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Sample records for active tuberculosis disease

  1. Increased Complement C1q Level Marks Active Disease in Human Tuberculosis

    PubMed Central

    Zhang, Mingxia; Liu, Haiying; Zhang, Guoliang; Deng, Qunyi; Huang, Jian; Gao, Zhiliang; Zhou, Boping; Feng, Carl G.; Chen, Xinchun

    2014-01-01

    Background Complement functions as an important host defense system and complement C5 and C7 have been implicated in immunopathology of tuberculosis. However, little is known about the role of other complement components in tuberculosis. Methods Complement gene expression in peripheral blood mononuclear cells of tuberculosis patients and controls were determined using whole genome transcriptional microarray assays. The mRNA and protein levels of three C1q components, C1qA, C1qB, and C1qC, were further validated by qRT-PCR and enzyme-linked immunosorbent assay, respectively. The percentages of C1q expression in CD14 positive cells were determined by flow cytometry. Finally, C1qC protein level was quantified in the pleural fluid of tuberculosis and non-tuberculosis pleurisy. Results C1q expression increases significantly in the peripheral blood of patients with active tuberculosis compared to healthy controls and individuals with latent TB infection. The percentage of C1q-expressing CD14 positive cells is significantly increased in active TB patients. C1q expression in the peripheral blood correlates with sputum smear positivity in tuberculosis patients and is reduced after anti-tuberculosis chemotherapy. Notably, receiver operating characteristic analysis showed that C1qC mRNA levels in peripheral blood efficiently discriminate active from latent tuberculosis infection and healthy controls. Additionally, C1qC protein level in pleural effusion shows improved power in discriminating tuberculosis from non-tuberculosis pleurisy when compared to other inflammatory markers, such as IL-6 and TNF-α. Conclusions C1q expression correlates with active disease in human tuberculosis. C1q could be a potential diagnostic marker to discriminate active tuberculosis from latent tuberculosis infection as well as tuberculosis pleurisy from non-tuberculosis pleurisy. PMID:24647646

  2. High Incidence of Tuberculosis Infection in Rheumatic Diseases and Impact for Chemoprophylactic Prevention of Tuberculosis Activation during Biologics Therapy

    PubMed Central

    Bai, Fengmin; Zhang, Shu; Jiang, Ting; Shen, Jie; Zhu, Qi; Yue, Tao; Shao, Lingyun; Gao, Yan; Feng, Yun; Weng, Xinhua; Zou, Hejian; Zhang, Ying

    2013-01-01

    We conducted a long-term follow-up study in patients with rheumatic diseases who were candidates for biologics treatment to evaluate the effects of biologic agents on the risk of tuberculosis infection and the effect of prophylactic treatment on tuberculosis activation. One hundred one patients with rheumatic diseases who were candidates for biologics treatment were recruited, and 57 healthy subjects were recruited as controls. Tuberculin skin test (TST) and the T-SPOT.TB test were performed for all subjects at baseline. Follow-up testing by the T-SPOT.TB assay was performed every 6 months in patients with rheumatic diseases and at 2 years of recruitment in the healthy controls. In patients with rheumatic diseases and healthy controls, the TST-positive (induration, ≥10 mm) rates were 37.6% (38/101) and 34.0% (18/53), respectively (P > 0.05), while the T-SPOT.TB-positive rates were 46.5% (47/101) and 21.1 (12/57), respectively (P = 0.0019). Fifty-two patients were followed up at month 6 with a T-SPOT.TB-positive rate of 40.4%, and 49 were followed up for ≥12 months with a T-SPOT.TB-positive rate of 36.7%, with no significant difference in the positive rate at different time points including baseline (P > 0.05). Long-term follow-up revealed that conversion to T-SPOT.TB positivity occurred only in the biologics treatment group, with a positive conversion rate of 11.2% (4/38). Most importantly, no latent tuberculosis developed into active tuberculosis during follow-up with T-SPOT.TB screening and preemptive treatment with isoniazid. Biologics treatment appears to increase the risk of tuberculosis infection. However, tuberculosis activation could be prevented by preemptive isoniazid treatment in patients with latent tuberculosis infection while receiving biologics therapy. PMID:23554465

  3. Tuberculosis and Cardiovascular Disease: Linking the Epidemics

    PubMed Central

    Huaman, Moises A.; Henson, David; Ticona, Eduardo; Sterling, Timothy R.; Garvy, Beth A.

    2016-01-01

    The burden of tuberculosis and cardiovascular disease (CVD) is enormous worldwide. CVD rates are rapidly increasing in low- and middle-income countries. Public health programs have been challenged with the overlapping tuberculosis and CVD epidemics. Monocyte/macrophages, lymphocytes and cytokines involved in cellular mediated immune responses against Mycobacterium tuberculosis are also main drivers of atherogenesis, suggesting a potential pathogenic role of tuberculosis in CVD via mechanisms that have been described for other pathogens that establish chronic infection and latency. Studies have shown a pro-atherogenic effect of antibody-mediated responses against mycobacterial heat shock protein-65 through cross reaction with self-antigens in human vessels. Furthermore, subsets of mycobacteria actively replicate during latent tuberculosis infection (LTBI), and recent studies suggest that LTBI is associated with persistent chronic inflammation that may lead to CVD. Recent epidemiologic work has shown that the risk of CVD in persons who develop tuberculosis is higher than in persons without a history of tuberculosis, even several years after recovery from tuberculosis. Together, these data suggest that tuberculosis may play a role in the pathogenesis of CVD. Further research to investigate a potential link between tuberculosis and CVD is warranted. PMID:26835156

  4. Infectious Diseases (ID) Learning Unit: How Rapidly to Evaluate for Active Tuberculosis Disease in Low-Prevalence Settings.

