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1.
Medicine (Baltimore) ; 101(35): e30405, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36107594

RESUMO

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), continues to pose a major public health problem and is the leading cause of mortality in people infected with human immunodeficiency virus (HIV). HIV infection greatly increases the risk of developing TB even before CD4+ T-cell counts decrease. Co-infection provides reciprocal advantages to both pathogens and leads to acceleration of both diseases. In HIV-coinfected persons, the diagnosis and treatment of tuberculosis are particularly challenging. Intensifying integration of HIV and tuberculosis control programmes has an impact on reducing diagnostic delays, increasing early case detection, providing prompt treatment onset, and ultimately reducing transmission. In this Review, we describe our current understanding of how these two pathogens interact with each other, new sensitive rapid assays for TB, several new prevention methods, new drugs and regimens.


Assuntos
Coinfecção , Infecções por HIV , Mycobacterium tuberculosis , Tuberculose , Adulto , Linfócitos T CD4-Positivos , Coinfecção/diagnóstico , Infecções por HIV/complicações , Humanos , Tuberculose/complicações , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico
2.
Medicine (Baltimore) ; 101(35): e30283, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36107603

RESUMO

BACKGROUND: Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome associated with infections, tumors and connective tissue disease. However rapid identification of the underlying infectious cause of HLH is challenging because traditional etiological diagnostics are time-consuming and sometimes fail to identify the pathogens. Metagenomic next-generation sequencing (mNGS) may be a potential optimal solution, which may help improve the clinical diagnosis of underlying infections in hematological diseases. CASE PRESENTATION: A 28-year-old man presented with a 2-month history of intermittent fever and cytopenia. The HLH was diagnosed based on the manifestations of fever, splenomegaly, anemia, thrombocytopenia, hyperferritinemia, hyperglyceridemia, and elevated IL-2R levels. High-through-put sequencing analysis detected a GZMB mutation. While the initial detection of cultures and smears of tuberculosis was negative, TB infection was eventually identified by mNGS of blood sample. The symptoms rapidly abated during the initial administration of TB. CONCLUSION: The present case proposed that mNGS might be an effective diagnostic tool for diagnosing rare infectious cause of secondary HLH. GZMB mutation was first discovered to be present in secondary HLH.


Assuntos
Tuberculose Latente , Linfo-Histiocitose Hemofagocítica , Neoplasias , Tuberculose , Adulto , Granzimas , Humanos , Tuberculose Latente/complicações , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Masculino , Mutação , Neoplasias/complicações , Tuberculose/complicações , Tuberculose/diagnóstico
3.
Int J Clin Pract ; 2022: 4044530, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36110263

RESUMO

Tuberculosis (TB) still remains the burden in Indonesia. One of the factors that may influence the treatment success of TB is patient's adherence. However, the hepatotoxicity of the TB medicine may decrease the patient's adherence. Our study's aim is to investigate the relationship between the patient's knowledge and the hepatotoxicity with medication adherence of TB patients in Banyumas Regency. This study was conducted at one Community Lung Health Center and two hospitals in Banyumas Regency, Purwokerto, Center of Java, Indonesia. The respondents were 91 TB patients with hepatotoxicity characterized by an increased aspartate transaminase (AST) and alanine aminotransferase (ALT). The level of the patients' knowledge about the hepatotoxicity effect was determined using a questionnaire. The patients' adherence was determined using the Medication Adherence Rating Scale -5 (MARS) questionnaire and pill count methods. Most of the patients were male (53.8%), the age was in the range of 18-29 years old (3.5%), they have no smoking history (59.3%), and their last education majorly was senior high school (46.2%). Most TB patients had poor knowledge (47.3%) and the hepatotoxic effect often appeared in grade 1 (61.5%). The TB patients with a good and moderate level of knowledge were 17.6% and 35.2%, respectively. The TB patients with moderate and severe hepatotoxicity were 39.4% and 1.1%, respectively. The measurement of the level of respondents' adherence using MARS-5 showed that 51.6% of patients had good adherence. We determined the rest of the drug-using pill count method, which resulted in 62.6% of patients adhering to taking antituberculosis drugs. TB patients with a sufficient knowledge and those with mild hepatotoxicity show the higher adherence (p < 0.001). There is a significant relationship between a high level of the patient's knowledge about hepatotoxicity effect, less severity of the hepatotoxic effect, and increased patient adherence in taking the medication.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Tuberculose , Adolescente , Adulto , Alanina Transaminase/uso terapêutico , Antituberculosos/efeitos adversos , Aspartato Aminotransferases/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Humanos , Indonésia/epidemiologia , Masculino , Adesão à Medicação , Tuberculose/induzido quimicamente , Tuberculose/tratamento farmacológico , Adulto Jovem
4.
Front Cell Infect Microbiol ; 12: 937416, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36093183

