The protective effects of ruscogenin against lipopolysaccharide-induced myocardial injury in septic mice.

ABSTRACT: Sepsis-induced myocardial dysfunction (SIMD) commonly occurs in individuals with sepsis and is a severe complication with high morbidity and mortality rates. The current study aimed to investigate the effects and potential mechanisms of the natural steroidal sapogenin ruscogenin (RUS) against lipopolysaccharide (LPS)-induced myocardial injury in septic mice. We found that RUS effectively alleviated myocardial pathological damage, normalized cardiac function, and increased survival in septic mice. RNA sequencing (RNA-seq) demonstrated that RUS administration significantly inhibited the activation of the NOD-like receptor signaling pathway in the myocardial tissues of septic mice. Subsequent experiments further confirmed that RUS suppressed myocardial inflammation and pyroptosis during sepsis. Additionally, cultured HL-1 cardiomyocytes were challenged with LPS, and we observed that RUS could protect these cells against LPS-induced cytotoxicity by suppressing inflammation and pyroptosis. Notably, both the in vivo and in vitro findings indicated that RUS inhibited NLRP3 upregulation in cardiomyocytes stimulated with LPS. As expected, knockdown of NLRP3 blocked the LPS-induced activation of inflammation and pyroptosis in HL-1 cells. Furthermore, the cardioprotective effects of RUS on HL-1 cells under LPS stimulation were abolished by the novel NLRP3 agonist BMS-986299. Taken together, our results suggest that RUS can alleviate myocardial injury during sepsis, at least in part by suppressing NLRP3-mediated inflammation and pyroptosis, highlighting the potential of this molecule as a promising candidate for SIMD therapy.

Association between a single nucleotide polymorphism of the ALOX5 gene and susceptibility to multisystem tuberculosis in a Chinese Han population.

BACKGROUND: Host genetic single nucleotide polymorphisms can exert an influence susceptibility to tuberculosis infection. Previous investigations have demonstrated an association between the polymorphism in the ALOX5 gene and a range of diseases, encompassing not only noninfectious conditions like asthma, acute myocardial infarction, and cerebral infarction but also infections caused by various pathogens. However, the relationship between ALOX5 gene polymorphism and susceptibility to tuberculosis has received limited research attention. The ALOX5 gene encodes arachidonic acid 5-lipoxygenase(5-LO), which serves as the initiating catalyst in the generation of the inflammatory mediator leukotriene. Leukotrienes, products derived from the 5-LO pathway, are potent proinflammatory lipid mediators that assume a pivotal role in tuberculosis infections.Consequently, ALOX5 gene variants may be intricately associated with the pathogenesis of tuberculosis. In instances where the host exhibits immunocompromisation, infection with Mycobacterium tuberculosis can impact multiple systems. The involvement of multiple systems significantly augments the complexity of treatment and escalates patient mortality rates. Regrettably, the underlying mechanisms driving multisystem tuberculosis pathogenesis remain enigmatic, with clinicians paying scant attention to this aspect. Although the protein encoded by the ALOX5 gene represents a pivotal enzyme that catalyzes the metabolism of arachidonic acid into LXA4, and thereby plays a significant role in the inflammatory response during tuberculosis infection, studies investigating ALOX5 gene polymorphism and its association with susceptibility to multisystem tuberculosis in the Chinese Han population are exceptionally scarce. Therefore, the primary objective of this study is to comprehensively examine the correlation between ALOX5 gene polymorphisms and susceptibility to tuberculosis within the Chinese Han population, with particular emphasis on multisystemic tuberculosis. METHODS: A case‒control study design was employed, encompassing 382 individuals with pulmonary tuberculosis and 367 individuals with multisystemic tuberculosis as the case groups, along with 577 healthy controls.Whole blood DNA was extracted from all patients and healthy controls. Subsequently, three tag polymorphisms (rs2029253, rs7896431, rs2115819) within the ALOX5 gene were selectively identified and genotyped. RESULTS: After adjusting for age and sex, the presence of allele A at rs2029253 exhibited a pronounced association with an elevated risk of TB susceptibility when compared to the tuberculosis group and healthy control group. (ORa: 2.174, 95% CI: 1.827-2.587; Pa<0.001, respectively). Notably, the rs2029253 AG genotype and AA genotype displayed a significantly increased susceptibility to tuberculosis (ORa: 2.236, 95% CI: 1.769-2.825; Pa <0.001 and ORa: 4.577, 95% CI: 2.950-7.100; Pa <0.001, respectively) compared to the GG genotype. Moreover, in the analysis utilizing genetic models, rs2029253 also exhibited a markedly heightened susceptibility to tuberculosis in additive models, dominant models, and recessive models (Pa <0.001). Conversely, no significant association was observed between rs7896431, rs2115819, and tuberculosis. In the subgroup analysis, when comparing the pulmonary tuberculosis group with the healthy control group, we observed no significant disparities in the distribution frequencies of alleles, genotypes, and gene models (additive model, dominant model, and recessive model) for the three tag SNPs, with P-values were >0.05 after adjusting for age and sex. Additionally, we noted that the presence of allele A at rs2029253 was linked to an increased susceptibility to tuberculosis in the multisystemic tuberculosis group relative to the healthy control group (ORa: 2.292, 95% CI: 1.870-2.810; Pa<0.001). Similarly, the rs2029253 AG genotype, AA genotype, and gene models, including the additive model, dominant model, and recessive model, demonstrated a significantly elevated risk of tuberculosis susceptibility. CONCLUSIONS: The polymorphism in the ALOX5 gene is associated with susceptibility to multisystemic tuberculosis in the Chinese Han population.