    PubMed

    Chida, Natasha; Shah, Maunank

    2016-03-01

    With declining tuberculosis (TB) incidence in low-prevalence settings, many clinicians are likely unaware that the approach to diagnosing active TB is evolving with newer technologies. Rapid molecular assays are commercially available, and more are likely to enter the market in the coming years. These tests, such as the Xpert MTB/RIF, which can detect TB and drug-resistance in 2 hours, are increasingly used in settings with higher TB prevalence; however, uptake has been slower in low-prevalence settings. Newer algorithms incorporating rapid TB diagnostics have the ability to alter current clinical and infection control practice patterns. In this learning unit, we review current and newly available tests for the detection of active TB disease and their usage in low-prevalence settings. PMID:27186583

  5. Infectious Diseases (ID) Learning Unit: How Rapidly to Evaluate for Active Tuberculosis Disease in Low-Prevalence Settings

    PubMed Central

    Chida, Natasha; Shah, Maunank

    2016-01-01

    With declining tuberculosis (TB) incidence in low-prevalence settings, many clinicians are likely unaware that the approach to diagnosing active TB is evolving with newer technologies. Rapid molecular assays are commercially available, and more are likely to enter the market in the coming years. These tests, such as the Xpert MTB/RIF, which can detect TB and drug-resistance in 2 hours, are increasingly used in settings with higher TB prevalence; however, uptake has been slower in low-prevalence settings. Newer algorithms incorporating rapid TB diagnostics have the ability to alter current clinical and infection control practice patterns. In this learning unit, we review current and newly available tests for the detection of active TB disease and their usage in low-prevalence settings. PMID:27186583

  6. Blood or Urine IP-10 Cannot Discriminate between Active Tuberculosis and Respiratory Diseases Different from Tuberculosis in Children

    PubMed Central

    Petrone, Linda; Cannas, Angela; Aloi, Francesco; Nsubuga, Martin; Sserumkuma, Joseph; Nazziwa, Ritah Angella; Jugheli, Levan; Lukindo, Tedson; Girardi, Enrico; Reither, Klaus; Goletti, Delia

    2015-01-01

    Objectives. Interferon-γ inducible protein 10 (IP-10), either in blood or in urine, has been proposed as a tuberculosis (TB) biomarker for adults. This study aims to evaluate the potential of IP-10 diagnostics in children from Uganda, a high TB-endemic country. Methods. IP-10 was measured in the blood and urine concomitantly taken from children who were prospectively enrolled with suspected active TB, with or without HIV infection. Clinical/microbiological parameters and commercially available TB-immune assays (tuberculin skin test (TST) and QuantiFERON TB-Gold In-Tube (QFT-IT)) were concomitantly evaluated. Results. One hundred twenty-eight children were prospectively enrolled. The analysis was performed on 111 children: 80 (72%) of them were HIV-uninfected and 31 (27.9%) were HIV-infected. Thirty-three healthy adult donors (HAD) were included as controls. The data showed that IP-10 is detectable in the urine and blood of children with active TB, independent of HIV status and age. However, although IP-10 levels were higher in active TB children compared to HAD, the accuracy of identifying “active TB” was low and similar to the TST and QFT-IT. Conclusion. IP-10 levels are higher in children with respiratory illness compared to controls, independent of “TB status” suggesting that the evaluation of this parameter can be used as an inflammatory marker more than a TB test. PMID:26346028

  7. The increased risk of active tuberculosis disease in patients with dermatomyositis – a nationwide retrospective cohort study

    PubMed Central

    Wu, Ping-Hsun; Lin, Yi-Ting; Yang, Yi-Hsin; Lin, Yu-Chih; Lin, Yi-Ching

    2015-01-01

    The risk of active tuberculosis (TB) in patients with dermatomyositis (DM) is poorly understood. The cohort study aimed to investigate the association between DM and the risk of active TB disease. We conducted a population based study on 4,958 patients with newly diagnosed DM and 19,832 matched controls according to age, sex, and index date between 1998 and 2008. The hazard ratios (HRs) and cumulative incidences of active TB disease between DM patients and controls were analyzed. During the study period, a total of 85 (1.7%) DM patients developed active TB disease, which was significantly higher than that of non-DM patients (0.64%). The incidence rate of active TB disease was higher among DM patients than controls (incidence rate ratio 2.95; 95% confidence interval [CI], 2.24 to 3.88). The Cox regression model demonstrated significantly higher active TB disease rate among DM patients compared with controls (adjusted HR, 2.64; 95% CI, 1.97 to 3.54; p < 0.001) after adjusting for age, sex, and underlying medical disorders. The most significant risk factors for developing active TB included male sex, diabetes mellitus comorbidity, and use of corticosteroids and azathioprine in DM patients. In conclusion, DM patients are at a greater risk for active TB disease. PMID:26573418

  8. Hepatitis C Virus Infection Is Associated With an Increased Risk of Active Tuberculosis Disease: A Nationwide Population-Based Study.