RESUMO

Background: T-SPOT.TB (T-SPOT) is widely used for the detection of Mycobacterium tuberculosis infection by detecting interferon-gamma (IFN-γ) release in T lymphocytes. This assay is performed on peripheral blood mononuclear cells (PBMCs) separated by Ficoll density gradient centrifugation, which often contain some residual platelets. Here, we investigated the impact of platelets on T-SPOT assay and related mechanisms. Methods: The correlation between platelet count, platelet-to-lymphocyte ratio (PLR), and the IFN-γ secreting T cells (ISCs) in positive control wells of T-SPOT assay were retrospectively analyzed. T-SPOT assay was performed with un-treated PBMCs, platelets-removed PBMCs, and platelets-enriched PBMCs to confirm the impact of platelets on T-SPOT assay. The activation of platelets and their impact on IFN-γ production in T cells were detected by flow cytometry (FCM). Platelets and T cells were cultured in a mixed culture system and co-culture system respectively, followed by detection of the frequencies of IFN-γ-producing T cells and the levels of intracellular IFN-γ in T cells by FCM. Moreover, the effect of platelet releasate on the T-SPOT assay was evaluated. Results: The ISCs in positive control wells of the T-SPOT assay showed a significant decrease with the increase in platelet count. The PLR of the peripheral blood were negatively correlated with the ISCs in positive control wells of the T-SPOT assay. Removal or enrichment of platelets significantly increased or decreased the ISCs and the positive rate of T-SPOT. Inhibition of platelet activation significantly increased the ISCs of T-SPOT. The frequencies of IFN-γ-producing T cells in PBMCs and the levels of intracellular IFN-γ were significantly reduced by the addition of platelets, both in the mixed culture system and the co-culture system. Platelet releasate upon thrombin activation significantly decreased the ISCs of T-SPOT. Conclusions: Platelets correlate with negative T-SPOT results by inhibiting IFN-γ production in T cells via degranulation.


Assuntos
Interferon gama , Tuberculose , Humanos , Leucócitos Mononucleares , Estudos Retrospectivos , Linfócitos T , Tuberculose/diagnóstico
5.
Front Cell Infect Microbiol ; 12: 947954, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36118035

RESUMO

Purpose: This study aimed to develop and validate a scoring system based on a nomogram of common clinical metrics to discriminate between active pulmonary tuberculosis (APTB) and inactive pulmonary tuberculosis (IPTB). Patients and methods: A total of 1096 patients with pulmonary tuberculosis (PTB) admitted to Wuhan Jinyintan Hospital between January 2017 and December 2019 were included in this study. Of these patients with PTB, 744 were included in the training cohort (70%; 458 patients with APTB, and 286 patients with IPTB), and 352 were included in the validation cohort (30%; 220 patients with APTB, and 132 patients with IPTB). Data from 744 patients from the training cohort were used to establish the diagnostic model. Routine blood examination indices and biochemical indicators were collected to construct a diagnostic model using the nomogram, which was then transformed into a scoring system. Furthermore, data from 352 patients from the validation cohort were used to validate the scoring system. Results: Six variables were selected to construct the prediction model. In the scoring system, the mean corpuscular volume, erythrocyte sedimentation rate, albumin level, adenosine deaminase level, monocyte-to-high-density lipoprotein ratio, and high-sensitivity C-reactive protein-to-lymphocyte ratio were 6, 4, 7, 5, 5, and 10, respectively. When the cut-off value was 15.5, the scoring system for recognizing APTB and IPTB exhibited excellent diagnostic performance. The area under the curve, specificity, and sensitivity of the training cohort were 0.919, 84.06%, and 86.36%, respectively, whereas those of the validation cohort were 0.900, 82.73, and 86.36%, respectively. Conclusion: This study successfully constructed a scoring system for distinguishing APTB from IPTB that performed well.