Association between a single nucleotide polymorphism of the IL23R gene and tuberculosis in a Chinese Han population: a case‒control study.

BACKGROUND: Severe tuberculosis constitutes a significant menace to human safety and well-being, with a considerable mortality rate. The severity of tuberculosis can be impacted by genetic variations in host genes, particularly single nucleotide polymorphisms (SNPs). METHODS: A case‒control study was undertaken, encompassing a cohort of 1137 tuberculosis patients (558 with severe tuberculosis and 579 with mild tuberculosis), alongside 581 healthy controls within the age range of fifteen to forty-five years. Whole blood DNA was extracted from all participants, and three tag polymorphisms (rs1884444, rs7518660, rs7539625) of the IL23R gene were selectively identified and genotyped. RESULTS: No significant correlation was observed between the IL23R gene polymorphisms (rs1884444, rs7518660, and rs7539625) and tuberculosis. Upon comparing the tuberculosis group with the healthy control group, the mild tuberculosis group with the healthy control group, and the severe tuberculosis group with the healthy control group, the obtained P-values were> 0.05. However, in the comparison between severe tuberculosis and mild tuberculosis, the presence of rs1884444 G alleles exhibited a significantly increased risk of severe tuberculosis after adjusting for age and sex (ORa: 1.199, 95% CI: 1.009-1.424; Pa=0.039, respectively). In subgroup analysis, after accounting for confounding factors, including age and sex, rs1884444 G alleles continued to demonstrate a significantly heightened risk of severe tuberculosis. Nonetheless, the comparison between the multisystemic tuberculosis group and the mild tuberculosis group was no significant difference. Notably, rs1884444 of the IL23R gene exhibited a noteworthy association with the risk of severe tuberculosis in the comparison between severe tuberculosis and mild tuberculosis before and after adjusting for age and sex (ORa: 1.301, 95% CI: 1.030-1.643; Pa=0.027, respectively). Furthermore, the presence of the rs1884444 G allele exhibited a significantly increased risk of severe tuberculosis after adjusting for age and sex in the comparison between tuberculous meningitis and mild tuberculosis (ORa: 1.646, 95% CI: 1.100-2.461; Pa=0.015, respectively). CONCLUSIONS: The present study suggests that there is no significant association between IL23R gene polymorphism and tuberculosis susceptibility in the Chinese Han population. However, it does indicate a potential link between IL23R polymorphism and an increased risk of developing severe tuberculosis.

Impacts of clofazimine on the treatment outcomes of drug-resistant tuberculosis.