    PubMed

    Wu, Ping-Hsun; Lin, Yi-Ting; Hsieh, Kun-Pin; Chuang, Hung-Yi; Sheu, Chau-Chyun

    2015-08-01

    Tuberculosis (TB) and hepatitis C virus (HCV) infection contribute to major disease mortality and morbidity worldwide. However, the causal link between HCV infection and TB risk remains unclear. We conducted a population-based cohort study to elucidate the association between HCV infection and TB disease by analyzing Taiwan National Health Insurance Database. We enrolled 5454 persons with HCV infection and 54,274 age- and sex-matched non-HCV-infected persons between January 1998 and December 2007. Time-dependent Cox proportional hazards regression analysis was used to measure the association between HCV infection and active TB disease. Incidence rate of active TB disease was higher among HCV infection than in control (134.1 vs 89.1 per 100,000 person-years; incidence rate ratio 1.51; P = 0.014). HCV infection was significantly associated with active TB disease in multivariate Cox regression (adjusted hazard ratio [HR] 3.20; 95% confidence interval [CI], 1.85-5.53; P < 0.001) and competing death risk event analysis (adjusted HR 2.11; 95% CI, 1.39-3.20; P < 0.001). Multivariate stratified analysis further revealed that HCV infection was a risk of active TB disease in most strata. This nationwide cohort study suggests that HCV infection is associated with a higher risk of developing active TB disease. PMID:26287416

  9. Tuberculosis: a disease without boundaries.

    PubMed

    Fogel, Nicole

    2015-09-01

    Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis (MTB) that usually affects the lungs leading to severe coughing, fever, and chest pains. Although current research in the past four years has provided valuable insight into TB transmission, diagnosis, and treatment, much remains to be discovered to effectively decrease the incidence of and eventually eradicate TB. The disease still puts a strain on public health, being only second to HIV/AIDS in causing high mortality rates. This review will highlight the history of TB as well as provide an overview of the current literature on epidemiology, pathogenesis and the immune response, treatment, and control of TB. In this race to combat a disease that knows no boundaries, it is necessary to have a conceptual and clear understanding of TB overall with the hope of providing better treatment through novel and collaborative research and public health efforts. PMID:26198113

  10. Latent tuberculosis screening tests and active tuberculosis infection rates in Turkish inflammatory bowel disease patients under anti-tumor necrosis factor therapy

    PubMed Central

    Çekiç, Cem; Aslan, Fatih; Vatansever, Sezgin; Topal, Firdevs; Yüksel, Elif Sarıtaş; Alper, Emrah; Dallı, Ayşe; Ünsal, Belkıs

    2015-01-01

    Background Tumor necrosis factor (TNF)-α inhibitors increase the risk of tuberculosis (TB). The objective of the present study was to determine the rate of active TB infection in inflammatory bowel disease (IBD) patients receiving anti-TNF therapy and to determine the results of their latent TB infection (LTBI) screening tests during the follow up. Methods This is a retrospective observational study of IBD patients receiving anti-TNF therapy. Tuberculin skin test (TST), interferon-γ release assay (IGRA), and chest radiography were used to determine LTBI. Active TB infection rate during anti-TNF treatment was determined. Results Seventy-six IBD patients (25 with ulcerative colitis, 51 with Crohn’s disease; 53 male; mean age 42.0±12.4 years) were included. Forty-four (57.9%) patients received infliximab and 32 (42.1%) adalimumab. Their median duration of anti-TNF therapy was 15 months. Forty-five (59.2%) patients had LTBI and received isoniazid (INH) prophylaxis. During the follow-up period, active TB was identified in 3 (4.7%) patients who were not receiving INH prophylaxis. There was a moderate concordance between the TST and the IGRA (kappa coefficient 0.44, 95% CI 0.24-0.76). Patients with or without immunosuppressive therapy did not differ significantly with respect to TST (P=0.318) and IGRA (P=0.157). Conclusion IBD patients receiving anti-TNF therapy and prophylactic INH have a decreased risk of developing active TB infection. However, despite LTBI screening, the risk of developing active TB infection persists. PMID:25831138

  11. Diagnostic 'omics' for active tuberculosis.

    PubMed

    Haas, Carolin T; Roe, Jennifer K; Pollara, Gabriele; Mehta, Meera; Noursadeghi, Mahdad

    2016-01-01

    The decision to treat active tuberculosis (TB) is dependent on microbiological tests for the organism or evidence of disease compatible with TB in people with a high demographic risk of exposure. The tuberculin skin test and peripheral blood interferon-γ release assays do not distinguish active TB from a cleared or latent infection. Microbiological culture of mycobacteria is slow. Moreover, the sensitivities of culture and microscopy for acid-fast bacilli and nucleic acid detection by PCR are often compromised by difficulty in obtaining samples from the site of disease. Consequently, we need sensitive and rapid tests for easily obtained clinical samples, which can be deployed to assess patients exposed to TB, discriminate TB from other infectious, inflammatory or autoimmune diseases, and to identify subclinical TB in HIV-1 infected patients prior to commencing antiretroviral therapy. We discuss the evaluation of peripheral blood transcriptomics, proteomics and metabolomics to develop the next generation of rapid diagnostics for active TB. We catalogue the studies published to date seeking to discriminate active TB from healthy volunteers, patients with latent infection and those with other diseases. We identify the limitations of these studies and the barriers to their adoption in clinical practice. In so doing, we aim to develop a framework to guide our approach to discovery and development of diagnostic biomarkers for active TB. PMID:27005907

