contamination of mycobacterial cultures, 120 patients with suspected tuberculosis were randomly assigned to rinse with chlorhexidine or cetylpyridinium mouthwash before collection. The culture contamination rate was significantly lower after rinsing with chlorhexidine before collection, especially for cultures grown in MGIT medium.
Assuntos
Anti-Infecciosos Locais/administração & dosagem , Antissépticos Bucais/administração & dosagem , Mycobacterium tuberculosis/isolamento & purificação , Escarro/microbiologia , Tuberculose/diagnóstico , Adolescente , Adulto , Cetilpiridínio/administração & dosagem , Clorexidina/administração & dosagem , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Objetivo: Comparar os resultados de cura por tuberculose entre pacientes supervisionados pelo membro familiar e pelo profissional de saúde. Métodos: Estudo de coorte prospectiva de 171 pacientes de Vitória, ES, no período de 2004 a 2007. Cada paciente foi acompanhado por seis meses até a finalização do tratamento. Dos pacientes estudados, 59 pacientes tratados eram supervisionados por um membro familiar e 112 pelos profissionais de saúde. Foram avaliados dados sociodemográficos e clínicos dos pacientes. Diferenças entre os grupos de estudo foram avaliadas utilizando o teste qui-quadrado ou teste t de Student ao nivel de significância de 5 por cento. Resultados: A maioria dos sujeitos do estudo apresentaram bacioscopia positiva e cultura confirmada para tuberculose. Dois pacientes tinham sorologia positiva para HIV. Um número maior de pacientes no grupo supervisionado por profissionais de saúde não eram alfabetizados, comparado com aqueles pacientes do grupo supervisionado por membros familiares (p = 0,01). Todos os pacientes supervisionados por um familiar foram...(AU)Objetivo: Comparar los resultados de cura por tuberculosis entre pacientes supervisados por ele miembro familiar y por el profesional de salud. Métodos: Estudio de cohorte prospectivo de 171 pacientes de Vitória, sureste de Brasil, en el período de 2004 a 2007. Cada paciente fue acompañado por seis meses hasta la finalización del tratamiento. De los pacientes estudiados, 59 pacientes tratados eran supervisados por un miembro familiar y 112 por los profesionales de salud. Fueron evaluados datos sociodemográficos y clínicos de los pacientes. Diferencias entre los grupos de estudio fueron evaluadas utilizando la prueba Chi-cuadrado o prueba t de Student al nivel de significancia de 5 por ciento. Resultados: La mayoría de los sujetos de estudio presentaron bacioscopia positiva y cultivo confirmado...
Assuntos
Humanos , Assistência Domiciliar , Cuidadores , Enfermagem Familiar , Pacientes Domiciliares , Resultado do Tratamento , Tuberculose/enfermagem , Estudos de CoortesRESUMO
OBJECTIVE: To compare tuberculosis cure rates among patients supervised by household members or health care workers. METHODS: Prospective cohort study of 171 patients treated by the program in Vitoria, Southeastern Brazil, from 2004 to 2007. Each patient was followed-up for six months until the end of the treatment. Of the patients studied, a household member supervised 59 patients and healthcare workers supervised 112 patients. Patients' sociodemographic and clinic data were analyzed. Differences between groups were assessed using chi-square test or Student's t-test. Significance level was set at 5%. RESULTS: Most patients had smear positive, culture confirmed pulmonary tuberculosis. Two patients were HIV-positive. There were more illiterate patients in the healthcare-supervised group, in comparison to those supervised by their families (p=0.01). All patients supervised by a household member were cured compared to 90% of the patients supervised by health care workers (p = 0.024). CONCLUSIONS: Successful tuberculosis treatment was more frequent when supervised by household members.
Assuntos
Cuidadores/normas , Terapia Diretamente Observada/normas , Família , Tuberculose Pulmonar/terapia , Adolescente , Adulto , Assistência Ambulatorial , Cuidadores/classificação , Distribuição de Qui-Quadrado , Terapia Diretamente Observada/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
A comparative study to evaluate contamination in cultures of morning sputum samples, comparing those collected at home under currently recommended conditions and those collected under supervision after patient orientation and education. The home and supervised collection groups produced 43 and 76 sputum samples, respectively. The contamination rate was nearly 3-times higher among samples collected at home than among those collected under supervision (37% vs. 13%, p < 0.05; OR = 0.25). The simple educational and hygiene measures described can decrease the contamination rate among sputum samples collected for diagnostic culture.