BACKGROUND: The purpose of this research was to evaluate the effect of clofazimine on drug-resistant tuberculosis treatment outcomes. METHODS: A systematic search was conducted in the PubMed, Web of Science and EMBASE databases to identify eligible studies published up to July 10, 2021. The search terms were as follows: "clofazimine," "tuberculosis," "multidrug resistant tuberculosis" or "extensively drug resistant tuberculosis" and their synonyms or similar words. Two researchers independently screened the titles, abstracts, and full texts for inclusion. Meta-analysis was performed with Stata version 16.0 (Stata Corp., College Station, Texas, USA). Risk ratios (RRs) with 95% CIs were calculated to evaluate the treatment outcome. RESULTS: Eight studies including 3219 participants were included in the meta-analysis. The meta-analysis found that the rates of treatment completion was higher in patients receiving clofazimine-containing regimens than in those not receiving clofazimine-containing regimens (RR: 1.185 (1.060-1.325), P = 0.003). Significant reduction in treatment failure (RR: 0.598 (0.473-0.756), P < 0.001) was found in the clofazimine treatment group. The subgroup analyses of randomized controlled trials (RCTs) found a higher rates of favorable outcomes, treatment completion and cure in the clofazimine group than in the control group (RR: 1.203 (1.029-1.407), P = 0.020; RR: 3.167 (2.043-4.908), P < 0.001; and RR: 1.251 (1.031-1.518), P = 0.023, respectively). Patients receiving clofazimine had a lower risk of treatment failure than those not receiving clofazimine (RR: 0.529 (0.454-0.616), P < 0.001). However, clofazimine treatment did not have a statistically significant effect on all-cause mortality in RCTs. CONCLUSIONS: This study demonstrated that compared with patients who do not receive clofazimine, this drug has the potential to achieve a higher favorable outcome, treatment completion and cure rates, and a lower treatment failure risk among drug-resistant tuberculosis cases.

Urine metabolomics and microbiome analyses reveal the mechanism of anti-tuberculosis drug-induced liver injury, as assessed for causality using the updated RUCAM: A prospective study.

Background: Anti-tuberculosis drug-induced liver injury (ATB-DILI) is one of the most common adverse reactions that brings great difficulties to the treatment of tuberculosis. Thus, early identification of individuals at risk for ATB-DILI is urgent. We conducted a prospective cohort study to analyze the urinary metabolic and microbial profiles of patients with ATB-DILI before drug administration. And machine learning method was used to perform prediction model for ATB-DILI based on metabolomics, microbiome and clinical data. Methods: A total of 74 new TB patients treated with standard first-line anti-TB treatment regimens were enrolled from West China Hospital of Sichuan University. Only patients with an updated RUCAM score of 6 or more were accepted in this study. Nontargeted metabolomics and microbiome analyses were performed on urine samples prior to anti-tuberculosis drug ingestion to screen the differential metabolites and microbes between the ATB-DILI group and the non-ATB-DILI group. Integrating electronic medical records, metabolomics, and microbiome data, four machine learning methods was used, including random forest algorithm, artificial neural network, support vector machine with the linear kernel and radial basis function kernel. Results: Of all included patients, 69 patients completed follow-up, with 16 (23.19%) patients developing ATB-DILI after antituberculosis treatment. Finally, 14 ATB-DILI patients and 30 age- and sex-matched non-ATB-DILI patients were subjected to urinary metabolomic and microbiome analysis. A total of 28 major differential metabolites were screened out, involving bile secretion, nicotinate and nicotinamide metabolism, tryptophan metabolism, ABC transporters, etc. Negativicoccus and Actinotignum were upregulated in the ATB-DILI group. Multivariate analysis also showed significant metabolic and microbial differences between the non-ATB-DILI and severe ATB-DILI groups. Finally, the four models showed high accuracy in predicting ATB-DILI, with the area under the curve of more than 0.85 for the training set and 1 for the validation set. Conclusion: This study characterized the metabolic and microbial profile of ATB-DILI risk individuals before drug ingestion for the first time. Metabolomic and microbiome characteristics in patient urine before anti-tuberculosis drug ingestion may predict the risk of liver injury after ingesting anti-tuberculosis drugs. Machine learning algorithms provides a new way to predict the occurrence of ATB-DILI among tuberculosis patients.

Plasma metabolomic and lipidomic alterations associated with anti-tuberculosis drug-induced liver injury.