Assuntos
Tuberculose Latente , Tuberculose Pulmonar , Tuberculose , Adenosina Desaminase , Proteína C-Reativa , Humanos , Lipoproteínas HDL , Nomogramas , Tuberculose Pulmonar/diagnóstico
6.
J Exp Med ; 219(11)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36069923

RESUMO

Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation-mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.


Assuntos
Ferroptose , Glutationa Peroxidase/metabolismo , Tuberculose , Animais , Glutationa/metabolismo , Peroxidação de Lipídeos , Camundongos , Camundongos Transgênicos , Necrose , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Tuberculose/imunologia , Tuberculose/metabolismo
7.
J Infect Dev Ctries ; 16(8): 1317-1322, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-36099375

RESUMO

INTRODUCTION: Tuberculosis (TB) continues to be a significant public health problem. The role of small non-coding RNAs, such as microRNAs (miRNAs), was investigated extensively in Mycobacterium tuberculosis (MTB) infection as well as in a variety of other pathophysiological processes in recent years. It was found that miRNAs act as regulators of both early reaction to MTB infection and in process of adaptation of the host immune cells during latent course of the disease. Molecule miRNA-146a is expressed exclusively in immune cells and it has the most prominent role in modulation of innate immunity. METHODOLOGY: We investigated the level of expression of miRNA-146a using an RT-qPCR technique in peripheral blood mononuclear cells of 44 patients with active pulmonary TB and 17 healthy individuals. We also analyzed the significance of miRNA-146a rs2910164 SNV for expression profile of miRNA-146a, in order to investigate potential usage of miRNA-146a as a biomarker for TB. RESULTS: There was statistically significant decrease of expression of miRNA-146a in TB group compared to control group. When gender cohorts were analyzed, the expression levels in TB male and TB female subgroup were significantly lower than the expression levels in the same gender control subgroups. CONCLUSIONS: Our results indicate that miRNA-146a plays a significant role in the pathogenesis of TB, suggesting that miRNA-146a could be used as a biomarker for active pulmonary TB.


Assuntos
MicroRNAs , Tuberculose Pulmonar , Tuberculose , Biomarcadores , Feminino , Humanos , Leucócitos Mononucleares , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Sérvia/epidemiologia , Tuberculose Pulmonar/genética
8.
J Infect Dev Ctries ; 16(8): 1372-1375, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-36099384

RESUMO

Tuberculosis remains a serious health problem in pregnant women. Tuberculosis during pregnancy is related to poor perinatal outcomes, including low birth weight, insufficient growth relative to gestational age, perinatal mortality, and maternal morbidity and mortality. Additionally, diabetes mellitus in pregnant women with tuberculosis is associated with a higher risk of maternal and fetal complications such as preeclampsia, preterm birth, hypoglycemia, and giant baby. We report two perinatal outcomes of (1) pregnancy during tuberculosis treatment and (2) tuberculosis in a pregnant woman with diabetes mellitus. Both women completed anti-tuberculosis treatments. This report emphasizes the importance of health promotion through family planning among women with tuberculosis. This case report also underscores the increased risk of developing tuberculosis in pregnant women with diabetes mellitus. Early diagnosis of tuberculosis in pregnant women is vital as it affects the health of both mother and child.


Assuntos
Nascimento Prematuro , Tuberculose Pulmonar , Tuberculose , Feminino , Promoção da Saúde , Humanos , Indonésia/epidemiologia , Lactente , Recém-Nascido , Gravidez , Resultado da Gravidez , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/epidemiologia
9.
J Clin Invest ; 132(18)2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36106635

RESUMO

Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, remains a leading cause of death from an infectious agent, resulting in more than a million deaths per year. Despite vaccines and chemotherapies, patients often harbor persister M. tuberculosis cells that resist immune assault and chemotherapeutic treatments, resulting in a latent TB infection (LTBI). In this issue of the JCI, Sharan et al. used an aerosol-based macaque model to show that weekly treatments with isoniazid and rifapentine for 3 months reduced active M. tuberculosis infection and LTBI. Lung tissue from treated animals showed fewer granulomas when compared with the untreated control animals. These findings suggest that it is possible to eliminate persister M. tuberculosis cells, thereby eliminating LTBI. If similar elimination routinely occurs in patients undergoing the isoniazid and rifapentine treatment, the hidden reservoir of M. tuberculosis associated with LTBI would be greatly reduced, allowing us to imagine, and eventually achieve, a world without TB.


