RESUMO
This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system. The most common adverse events seen in the NTZ group were gastrointestinal complaints and headache. The mean change in TTP in sputum over 14 days in the NTZ group was 3.2 h ± 22.6 h and was not statistically significant (P = 0.56). The mean change in TTP in the standard therapy group was significantly increased, at 134 h ± 45.2 h (P < 0.0001). The mean NTZ MIC for Mycobacterium tuberculosis isolates was 12.3 µg/ml; the mean NTZ maximum concentration (Cmax) in plasma was 10.2 µg/ml. Negligible NTZ levels were measured in sputum. At the doses used, NTZ did not show bactericidal activity against M. tuberculosis Plasma concentrations of NTZ were below the MIC, and its negligible accumulation in pulmonary sites may explain the lack of bactericidal activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02684240.).
Assuntos
Antituberculosos/farmacocinética , Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Nitrocompostos/farmacocinética , Nitrocompostos/uso terapêutico , Tiazóis/farmacocinética , Tiazóis/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Antituberculosos/efeitos adversos , Feminino , Haiti , Humanos , Masculino , Testes de Sensibilidade Microbiana , Nitrocompostos/efeitos adversos , Escarro/microbiologia , Tiazóis/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Peripheral blood transcriptome signatures that distinguish active pulmonary tuberculosis (TB) from control groups have been reported, but correlations of these signatures with sputum mycobacterial load are incompletely defined. METHODS: We assessed the performance of published TB transcriptomic signatures in Haiti, and identified transcriptomic biomarkers of TB bacterial load in sputum as measured by Xpert® MTB/RIF molecular testing. People in Port au Prince, Haiti, with untreated pulmonary TB (n = 51) formed the study cohort: 19 people with low and 32 with high sputum Mycobacterium tuberculosis load. Peripheral whole blood transcriptomes were generated using RNA sequencing. RESULTS: Twenty of the differentially expressed transcripts in TB vs. no TB were differentially expressed in people with low vs. high sputum mycobacterial loads. The difference between low and high bacterial load groups was independent of radiographic severity. In a published data set of transcriptomic response to anti-tuberculosis treatment, this 20-gene subset was more treatment-responsive at 6 months than the full active TB signature. CONCLUSION: We identified genes whose transcript levels in the blood distinguish active TB with high vs. low M. tuberculosis loads in the sputum. These transcripts may reveal mechanisms of mycobacterial control of M. tuberculosis during active infection, as well as identifying potential biomarkers for bacterial response to anti-tuberculosis treatment.
Assuntos
Mycobacterium tuberculosis/genética , Escarro/microbiologia , Transcriptoma , Tuberculose Pulmonar/diagnóstico , Adulto , Carga Bacteriana , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Haiti , Humanos , Masculino , Mycobacterium tuberculosis/isolamento & purificação , Sensibilidade e Especificidade , Análise de Sequência de RNARESUMO
Numerous studies have investigated the potential relationship between the human leukocyte antigen (HLA)-G 14-bp insertion/deletion (INS/DEL) polymorphisms and autoimmune disease (AID). However, published results are inconclusive. Our aim was to determine whether the 14-bp INS/DEL polymorphism in the HLA-G gene contributes to the risk of AID. A systemic literature search of the PubMed and EMBASE databases was conducted to identify eligible studies investigating the association of the HLA-G 14-bp INS/DEL polymorphism with AID. Our analysis included 11 publications involving a total of 6462 individuals. Overall, no significant association between the HLA-G 14-bp INS/DEL polymorphism and AID was detected in any comparison model. Further subgroup analyses based on AID types and ethnicity also revealed no significant associations. Our results suggest that the HLA-G 14-bp INS/DEL polymorphism is unrelated to the development of AID. Further studies including larger sample sizes are warranted to confirm these results.
Assuntos
Doenças Autoimunes/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Antígenos HLA-G/genética , Mutação INDEL , Polimorfismo Genético , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Estudos de Casos e Controles , Humanos , Razão de ChancesRESUMO
The construction of live recombinant bacterial vaccines requires a reasonably sophisticated genetic system for the introduction, stabilization and expression of foreign antigen genes. Bacteriophages offer a rich collection of tools that can be used for vaccine construction, including site-specific integration-proficient vectors, non-antibiotic selectable markers and signals for efficient transcription and translation of foreign genes. We describe the characterization of a temperate phage of the mycobacteria, mycobacteriophage L5, and application of these phage studies for the construction of recombinant BCG vaccines.