  12. T-Cell Immunophenotyping Distinguishes Active From Latent Tuberculosis

    PubMed Central

    Pollock, Katrina M.; Whitworth, Hilary S.; Montamat-Sicotte, Damien J.; Grass, Lisa; Cooke, Graham S.; Kapembwa, Moses S.; Kon, Onn M.; Sampson, Robert D.; Taylor, Graham P.; Lalvani, Ajit

    2013-01-01

    Background. Changes in the phenotype and function of Mycobacterium tuberculosis (M. tuberculosis)-specific CD4+ and CD8+ T-cell subsets in response to stage of infection may allow discrimination between active tuberculosis and latent tuberculosis infection. Methods. A prospective comparison of M. tuberculosis-specific cellular immunity in subjects with active tuberculosis and latent tuberculosis infection, with and without human immunodeficiency virus (HIV) coinfection. Polychromatic flow cytometry was used to measure CD4+ and CD8+ T-cell subset phenotype and secretion of interferon γ (IFN-γ), interleukin 2 (IL-2), and tumor necrosis factor α (TNF-α). Results. Frequencies of CD4+ and CD8+ cells secreting IFN-γ-only, TNF-α-only and dual IFN-γ/TNF-α were greater in active tuberculosis vs latent tuberculosis infection. All M. tuberculosis-specific CD4+ subsets, with the exception of IL-2-only cells, switched from central to effector memory phenotype in active tuberculosis vs latent tuberculosis infection, accompanied by a reduction in IL-7 receptor α (CD127) expression. The frequency of PPD-specific CD4+ TNF-α-only-secreting T cells with an effector phenotype accurately distinguished active tuberculosis from latent tuberculosis infection with an area under the curve of 0.99, substantially more discriminatory than measurement of function alone. Conclusions. Combined measurement of T-cell phenotype and function defines a highly discriminatory biomarker of tuberculosis disease activity. Unlocking the diagnostic and monitoring potential of this combined approach now requires validation in large-scale prospective studies. PMID:23966657

  13. Clinical features of active tuberculosis that developed during anti-tumor necrosis factor therapy in patients with inflammatory bowel disease

    PubMed Central

    Lee, Jang Wook; Park, Ji Hoon; Kim, Jeong Wook; Kang, Sang Bum; Koo, Ja Seol; Kim, Young-Ho; Kim, You Sun; Joo, Young Eun; Chang, Sae Kyung

    2016-01-01

    Background/Aims Anti-tumor necrosis factor (TNF) therapy for active ulcerative colitis (UC) and Crohn's disease (CD) is associated with increased risks of tuberculosis (TB) infection. We analyzed the incidence and clinical features of Korean patients with inflammatory bowel disease (IBD) who developed active TB during anti-TNF therapy. Methods Ten cases of active TB developed in patients treated with infliximab (n=592) or adalimumab (n=229) for UC (n=160) or CD (n=661) were reviewed. We analyzed demographics, interval between start of anti-TNF therapy and active TB development, tests for latent TB infection (LTBI), concomitant medications, and the details of diagnosis and treatments for TB. Results The incidence of active TB was 1.2% (10/821): 1.5% (9/592) and 0.4% (1/229) in patients receiving infliximab and adalimumab, respectively. The median time to the development of active TB after initiation of anti-TNF therapy was three months (range: 2–36). Three patients had past histories of treatment for TB. Positive findings in a TB skin test (TST) and/or interferon gamma releasing assay (IGRA) were observed in three patients, and two of them received anti-TB prophylaxis. Two patients were negative by both TST and IGRA. The most common site of active TB was the lungs, and the active TB was cured in all patients. Conclusions Active TB can develop during anti-TNF therapy in IBD patients without LTBI, and even in those with histories of TB treatment or LTBI prophylaxis. Physicians should be aware of the potential for TB development during anti-TNF therapy, especially in countries with a high prevalence of TB. PMID:27175115

  14. Tuberculosis

    MedlinePlus

    Tuberculosis (TB) is a disease caused by bacteria called Mycobacterium tuberculosis. The bacteria usually attack the lungs, but they can also damage other parts of the body. TB spreads through the air when a person with ...

  15. Activities of the korean institute of tuberculosis.

    PubMed

    Ryoo, Sungweon; Kim, Hee Jin

    2014-12-01

    The Korean National Tuberculosis Association (KNTA) set up the Korean Institute of Tuberculosis (KIT) in 1970 to foster research and technical activities pertaining to tuberculosis (TB). The KNTA/KIT had successfully conducted a countrywide TB prevalence survey from 1965 to 1995 at 5-year intervals. The survey results (decline in TB rates) established Korea as a country that had successfully implemented national control programs for TB. The KIT developed the Korea Tuberculosis Surveillance System and the Laboratory Management Information System, both of which were transferred to the Korea Centers for Disease Control and Prevention after its establishment. The KIT functions as a central and supranational reference TB laboratory for microbiological and epidemiological research and provides training and education for health-care workers and medical practitioners. Recently, the KIT has expanded its activities to countries such as Ethiopia, Laos, and Timor-Leste to support TB control and prevention. The KIT will continue to support research activities and provide technical assistance in diagnosing the infection until it is completely eliminated in Korea. PMID:25861580

  16. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... active tuberculosis. 3.374 Section 3.374 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS... Considerations Relative to Specific Diseases § 3.374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service department diagnosis of active pulmonary tuberculosis will be accepted unless a board...