Background: Anti-tuberculosis drug-induced liver injury (ATB-DILI) is an adverse reaction with a high incidence and the greatest impact on tuberculosis treatment. However, there is a lack of effective biomarkers for the early prediction of ATB-DILI. Herein, this study uses UPLC‒MS/MS to reveal the plasma metabolic profile and lipid profile of ATB-DILI patients before drug administration and screen new biomarkers for predicting ATB-DILI. Methods: A total of 60 TB patients were enrolled, and plasma was collected before antituberculosis drug administration. The untargeted metabolomics and lipidomics analyses were performed using UPLC‒MS/MS, and the high-resolution mass spectrometer Q Exactive was used for data acquisition in both positive and negative ion modes. The random forest package of R software was used for data screening and model building. Results: A total of 60 TB patients, including 30 ATB-DILI patients and 30 non-ATB-DILI subjects, were enrolled. There were no significant differences between the ATB-DILI and control groups in age, sex, smoking, drinking or body mass index (p > 0.05). Twenty-two differential metabolites were selected. According to KEGG pathway analysis, 9 significantly enriched metabolic pathways were found, and both drug metabolism-other enzymes and niacin and nicotinamide metabolic pathways were found in both positive and negative ion models. A total of 7 differential lipid molecules were identified between the two groups. Ferroptosis and biosynthesis of unsaturated fatty acids were involved in the occurrence of ATB-DILI. Random forest analysis showed that the model built with the top 30 important variables had an area under the ROC curve of 0.79 (0.65-0.93) for the training set and 0.79 (0.55-1.00) for the validation set. Conclusion: This study demonstrated that potential markers for the early prediction of ATB-DILI can be found through plasma metabolomics and lipidomics. The random forest model showed good clinical predictive value for ATB-DILI.

Efficacy of bedaquiline in the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) remains a major public health concern worldwide. Bedaquiline, a novel diarylquinoline, was added to the WHO-recommended all-oral regimen for patients with multidrug-resistant tuberculosis. We performed a systematic review and meta-analysis to determine the effect of bedaquiline on tuberculosis treatment outcomes. METHODS: We searched the PubMed, Web of Science and EMBASE databases for relevant studies published up to March 12, 2021. We included studies in which some participants received bedaquiline and others did not. Stata version 16.0 (Stata Corp., College Station, Texas, USA) was used to analyze the results of the meta-analysis. Risk ratios (RRs) with 95% confidence intervals (95% CIs) were calculated to evaluate the effect of bedaquiline on drug-resistant tuberculosis. Between-study heterogeneity was examined by the I-squared test. Randomized controlled trials were assessed for quality using the Jadad scale, and cohort studies were assessed using the Newcastle-Ottawa scale. RESULTS: Eight studies, including 2 randomized controlled trials and 6 cohort studies involving a total of 21,836 subjects, were included. When compared with the control, bedaquiline treatment was associated with higher rates of culture conversion (risk ratio (RR):1.272 (1.165-1.389), P < 0.001). We found substantial evidence of a significant reduction in all-cause death (RR: 0.529 (0.454-0.616), P < 0.001)) in the bedaquiline treatment group. There was no significant reduction in treatment success (RR = 0.980 (0.948-1.013, P = 0.234)). CONCLUSIONS: This study demonstrated that compared with patients who do not receive bedaquiline, this drug has the potential to achieve a higher culture conversion rate and a lower mortality risk among drug-resistant tuberculosis cases.

Genetic association of TOLLIP gene polymorphisms and HIV infection: a case-control study.

BACKGROUND: Previous studies have indicated that host genetic factors play an essential role in immunity to human immunodeficiency virus (HIV) infection. We aimed to investigate the association between the toll-interacting protein (TOLLIP) and mannose-binding lectin 2 (MBL2) genes and HIV infection susceptibility among Chinese Han patients. METHODS: This is a case-control study. A total of 435 HIV-infected patients and 1013 seronegative healthy individuals were recruited. DNA was extracted from whole blood. Two SNPs in the MBL2 gene (rs7096206 and rs1800450) and three SNPs in the TOLLIP gene (rs5743899, rs3750920, and rs5743867) were selected and genotyped using a SNPscan Kit (Cat#: G0104, Genesky Biotechnologies Inc., Shanghai, China). Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated using unconditional binary logistic regression. RESULTS: A significant association between the minor alleles rs5743899 (C allele) and rs5743867 (G allele) in the TOLLIP gene and susceptibility to HIV infection was found in this study after adjusting for age and sex (Pa = 0.011 and < 0.001, respectively). The rs5743867 in the TOLLIP gene was significantly associated with the risk of HIV infection in dominant, recessive, and additive models when adjusted for age and sex (Pa < 0.05). No significant association was found between MBL2 gene polymorphisms and HIV infection. CONCLUSION: Our study found a statistically significant association between the two SNPs (rs5743867 and rs5743899) in the TOLLIP gene and susceptibility to HIV infection in a Chinese Han population.

Treatment outcomes of tuberculous meningitis in adults: a systematic review and meta-analysis.