Assuntos
Tuberculose Latente , Mycobacterium tuberculosis , Tuberculose , Animais , Imaginação , Isoniazida , Tuberculose Latente/tratamento farmacológico , Tuberculose/tratamento farmacológico , Tuberculose/prevenção & controle
10.
Zhonghua Liu Xing Bing Xue Za Zhi ; 43(9): 1462-1468, 2022 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-36117355

RESUMO

Objective: To analyze the genomic mutation of Mycobacterium tuberculosis (M. tuberculosis) isolated in endogenous activation period and estimate the molecular clock based on the whole genome sequencing data. Methods: Literatures of the whole genome research of endogenous reactivated tuberculosis were retrieved, and the corresponding whole genome sequencing data were downloaded. We extracted the single nucleotide polymorphisms (SNPs) and strain isolation time of initial treatment and relapse of tuberculosis cases, explored the relationship between the different SNPs and interval between initial treatment and relapse by Poisson regression model, calculated the M. tuberculosis molecular clock, and estimated the mutation rate. Results: When the generation time of M. tuberculosis was 18 hours, the mutation rate in 0-2 years, i.e. short-term endogenous activation, was 6.47×10-10 (95%CI: 5.59×10-10-7.44×10-10), which was significantly higher than that in 2-14 years in long term endogenous activation (3.27×10-10, 95%CI: 2.88×10-10-3.69×10-10). The mutation rates of 0-, 1-, 2-, 3-, 5- and 7-14 years were 7.10×10-10, 6.06×10-10, 4.24×10-10, 5.34×10-10, 2.59×10-10 and 1.26×10-10 respectively. Conclusions: In the period of endogenous reactivation, the mutation rate of M. tuberculosis decreases with the interval time between initial treatment and relapse, which verifies the clinically observed phenomenon that the relapse often occurs within two years after the initial treatment of tuberculosis.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Genoma Bacteriano , Humanos , Mycobacterium tuberculosis/genética , Recidiva , Tuberculose/microbiologia , Sequenciamento Completo do Genoma
11.
PLoS One ; 17(9): e0273517, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36048884

RESUMO

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) poses a major threat to the global public health. Importantly, latent tuberculosis infection (LTBI) still impedes the elimination of TB incidence since it has a substantial risk to develop active disease. A multi-stage subunit vaccine comprising active and latency antigens of Mtb has been raised as the promising vaccine to trigger immune protection against all stages of TB. Therefore, the discovery of new antigens that could trigger broad immune response is essential. While current development of TB vaccine mainly focuses on protective immunity mediated by adaptive immune response, the knowledge on triggering the innate immune response by antigens is still limited. We showed that recombinant dormancy-associated Mtb proteins Rv2659c and Rv1738 were recognized by human innate immune recognition molecules, Toll-like receptors (TLRs) 2 and 4 by using HEK-Blue™ hTLR2/hTLR4 systems. We further demonstrated that these two proteins activated phosphorylated NF-κB p65 (Ser536) in the human CD14+ blood cells. We also investigated that these two proteins significantly induced level of pro- and anti-inflammatory cytokines (IL-1ß, IL-6, IL-8, IL-10 and TNF-α) which were mediated through TLR2 and TLR4 pathways in human peripheral blood mononuclear cells (hPBMCs). These findings suggest that proteins Rv2659c and Rv1738 stimulated innate immune response targeting TLR2 and TLR4 to produce inflammatory cytokines, and their benefits would be valuable for the development of an effective prophylactic tuberculosis vaccine.


Assuntos
Proteínas de Bactérias , Imunidade Inata , Mycobacterium tuberculosis , Receptores Toll-Like , Tuberculose , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Citocinas/metabolismo , Humanos , Imunidade Inata/genética , Leucócitos Mononucleares/metabolismo , Mycobacterium tuberculosis/imunologia , Proteínas Recombinantes/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Receptores Toll-Like/genética , Tuberculose/genética , Vacinas contra a Tuberculose
12.
Lancet Glob Health ; 10(10): e1463-e1472, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36049488