  17. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... active tuberculosis. 3.374 Section 3.374 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS... Considerations Relative to Specific Diseases § 3.374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service department diagnosis of active pulmonary tuberculosis will be accepted unless a board...

  18. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... active tuberculosis. 3.374 Section 3.374 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS... Considerations Relative to Specific Diseases § 3.374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service department diagnosis of active pulmonary tuberculosis will be accepted unless a board...

  19. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... active tuberculosis. 3.374 Section 3.374 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS... Considerations Relative to Specific Diseases § 3.374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service department diagnosis of active pulmonary tuberculosis will be accepted unless a board...

  20. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... active tuberculosis. 3.374 Section 3.374 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS... Considerations Relative to Specific Diseases § 3.374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service department diagnosis of active pulmonary tuberculosis will be accepted unless a board...

  1. Tuberculosis: Learn the Signs and Symptoms of TB Disease

    MedlinePlus

    ... What's this? Submit Button Past Emails CDC Features Tuberculosis (TB) Disease: Symptoms & Risk Factors Language: English Español (Spanish) Recommend on Facebook Tweet Share Compartir Tuberculosis (TB) is a disease caused by bacteria that ...

  2. [Guidelines for the diagnosis and treatment of latent tuberculosis infection and active tuberculosis in patients with inflammatory joint diseases proposed for treatment with tumour necrosis factor alpha antagonist drugs].

    PubMed

    Fonseca, João Eurico; Lucas, Helena; Canhão, Helena; Duarte, Raquel; Santos, Maria José; Villar, Miguel; Faustino, Augusto; Raymundo, Elena

    2006-01-01

    The Portuguese Society of Rheumatology (SPR) and the Portuguese Society of Pulmonology (SPP) have developed guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (AT) in patients with inflammatory joint diseases (IJD), namely rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, treated with tumour necrosis factor alpha (TNF-a) antagonists. Due to the high risk of tuberculosis (TB) in patients with IJD, LTBI and AT screening should be performed as soon as possible, ideally at the moment of IJD diagnosis. Even if TB screening was performed at the beginning of the disease, the evaluation should be repeated before starting anti-TNF-a therapy. When TB (LTBI or AT) treatment is indicated, it should be performed before the beginning of anti-TNF-a therapy. If the IJD activity requires urgent anti-TNF-a therapy, these drugs can be started after two months of antituberculosis therapy in AT cases, or after one month in LTBI cases. Chest X-ray is mandatory for all patients. If abnormal, e.g. Gohn complex, the patient should be treated as LTBI; residual lesions require the exclusion of AT and patients with history of untreated or incomplete TB treatment should be treated as LTBI. In cases of suspected active lesions, AT diagnosis should be confirmed and adequate therapy initiated. Tuberculin skin test (TST), with two units of RT23, should be performed in all patients. If induration is less than 5 mm, the test should be repeated after 1 to 2 weeks, on the opposite forearm, and should be considered negative if the result is again inferior to 5 mm. Positive TST implicates LTBI treatment. If TST is performed in immunosuppressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNF-a therapy, even in the presence of a negative test. PMID:17117328

  3. CCL2 Responses to Mycobacterium tuberculosis Are Associated with Disease Severity in Tuberculosis

    PubMed Central

    Hasan, Zahra; Cliff, Jacqueline M.; Dockrell, Hazel M.; Jamil, Bushra; Irfan, Muhammad; Ashraf, Mussarat; Hussain, Rabia

    2009-01-01

    Background Leucocyte activating chemokines such as CCL2, CCL3, and CXCL8 together with proinflammatory IFNγ, TNFα and downmodulatory IL10 play a central role in the restriction of M. tuberculosis infections, but is unclear whether these markers are indicative of tuberculosis disease severity. Methodology We investigated live M. tuberculosis- and M. bovis BCG- induced peripheral blood mononuclear cell responses in patients with tuberculosis (TB) and healthy endemic controls (ECs, n = 36). TB patients comprised pulmonary (PTB, n = 34) and extrapulmonary groups, subdivided into those with less severe localized extrapulmonary TB (L-ETB, n = 16) or severe disseminated ETB (D-ETB, n = 16). Secretion of CCL2, IFNγ, IL10 and CCL3, and mRNA expression of CCL2, TNFα, CCL3 and CXCL8 were determined. Results M. tuberculosis- and BCG- induced CCL2 secretion was significantly increased in both PTB and D-ETB (p<0.05, p<0.01) as compared with L-ETB patients. CCL2 secretion in response to M. tuberculosis was significantly greater than to BCG in the PTB and D-ETB groups. M. tuberculosis-induced CCL2 mRNA transcription was greater in PTB than L-ETB (p = 0.023), while CCL2 was reduced in L-ETB as compared with D-ETB (p = 0.005) patients. M. tuberculosis –induced IFNγ was greater in L-ETB than PTB (p = 0.04), while BCG-induced IFNγ was greater in L-ETB as compared with D-ETB patients (p = 0.036). TNFα mRNA expression was raised in PTB as compared with L-ETB group in response to M. tuberculosis (p = 0.02) and BCG (p = 0.03). Mycobacterium-induced CCL3 and CXCL8 was comparable between TB groups. Conclusions The increased CCL2 and TNFα in PTB patients may support effective leucocyte recruitment and M. tuberculosis localization. CCL2 alone is associated with severity of TB, possibly due to increased systemic inflammation found in severe disseminated TB or due to increased monocyte infiltration to lung parenchyma in pulmonary disease. PMID