BACKGROUND: Tuberculous meningitis is the most devastating presentation of disease with Mycobacterium tuberculosis. We sought to evaluate treatment outcomes for adult patients with this disease. METHODS: The Ovid MEDLINE, EMBASE, Cochrane Library and Web of Science databases were searched to identify all relevant studies. We pooled appropriate data to estimate treatment outcomes at the end of treatment and follow-up. RESULTS: Among the articles identified, 22 met our inclusion criteria, with 2437 patients. In a pooled analysis, the risk of death was 24.7% (95%CI: 18.7-31.9). The risk of neurological sequelae among survivors was 50.9% (95%CI: 40.2-61.5). Patients diagnosed in stage III or human immunodeficiency virus (HIV) positive were significantly more likely to die (64.8, 53.4% respectively) during treatment. The frequency of cerebrospinal fluid (CSF) acid-fast-bacilli smear positivity was 10.0% (95% CI 5.5-17.6), 23.8% (15.2-35.3) for CSF culture positivity, and 22.3% (17.8-27.5) for CSF polymerase chain reaction positivity. We found that the headache, fever, vomiting, and abnormal chest radiograph were the most common symptoms and diagnostic findings among tuberculous meningitis patients. CONCLUSIONS: Despite anti-tuberculosis treatment, adult tuberculous meningitis has very poor outcomes. The mortality rate of patients diagnosed in stage III or HIV co-infection increased significantly during treatment.

Functional study of the association of CHI3L1 polymorphisms with asthma susceptibility in the Southwest Chinese Han population.

Background: Chitinase 3-like 1 (CHI3L1) is involved in the Th2 cell mediated pathway, tissue remodeling and fibrosis. Correlations of CHI3L1 gene polymorphisms with asthma in previous studies have been inconsistent. The present study was designed to investigate the association between CHI3L1 polymorphisms and asthma in the southwest Chinese Han population. Methods: Two single nucleotide polymorphisms (SNPs), rs4950928 and rs10399931, were genotyped in 410 asthma patients and 418 healthy controls from Southwest China. Dual-luciferase reporter gene analysis was performed to detect allele-dependent promoter activity of CHI3L1 variants in HEK293 cells. Real-time quantitative PCR was applied to detect the relative mRNA expression associated with different genotypes of CHI3L1 rs10399931. A meta-analysis was performed using data collected from previously published reports and the present study. Results: No significant association was found between rs4950928 and asthma. The rs10399931 CT/TT genotype increased the risk of asthma under the dominant model (P = 0.031, OR = 1.428, 95% CI, 1.033-1.974), while the CT genotype showed the same tendency under the heterozygous model (P = 0.003, OR = 1.680, 95% CI, 1.186-2.380). No statistically significant difference was found between alleles T and C of rs10399931in the dual-luciferase reporter gene analysis (P = 0.201). The rs10399931 CT/TT genotypes reduced the relative mRNA expression detected by real-time quantitative PCR (P = 0.002). There was no significant association between the CHI3L1 rs4950928 polymorphism and the risk of asthma in the meta-analysis. Conclusion: In the southwest Chinese Han population, the CHI3L1 rs10399931 CT/TT genotypes may increase the risk of asthma. rs10399931 may be a functional variant of CHI3L1 due to its effect on mRNA expression.

Abbott RealTime MTB and MTB RIF/INH assays for the diagnosis of tuberculosis and rifampicin/isoniazid resistance.

BACKGROUND: The Abbott RealTime MTB (Abbott-RT) and Abbott RealTime MTB RIF/INH Resistance (Abbott-RIF/INH) assays have been introduced for the detection of tuberculosis (TB) and drug-resistant tuberculosis (DR-TB). We performed a systematic review and meta-analysis to assess the accuracy of Abbott-RT and Abbott-RIF/INH for the detection of TB and DR-TB. METHODS: The Ovid MEDLINE, EMBASE, Cochrane and Web of Science databases were searched to identify eligible articles for the systematic review. The pooled analyses were calculated with a bivariate model. Hierarchical summary receiver operating characteristic curves and the area under the curve (AUC) were used to summarize overall diagnostic performance. Deeks' test was performed to evaluate potential publication bias. RESULTS: For the Abbott-RT assay, 9 studies including 3, 640 patients met the study criteria. The pooled sensitivity of Abbott-RT for detecting TB was 0.96 (95% CI: 0.88-0.99) and specificity was 0.97 (95% CI: 0.93-0.99). For DR-TB, four studies were included to evaluate the diagnosis accuracy of Abbott-RIF/INH. The pooled sensitivity was 0.88 (95% CI, 0.82-0.93) and specificity was 0.99 (95% CI, 0.96-0.99). No publication bias was found. CONCLUSION: Both Abbott-RT and Abbott-RIF/INH assays have good sensitivity, specificity and accuracy for the diagnosis of TB and DR-TB.