RESUMO

BACKGROUND: In 2019, tuberculosis incidence and mortality in Brazil were 46 and 3·3 per 100 000 population, respectively, and the country has reported rising tuberculosis case rates since 2016, following an economic crisis beginning in mid-2014. We aimed to estimate the number of excess tuberculosis cases and deaths during the recession period, and assessed potential causes. METHODS: In this multi-level regression modelling study, we extracted tuberculosis case notifications from Brazil's National Notifiable Disease Information System (known as SINAN), and tuberculosis deaths from the Mortality Information System (known as SIM), for all ages. We fitted mixed-effects regression models estimating trends in these outcomes-stratified by sex, age group, and state-during the pre-recession period (Jan 1, 2010-Dec 31, 2014). We calculated excess cases and deaths between Jan 1, 2015, and Dec 31, 2019 (the recession period) as the difference between reported values and a counterfactual of continued pre-recession trends. We examined the relationship between excess cases and possible explanatory factors using ordinary least squares regression. We tested the robustness of our findings to alternative model specifications related to the pre-recession period and criteria for defining tuberculosis deaths. FINDINGS: We estimated 22 900 excess tuberculosis cases (95% uncertainty interval 18 100-27 500) during 2015-19. By 2019, reported cases were 12% (10-13) higher than predicted by historical trends. 54% (44-66) of excess cases occurred among 20-29-year-old men. In this group, reported cases in 2019 were 30% (25-36) higher than predicted. Excess cases were positively associated with an increasing fraction of cases among incarcerated individuals (p=0·001) and higher unemployment (p=0·04) at the state level. Estimated excess deaths for 2015-19 were not statistically significant from 0 (-600 [-2100 to 1000]). These results were robust to alternative definitions of the pre-recession period and criteria for defining tuberculosis deaths. INTERPRETATION: Tuberculosis cases in Brazil rose substantially in 2015-19 during the recession, largely affecting young men. This increase seems to be linked to increasing tuberculosis transmission among incarcerated populations. Rising tuberculosis case rates threaten tuberculosis control in Brazil, and highlight the threat posed by prison-based tuberculosis transmission. FUNDING: US National Institutes of Health. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.


Assuntos
Recessão Econômica , Tuberculose , Adulto , Brasil/epidemiologia , Humanos , Masculino , Sistema de Registros , Tuberculose/epidemiologia , Desemprego , Adulto Jovem
14.
Virulence ; 13(1): 1543-1557, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36052440

RESUMO

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a leading cause of infectious disease mortality. Animal infection models have contributed substantially to our understanding of TB, yet their biological and non-biological limitations are a research bottleneck. There is a need for more ethically acceptable, economical, and reproducible TB infection models capable of mimicking key aspects of disease. Here, we demonstrate and present a basic description of how Galleria mellonella (the greater wax moth, Gm) larvae can be used as a low cost, rapid, and ethically more acceptable model for TB research. This is the first study to infect Gm with the fully virulent MTB H37Rv, the most widely used strain in research. Infection of Gm with MTB resulted in a symptomatic lethal infection, the virulence of which differed from both attenuated Mycobacterium bovis BCG and auxotrophic MTB strains. The Gm-MTB model can also be used for anti-TB drug screening, although CFU enumeration from Gm is necessary for confirmation of mycobacterial load reducing activity of the tested compound. Furthermore, comparative virulence of MTB isogenic mutants can be determined in Gm. However, comparison of mutant phenotypes in Gm against conventional models must consider the limitations of innate immunity. Our findings indicate that Gm will be a practical, valuable, and advantageous additional model to be used alongside existing models to advance tuberculosis research.


Assuntos
Mariposas , Mycobacterium tuberculosis , Tuberculose , Animais , Antituberculosos , Mariposas/microbiologia , Mycobacterium tuberculosis/genética , Tuberculose/microbiologia , Virulência
15.
N Engl J Med ; 387(9): 810-823, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36053506

RESUMO

BACKGROUND: The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear. METHODS: We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated. RESULTS: A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups. CONCLUSIONS: A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).