  4. [Recommendations for the diagnosis and treatment of latent and active tuberculosis in patients with inflammatory joint diseases treated with tumour necrosis factor alpha inhibitors].

    PubMed

    Fonseca, João Eurico; Lucas, Helena; Canhão, Helena; Duarte, Raquel; Santos, Maria José; Villar, Miguel; Faustino, Augusto; Raymundo, Elena

    2006-01-01

    The Portuguese Society of Rheumatology (SPR) and the Portuguese Society of Pulmonology (SPP) have developed guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (AT) in patients with inflammatory joint diseases (IJD), namely rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, treated with tumour necrosis factor alpha (TNF-alpha) antagonists. Due to the high risk of tuberculosis (TB) in patients with IJD, LTBI and AT screening should be performed as soon as possible, ideally at the moment of IJD diagnosis. Even if TB screening was performed at the beginning of the disease, the evaluation should be repeated before starting anti-TNF-alpha therapy. When TB (LTBI orAT) treatment is indicated, it should be performed before the beginning of anti-TNF-alpha therapy. If the IJD activity requires urgent anti-TNF-alpha therapy, these drugs can be started after two months of antituberculosis therapy in AT cases, or after one month in LTBI cases. Chest X-ray is mandatory for all patients. If abnormal, e.g. Gohn complex, the patient should be treated as LTBI; residual lesions require the exclusion of AT and patients with history of untreated or incomplete TB treatment should be treated as LTBI. In cases of suspected active lesions, AT diagnosis should be confirmed and adequate therapy initiated. Tuberculin skin test (TST), with two units of RT23, should be performed in all patients. If induration is less than 5 mm, the test should be repeated after 1 to 2 weeks, on the opposite forearm, and should be considered negative if the result is again inferior to 5 mm. Positive TST implicates LTBI treatment. IfTST is performed in immunosupressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNFalpha therapy, even in the presence of a negative test. PMID:17094335

  5. Recommendations for the diagnosis and treatment of latent and active tuberculosis in inflammatory joint diseases candidates for therapy with tumor necrosis factor alpha inhibitors: March 2008 update.

    PubMed

    Fonseca, João Eurico; Lucas, Helena; Canhão, Helena; Duarte, Raquel; Santos, Maria José; Villar, Miguel; Faustino, Augusto; Raymundo, Elena

    2008-01-01

    The Portuguese Society of Rheumatology and the Portuguese Society of Pulmonology have updated the guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (ATB) in patients with inflammatory joint diseases (IJD) that are candidates to therapy with tumour necrosis factor alpha (TNFalpha) antagonists. In order to reduce the risk of tuberculosis (TB) reactivation and the incidence of new infections, TB screening is recommended to be done as soon as possible, ideally at the moment of IJD diagnosis, and patient assessment repeated before starting anti-TNFalpha therapy. Treatment for ATB and LTBI must be done under the care of a TB specialist. When TB treatment is indicated, it should be completed prior to starting anti-TNFalpha therapy. If the IJD activity justifies the need for immediate treatment, anti-TNFalpha therapy can be started two months after antituberculous therapy has been initiated, in the case of ATB, and one month after in the case of LTBI. Chest X-ray is mandatory for all patients. If Gohn s complex is present, the patient should be treated for LTBI; healed lesions require the exclusion of ATB. In cases of suspected active lesions ATB should be excluded/confirmed and adequate therapy initiated. Tuberculin skin test, with two units of RT23, should be performed in all patients. If the induration is <5 mm, the test should be repeated within 1 to 2 weeks, on the opposite forearm, and will be considered negative only if the result is again <5 mm. Positive TST implicates LTBI treatment, unless previous proper treatment was provided. If TST is performed in immunossuppressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNFalpha therapy, even in the presence of a negative test, after risk/benefit assessment. PMID:18344925

  6. Recommendations for the diagnosis and treatment of latent and active tuberculosis in inflammatory joint diseases candidates for therapy with tumor necrosis factor alpha inhibitors - March 2008 update.