Polymorphisms of cytokine genes and tuberculosis in two independent studies.

Cytokine gene single nucleotide polymorphisms (SNPs) can influence cytokine levels, which may be associated with tuberculosis (TB) susceptibility. There is evidence that interleukin 1B (IL1B), tumor necrosis factor-alpha (TNF-alpha), and IL6 may be involved in the progression of TB. Using a self-validating case-control design, we selected eleven functional SNPs in IL1B, TNF and IL6 to detect their association with TB in Chinese Han and Tibetan populations. The associations between SNPs and TB were estimated by computing the odds ratios (ORs) and 95% confidence intervals (95% CI) using logistic regression analyses. We found that the IL1B rs16944 polymorphism was associated with decreased risk of TB in the two studies. The G allele at rs2069837 of IL6 was significantly more common in controls than in TB patients in the Han population. Moreover, TNF rs1799964 and rs1800630 were risk factors for susceptibility to TB, which were validated in the Chinese Tibetan population. In addition, TNF rs1799724 and rs1800629 were associated with TB, but only in the Tibetan population. In conclusion, SNPs of the IL1B and TNF gene were associated with TB susceptibility in Chinese Han and Tibetan populations. IL6 polymorphism may be considered as a protective factor for TB in the Chinese Han population, but not the Tibetan population.

Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity.

A combination therapy of multiple drugs including isoniazid, rifampicin, ethambutol and pyrazinamide has been proven to be an effective option for the vast majority of tuberculosis (TB) patients. However, various adverse drug reactions (ADRs) limit its merit, with anti-TB drug-induced hepatotoxicity (ATDH) being a common and sometimes severe ADR. This study aimed to investigate the association between polymorphisms in two nuclear receptor genes, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), and the risk of ATDH in a Chinese population. Subjects with or without hepatotoxicity during anti-TB treatment were recruited. DNA was extracted from peripheral blood and genotypes of the selected single nucleotide polymorphisms (SNPs) were determined by using the improved multiplex ligation detection reaction technique. Three genetic models (additive, dominant, and recessive) as well as haplotype, SNP-SNP interaction analyses were used to evaluate the genetic risk of ATDH. A total of 502 subjects (203 ATDH and 299 non-ATDH) were enrolled. The results showed that the minor allele of rs7643645 and the H0010001 haplotype in PXR were associated with decreased risk of ATDH, suggesting that drug-metabolizing enzymes regulated by PXR are involved in the pathogenesis of ATDH. More studies are required to verify this result.

Association of TLR8 and TLR9 polymorphisms with tuberculosis in a Chinese Han population: a case-control study.

BACKGROUND: Toll-like receptor (TLR) single nucleotide polymorphisms (SNPs) have been associated with regulation of TLR expression and development of active tuberculosis (TB). The objectives of this study were to determine whether TLR8 and TLR9 SNPs were associated with the development of latent TB infection (LTBI) and the subsequent pulmonary TB (PTB) in a Chinese Han population. METHODS: Two independent samples were enrolled. The first sample contained 584 TB cases and 608 controls; the second sample included 204 healthy controls, 201 LTBI subjects and 209 bacteria-confirmed active PTB patients. Three SNPs (rs3764880, rs187084 and rs5743836) were genotyped. The associations between the SNPs and risk of LTBI or PTB were investigated using unconditional logistic regression analysis. RESULTS: The A-allele of TLR8 rs3764880 SNP was protective against the development of TB in males (A vs G, OR = 0.58, 95%CI = 0.37-0.91). The AA genotype of rs3764880 SNP was found to increase the risk of PTB among females with an OR of 4.81 (1.11-20.85). The G allele of TLR9 SNP rs187084 was found to increase the risk of PTB (G vs A, P = 0.01, OR = 1.48, 95% CI = 1.10-2.00), the significance was also observed under dominant genetic models. The GA-genotype of TLR9 rs187084 SNP was found to increase the risk of PTB with an OR of 1.68 (1.07-2.65), but was found to decrease the risk of MTB infection with an OR = 0.64 (0.41-0.98). TLR9_rs5743836 SNP was excluded from the data analyses, because the minimum allele frequency was< 1%. CONCLUSIONS: Our findings in two independent samples indicated that SNPs in TLR8 and TLR9 were associated with the development of TB, and highlight that SNPs may have different effects on disease pathogenesis and progression.