Assuntos
Antituberculosos , Linezolida , Nitroimidazóis , Tuberculose Resistente a Múltiplos Medicamentos , Aminoglicosídeos/uso terapêutico , Antituberculosos/efeitos adversos , Antituberculosos/uso terapêutico , Diarilquinolinas/efeitos adversos , Fluoroquinolonas , Humanos , Linezolida/efeitos adversos , Linezolida/uso terapêutico , Nitroimidazóis/efeitos adversos , Nitroimidazóis/uso terapêutico , Rifampina/uso terapêutico , Medição de Risco , Resultado do Tratamento , Tuberculose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
16.
Drug Deliv ; 29(1): 2912-2924, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36081335

RESUMO

Vaccinations, especially DNA vaccines that promote host immunity, are the most effective interventions for tuberculosis (TB) control. However, the vaccine delivery system exhibits a significant impact on the protective effects of the vaccine. Recently, effective nanomaterial-based delivery systems (including nanoparticles, nanogold, nanoliposomes, virus-like particles, and virus carriers) have been developed for DNA vaccines to control TB. This review highlights the historical development of various nanomaterial-based delivery systems for TB DNA vaccines, along with the emerging technologies. Nanomaterial-based vaccine delivery systems could enhance the efficacy of TB vaccination; therefore, this summary could guide nanomaterial selection for optimal and safe vaccine delivery, facilitating the design and development of highly effective TB vaccines.


Assuntos
Mycobacterium tuberculosis , Nanoestruturas , Vacinas contra a Tuberculose , Tuberculose , Vacinas de DNA , DNA , Humanos , Tuberculose/prevenção & controle , Vacinação
17.
Zhonghua Jie He He Hu Xi Za Zhi ; 45(9): 894-903, 2022 Sep 12.
Artigo em Chinês | MEDLINE | ID: mdl-36097927

RESUMO

Objective: To identify the differentially expressed genes (DEGs) induced by tuberculosis peptide-based vaccine MP3RT in a humanized mouse model using transcriptomics technology. Methods: This study was conducted from August 2019 to February 2022. We used edgeR software to screen DEGs with a fold change greater than or equal to 1.5 and a P value less than 0.05 as screening conditions. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and protein interaction network analyses were performed on the screened DEGs. Then, these DEGs were verified by RT-qPCR and statistically analyzed by GraphPad Prism 8 software. Results: A total of 367 DEGs (214 up-regulated and 153 down-regulated) were identified by transcriptomics. Bioinformatics analysis showed that the GO enrichment of the DEGs mentioned above significantly focused on cell metabolism, growth, apoptosis, inflammation, and other terms. In contrast, the KEGG enrichment significantly focused on inflammatory pathways such as the MAPK signaling pathway. Protein interaction network analysis showed that protein Abl1 had the highest aggregation, the highest aggregation coefficient, and the best connectivity. RT-qPCR results showed that gene expressions of cpne4 (t=2.48, P=0.048 0), h2-q10 (t=2.95, P=0.025 6), mef2c (t=2.87, P=0.028 4), cr2 (t=3.23, P=0.178), ablim1 (t=2.91, P=0.033 5), dll1 (t=2.70, P=0.027 3) and ms4a2 (t=3.03, P=0.019 2) genes in the MP3RT group were significantly up-regulated than those in the PBS group, while gene expressions of cd163l1 (t=2.56, P=0.043 0), il1r1 (t=2.91, P=0.022 7) and cd34 (t=2.42, P=0.046 2) genes in the MP3RT group were significantly down-regulated than those in the PBS group. Conclusions: The MP3RT vaccine induced 367 DEGs in humanized mice, which were associated with metabolic and immune responses. Furthermore, we found that p38 MAPK and JNK/MAPK signaling pathways played an important role in the molecular mechanism of the MP3RT vaccine.


Assuntos
Vacinas contra a Tuberculose , Tuberculose , Animais , Perfilação da Expressão Gênica , Proteínas com Domínio LIM , Camundongos , Proteínas dos Microfilamentos , Peptídeos , Transcriptoma
18.
Zhonghua Jie He He Hu Xi Za Zhi ; 45(9): 941-946, 2022 Sep 12.
Artigo em Chinês | MEDLINE | ID: mdl-36097933

RESUMO

Tuberculosis is a major public health problem threatening human health and life. Although the level of diagnosis and treatment of tuberculosis has greatly improved in recent years, it is still one of the major infectious diseases causing human death. Tuberculosis has the characteristics of both chronic and infectious diseases, and is affected by many factors. Identification of the risk factors associated with tuberculosis death has certain guiding value for the prevention and control of tuberculosis. This articled reviewed recent studies on risk factors associated with tuberculosis death both in China and abroad. Male, old age, smoking, drinking, low socioeconomic level, malnutrition, drug resistance, AIDS and diabetes mellitus were found to increase the risk of tuberculosis mortality. It is expected that these findings could provide useful information to clinicians for taking necessary interventions to reduce tuberculosis mortality.