    PubMed

    Fonseca, João Eurico; Lucas, Helena; Canhão, Helena; Duarte, Raquel; Santos, Maria José; Villar, Miguel; Faustino, Augusto; Raymundo, Elena

    2008-01-01

    The Portuguese Society of Rheumatology and the Portuguese Society of Pulmonology have updated the guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (ATB) in patients with inflammatory joint diseases (IJD) that are candidates to therapy with tumour necrosis factor alpha (TNFα) antagonists. In order to reduce the risk of tuberculosis (TB) reactivation and the incidence of new infections, TB screening is recommended to be done as soon as possible, ideally at the moment of IJD diagnosis, and patient assessment repeated before starting anti-TNFα therapy. Treatment for ATB and LTBI must be done under the care of a TB specialist. When TB treatment is indicated, it should be completed prior to starting anti-TNFα therapy. If the IJD activity justifies the need for immediate treatment, anti-TNFα therapy can be started two months after antituberculous therapy has been initiated, in the case of ATB, and one month after in the case of LTBI. Chest X-ray is mandatory for all patients. If Gohn's complex is present, the patient should be treated for LTBI; healed lesions require the exclusion of ATB. In cases of suspected active lesions, ATB should be excluded/confirmed and adequate therapy initiated. Tuberculin skin test, with two units of RT23, should be performed in all patients. If the induration is <5 mm, the test should be repeated within 1 to 2 weeks, on the opposite forearm, and will be considered negative only if the result is again <5 mm. Positive TST implicates LTBI treatment, unless previous proper treatment was provided. If TST is performed in immunossuppressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNF-α therapy, even in the presence of a negative test, after risk / benefit assessment. Rev Port Pneumol 2007; XIV (2): 271-283. PMID:25966834

  7. [Increased IL-4 production in response to virulent Mycobacterium tuberculosis in tuberculosis patients with advanced disease].

    PubMed

    Ordway, Diane J; Martins, Marta S; Costa, Leonor M; Freire, Mónica S; Arroz, Maria J; Dockrell, Hazel M; Ventura, Fernando A

    2005-01-01

    The study was designed to compare immune responses to Mycobacterium tuberculosis bacilli and antigens in healthy Portuguese subjects and pulmonary tuberculosis patients (TB), and to correlate immune status with clinical severity of tuberculosis disease. PBMC were cultured and stimulated with live and killed M. tuberculosis H37Rv and purified protein derivative (PPD) and lymphoproliferation and production of IFN-gamma and IL-5/IL-4 by these cultures were evaluated by the use of ELISA and multi-parameter flow cytometry. PBMC from 30 tuberculosis patients demonstrated significantly reduced amounts of proliferation and IFN-gamma when stimulated with live M. tuberculosis compared the control group. Of 15 tuberculosis patients tested for intracellular IL-4 following stimulation with M. tuberculosis, 7 showed greatly increased IL-4 production in CD8+ and gammadelta+ T cells. Tuberculosis patients demonstrated an increase of intracellular IL-4 after PBMC were stimulated with live M. tuberculosis in the CD4+ phenotype, but more notably in CD8+ and gammadelta TCR+ subsets. Increased production of IL-4 in tuberculosis patients was primarily in individuals with advanced involvement of lung parenchymal with high bacterial loads in sputum. These results suggest that an alteration in type 1 and type 2 cytokine balance can occur in patients with tuberculosis at an advanced clinical stage of disease. PMID:16202332

  8. Mycobacterium tuberculosis infection as a zoonotic disease: transmission between humans and elephants.

    PubMed Central

    Michalak, K.; Austin, C.; Diesel, S.; Bacon, M. J.; Zimmerman, P.; Maslow, J. N.

    1998-01-01

    Between 1994 and 1996, three elephants from an exotic animal farm in Illinois died of pulmonary disease due to Mycobacterium tuberculosis. In October 1996, a fourth living elephant was culture-positive for M. tuberculosis. Twenty-two handlers at the farm were screened for tuberculosis (TB); eleven had positive reactions to intradermal injection with purified protein derivative. One had smear-negative, culture-positive active TB. DNA fingerprint comparison by IS6110 and TBN12 typing showed that the isolates from the four elephants and the handler with active TB were the same strain. This investigation indicates transmission of M. tuberculosis between humans and elephants. PMID:9621200

  9. Monoarticular Poncet Disease after Pulmonary Tuberculosis: A Rare Case Report and Review of Literature

    PubMed Central

    Garg, Paritosh; Gupta, Nikhil; Arora, Mohit

    2016-01-01

    Introduction: Tuberculosis is a major health problem worldwide, more so in Asian countries and especially India. Being a communicable disease, it can affect the lives of many people. Tuberculosis has varied manifestations and can affect almost every part of the human body. Pulmonary tuberculosis is the most common form. Poncet disease (tuberculous rheumatism) is a polyarticular arthritis that occurs during acute tuberculosis infection in which no mycobacterial involvement can be found or no other known cause of polyarthritis is detected. Case presentation: We describe an atypical presentation of active pulmonary tuberculosis with monoarticular Poncet disease of the right knee in a 24-year-old woman. Discussion: The diagnosis of Poncet disease is mainly clinical with exclusion of other causes. It generally presents as an acute or subacute form; however, chronic forms have been described in the literature. PMID:27455057

  10. Plasma metabolomics in human pulmonary tuberculosis disease: a pilot study.

    PubMed

    Frediani, Jennifer K; Jones, Dean P; Tukvadze, Nestan; Uppal, Karan; Sanikidze, Eka; Kipiani, Maia; Tran, ViLinh T; Hebbar, Gautam; Walker, Douglas I; Kempker, Russell R; Kurani, Shaheen S; Colas, Romain A; Dalli, Jesmond; Tangpricha, Vin; Serhan, Charles N; Blumberg, Henry M; Ziegler, Thomas R