Reversible recurrent profound thrombocytopenia due to linezolid in a patient with multi-drug resistant tuberculosis: A case report.

RATIONALE: Thrombocytopenia caused by linezolid (LZD) is common, with a reported prevalence as high as 11.8%. Platelets typically reach normal levels 7 days after LZD withdrawal. However, recurrent profound thrombocytopenia due to LZD usage and a persistent profound drop in platelet count after LZD withdrawal have not been reported. PATIENT CONCERNS: We report a case of a 75-year-old woman, who presented with recurrent profound thrombocytopenia induced by LZD treatment for multidrug-resistant tuberculosis (MDR-TB). DIAGNOSES: Laboratory data and symptoms during and after LZD usage and reusage indicated severe thrombocytopenia. INTERVENTIONS: LZD was discontinued due to recurrent thrombocytopenia and the platelet count continued to drop for 9 days and returned to normal gradually 16 days after LZD withdrawal and supportive care including platelet transfusion. OUTCOMES: There was no recurrence of thrombocytopenia during 10 months of follow-up during treatment for MDR-TB with a regimen without LZD. LESSONS: Recurrent profound thrombocytopenia can happen after several doses of LZD rechallenging. Therefore, reuse of LZD should be avoided after recovery from severe thrombocytopenia due to LZD.

Association between tobacco smoking and drug-resistant tuberculosis.

BACKGROUND: Tobacco smoking is a risk factor for tuberculosis but little is known about the relationship between tobacco smoking and drug-resistant tuberculosis (DR-TB). We undertook a systematic review and meta-analysis to quantitatively assess the association between DR-TB and tobacco smoking. METHODS: We searched for relevant studies in the Ovid MEDLINE, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, WANFANG, and WEIPU data-bases from inception to September 1, 2017. Results were expressed as odds ratios (ORs) with accompanying 95% CIs, and subgroup analyses were performed by study design, smoking type, DR-TB type, and multivariate analysis. RESULTS: Thirty-three studies related to tobacco smoking and DR-TB were included. We found substantial evidence that tobacco smoking is associated with an increased risk of DR-TB (OR 1.57, 95% CI 1.33-1.86). Associations were also found in subgroup analyses: for multidrug-resistant tuberculosis (OR 1.49, 95% CI 1.19-1.86) and for any DR-TB (OR 1.70, 95% CI 1.3-2.23); the pooled OR was 1.45 (95% CI 1.11-1.90) for current smoking, 2.25 (95% CI 1.46-3.47) for past smoking, and 1.56 (95% CI 1.22-1.98) for smoking history; and similar ORs were also observed in study design and multivariate analysis subgroup analysis. CONCLUSION: This study demonstrated that tobacco smoking is an independent risk factor for DR-TB.

Polymorphisms in Toll-Like Receptor 10 and Tuberculosis Susceptibility: Evidence from Three Independent Series.

Background: The toll-like receptor 2 (TLR2)-mediated immune response is critical for host defense against Mycobacterium tuberculosis. There is evidence that TLR10, a TLR2 signaling modulator, may be involved in progression of tuberculosis (TB). Methods: Using a self-validating case-control design, we tested for an association between seven TLR10 polymorphisms and susceptibility to TB in three independent series with two distinct populations. Single-nucleotide polymorphism (SNP) genotypes were determined by the SNPscanTM method. Three genetic models (additive, dominant, and recessive) as well as multiple-SNP score analyses were used to evaluate the risk of TB associated with the TLR10 SNPs. Results: By comparing TB patients with healthy controls, we observed two SNPs (rs11466617 and rs4129009) that were associated with decreased risk of TB in the Tibetan population, but did not in the Chinese Han population. Further analysis demonstrated that the rs11466617 Chengdu cohort genotype served as a protective factor against the progression of latent TB infection (LTBI) to active TB under the recessive model. None of the SNPs were significantly different in comparisons of TB-uninfected people with LTBI individuals. Additionally, when the underlying four TB-associated loci were considered together in a multiple-SNP score analysis, we observed an allele dose-dependent decrease in TB risk in Tibetans. Conclusion: Variants of TLR10 may show an ethnic specificity on susceptibility to TB in Tibetan individuals. rs11466617 affected the susceptibility to progress from LTBI to active TB disease, but was not associated with the establishment of LTBI after M. tuberculosis exposure. More studies are needed to verify this genetic epidemiological result and unravel the role of TLR10 SNPs in the pathogenesis of TB.