Assuntos
Doenças Transmissíveis , Diabetes Mellitus , Desnutrição , Tuberculose , Humanos , Masculino , Fatores de Risco , Tuberculose/epidemiologia
19.
Pak J Biol Sci ; 25(7): 669-675, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36098174

RESUMO

<b>Background and Objective:</b> <i> Etlingera rubroloba</i> (<i>E. rubroloba</i>) A.D. Poulsen is an endemic plant in South-East Sulawesi and is a newly discovered species. This plant is expected to have the potential as an immunomodulator in patients with diabetes mellitus (DM), which can prevent tuberculosis infection by increasing the phagocytic function of macrophage cells and interleukin-12 (IL-12) levels. <b>Materials and Methods:</b> Phytochemical analysis of the ethanolic extract of the fruit of <i>E. rubroloba</i> A.D. Poulsen using Liquid Chromatography-Mass Spectrometry (LC-MS/MS) was carried out. The immunomodulatory potential <i>in vivo</i> on BALB/c mice model DM was carried out by oral induction of TB antigen with extract dose, control positive, negative and normal groups. Furthermore, the phagocytic activity of macrophage cells can be seen with a microscope and the levels of IL-12 with the Elisa kit. <b>Results:</b> The results showed the ethanol extract of the fruit of <i>E. rubroloba</i> contained eight chemical compounds and had potential as immunomodulators in BALB/c DM mice induced by TB antigen by increasing the phagocytic activity of macrophage cells and levels of IL-12, which were significantly different from the negative control (p<0.05). <b>Conclusion:</b> The chemical composition of the ethanol extract of the fruit of <i>E. rubroloba</i> has the potential as an immunomodulator in TB antigen-induced DM <i>in vivo</i>.


Assuntos
Diabetes Mellitus , Tuberculose , Adjuvantes Imunológicos , Animais , Cromatografia Líquida , Diabetes Mellitus/epidemiologia , Etanol , Frutas , Interleucina-12 , Camundongos , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Espectrometria de Massas em Tandem , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia
20.
Pak J Biol Sci ; 25(8): 725-731, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36098198

RESUMO

<b>Background and Objective:</b> Immune complexes and pro-inflammatory cytokines deduced from communicable diseases have been manifested to induce pro coagulopathy and tissue factor (TF) assertion in macrophages and the endothelial cells that remain at critical risk in tuberculosis (TB) patients. The current study was carried out among Sudanese patients with Pulmonary tuberculosis aimed to determine the long-term impacts of Tb infection on the coagulation cascade. <b>Materials and Methods:</b> A cross-sectional study was conducted among 30 patients who are already diagnosed with tuberculosis compared with the control group. Pulmonary Tuberculosis diagnosis of cases was emphasized in accordance with clinical examination, chest X-ray and positive Ziehl-Neelsen (ZN) smear. The questionnaire was used for the collection of demographic and baseline data. About 2.5 mL of venous blood was collected in trisodium citrate containers and 2.5 mL of blood was collected in EDTA container. SPSS version 21 statistical software was used for statistical analysis. <b>Results:</b> PLT count showed a significant difference (p = 0.03) with a mean (329.20×10<sup>3</sup> and 287.60×10<sup>3</sup> µL<sup></sup><sup>1</sup>) among patients and control, respectively. APPT shows a significant difference (p = 0.00), Mean of PLT decreased as the disease progressed (336.20±36.02, 345.43±16.02, 511.04±42.02) showed a significant correlation between PLT count of test and duration of disease (p = 0.00). Additionally, a significant correlation between PLT count, MPV and APTT and the status of the patient's drug resistance was revealed (p<u><</u>0.02, 0.01 and 0.02). <b>Conclusion:</b> There is a significant alteration in coagulation parameters (PT, APTT and platelets count) among Sudanese pulmonary tuberculosis patients, which may indicate a feature of a hypercoagulable state.


Assuntos
Tuberculose Pulmonar , Tuberculose , Estudos Transversais , Células Endoteliais , Humanos , Mediadores da Inflamação , Escarro , Tromboplastina , Tuberculose Pulmonar/diagnóstico
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