Bone marrow granulomas in a high tuberculosis prevalence setting: A clinicopathological study of 110 cases.

Granulomas were reported in 0.3% to 3% of bone marrow biopsies. The aim of the study was to evaluate the incidence and etiology of bone marrow granulomas (BMGs) in the West China Hospital, which located at a high tuberculosis (TB) prevalence area in China.A retrospective case review was performed on 11,339 bone marrow biopsies at the West China Hospital of Sichuan University between January 2011 and December 2015. Cases with BMGs were retrieved and their clinical data and histopathological features were collected, examined, and analyzed.Out of 11,339, 110 cases showed granulomatous lesions in the bone marrow biopsies (0.97%). Etiologies were indentified in 80 cases (72.8%), with infections being the most common (64.5%), following by malignancies (4.5%) and autoimmune diseases (3.6%). Among infectious cases, 87.32% (62/71) cases were diagnosed as TB, a positive acid-fast stain or/and polymerase chain reaction (PCR) result for mycobacterium TB DNA fragment amplification was obtained for 35 cases. In 30 cases (27.27%), a definite diagnosis could not be established.In a TB high prevalence region in China, with a combined histological, clinical, serological, and molecular approach, we were able to clarify the cause in 72.73% of the bone marrow granulomatous cases. TB is the most common underlying etiologies. Therefore, acid-fast stain and quantitative PCR for mycobacterium TB DNA amplification are recommended as a routine for bone marrow biopsies in TB high prevalence regions.

[Association of rs1495741 Single Nucleotide Polymorphism with Susceptibility of Anti-tuberculosis Drug-induced Hepatotoxicity].

OBJECTIVE: To investigate the potential association between the polymorphism of N- acetyltransferase 2 (NAT2) gene and anti-tuberculosis drug-induced hepatotoxicity (ATDH) in Han population. METHODS: The SNP rs1495741 was genotyped by using multiplex ligation detection reaction (MLDR) technique, and logistic regression analysis was used to analyze the association between this SNP and the susceptibility of ATDH. RESULTS: There were 247 PTB patients enrolled in this study, including 24 ATDH, and 223 controls (PTB without ATDH). No significant difference in genotype and allele distribution was observed for rs1495741 in NAT2 between the controls and ATDH group. After adjusting age, sex, body mass index (BMI) and smoking history, the SNP of rs1495741 showed a significant association with ATDH 〔odds ratio (OR)=2.728 (95% confidence interval: 1.022-7.281)〕 under recessive model (AA vs. GA+GG). CONCLUSIONS: The rs1495741 in NAT2 seems related to the development of ATDH among PTB patients, AA genotype of rs1495741 may be a causative factor for increased susceptibility to ATDH.

Macrolide-resistant Mycoplasma pneumoniae prevalence and clinical aspects in adult patients with community-acquired pneumonia in China: a prospective multicenter surveillance study.

BACKGROUND: Drug resistant Mycoplasma pneumoniae (MP) is a rising issue in the management of community-acquired pneumonia (CAP). Epidemiological monitoring is essential for identifying resistant patterns of MP isolates against various antibiotics in adult CAP patients. METHODS: This is a prospectively designed multicenter study conducted on adult patients with CAP visiting six teaching hospitals in the cities of Beijing, Shanghai and Guangzhou between September 2010 and June 2012. RESULTS: A total of 520 adult patients (mean age: 45.7±26.2 years) with CAP visiting teaching hospitals in the cities of Beijing, Shanghai and Guangzhou were included. Of the 520 patients, only 75 (14.42%) were confirmed MP positive by means of culture and real-time PCR methods. Quinolones were the most common initially prescribed antimicrobial, followed by ß-lactams and ß-lactams plus quinolones. Macrolide resistance was as high as 80% and 72% against erythromycin (ERY) and azithromycin (AZM) respectively, which were associated with the A2063G transition mutation in domain V of the 23S ribosomal RNA (rRNA) gene. Six strains with mild to moderate ERY-resistant level were still susceptible to AZM. Tetracycline (TET), minocycline (MIN) and quinolones [moxifloxacin (MOX) and fluoroquinolones] had no signs of resistance. CONCLUSIONS: High resistance was observed with macrolides, whereas, none of the MP strains were resistant to fluoroquinolones and TET. Hence, macrolide resistant MP (MRMP)_infections could be well treated with fluoroquinolones. However, few isolated strains had minimal inhibitory concentration (MIC) values on the edge of resistance to quinolones, alarming a quinolone-resistant MP in the near future.