    2014-01-01

    We aimed to characterize metabolites during tuberculosis (TB) disease and identify new pathophysiologic pathways involved in infection as well as biomarkers of TB onset, progression and resolution. Such data may inform development of new anti-tuberculosis drugs. Plasma samples from adults with newly diagnosed pulmonary TB disease and their matched, asymptomatic, sputum culture-negative household contacts were analyzed using liquid chromatography high-resolution mass spectrometry (LC-MS) to identify metabolites. Statistical and bioinformatics methods were used to select accurate mass/charge (m/z) ions that were significantly different between the two groups at a false discovery rate (FDR) of q<0.05. Two-way hierarchical cluster analysis (HCA) was used to identify clusters of ions contributing to separation of cases and controls, and metabolomics databases were used to match these ions to known metabolites. Identity of specific D-series resolvins, glutamate and Mycobacterium tuberculosis (Mtb)-derived trehalose-6-mycolate was confirmed using LC-MS/MS analysis. Over 23,000 metabolites were detected in untargeted metabolomic analysis and 61 metabolites were significantly different between the two groups. HCA revealed 8 metabolite clusters containing metabolites largely upregulated in patients with TB disease, including anti-TB drugs, glutamate, choline derivatives, Mycobacterium tuberculosis-derived cell wall glycolipids (trehalose-6-mycolate and phosphatidylinositol) and pro-resolving lipid mediators of inflammation, known to stimulate resolution, efferocytosis and microbial killing. The resolvins were confirmed to be RvD1, aspirin-triggered RvD1, and RvD2. This study shows that high-resolution metabolomic analysis can differentiate patients with active TB disease from their asymptomatic household contacts. Specific metabolites upregulated in the plasma of patients with active TB disease, including Mtb-derived glycolipids and resolvins, have potential as biomarkers

  11. Association-rule-based tuberculosis disease diagnosis

    NASA Astrophysics Data System (ADS)

    Asha, T.; Natarajan, S.; Murthy, K. N. B.

    2010-02-01

    Tuberculosis (TB) is a disease caused by bacteria called Mycobacterium tuberculosis. It usually spreads through the air and attacks low immune bodies such as patients with Human Immunodeficiency Virus (HIV). This work focuses on finding close association rules, a promising technique in Data Mining, within TB data. The proposed method first normalizes of raw data from medical records which includes categorical, nominal and continuous attributes and then determines Association Rules from the normalized data with different support and confidence. Association rules are applied on a real data set containing medical records of patients with TB obtained from a state hospital. The rules determined describes close association between one symptom to another; as an example, likelihood that an occurrence of sputum is closely associated with blood cough and HIV.

  12. Adrenal function in patients with active tuberculosis.

    PubMed Central

    Barnes, D J; Naraqi, S; Temu, P; Turtle, J R

    1989-01-01

    Although tuberculosis is a recognised cause of adrenal insufficiency, little is known about adrenal function in patients with active tuberculosis. Ninety Melanesian adults with active tuberculosis (30 pulmonary, 30 miliary, 30 extrapulmonary) had adrenal function assessed prospectively before and three to four weeks after starting antituberculous chemotherapy. Basal serum cortisol concentrations were normal in 55 (61%) and raised in 35 (39%) of the subjects. No patient had a low basal cortisol concentration. After Synacthen stimulation, cortisol responses were normal in 81 (92%) of the patients and subnormal in seven (8%). After antituberculous chemotherapy the response to Synacthen stimulation was normal in all but one patient. It is concluded that adrenal dysfunction is an uncommon problem in patients with active tuberculosis, and that, contrary to recent reports, antituberculous chemotherapy regimens that include rifampicin do not have an adverse effect on adrenal function. PMID:2763243

  13. Tuberculosis or sarcoidosis: Opposite ends of the same disease spectrum?

    PubMed

    Agrawal, Rupesh; Kee, Ae Ra; Ang, Leslie; Tun Hang, Yeo; Gupta, Vishali; Kon, Onn Min; Mitchell, Donald; Zierhut, Manfred; Pavesio, Carlos

    2016-05-01

    Tuberculosis and sarcoidosis are chronic systemic diseases that have similar pulmonary and extra-pulmonary manifestations. Multiple studies have found an epidemiological, molecular, and immunological link between the two. It has been suggested that mycobacterium tuberculosis could be a common pathophysiologic mechanism for tuberculosis and sarcoidosis, and that both clinical entities can trigger similar immunological response in patients. Due to this close association, together with possible coexistence in the same patient, the diagnosis of one disease from another may be difficult. In our paper, we suggest that tuberculosis and sarcoidosis are two ends of the same spectrum. Given the pathophysiological and clinical link between the two, we also propose a classification system for tuberculosis and sarcoidosis: Sarcoidosis (S); Sarcoid-Tuberculous (ST); Tuberculous Sarcoid (TS) and Tuberculosis (TB). More research and clinical trials should first be done to affirm the link between the two disease entities. PMID:27156614

  14. Determination of Urinary Neopterin/Creatinine Ratio to Distinguish Active Tuberculosis from Latent Mycobacterium tuberculosis Infection

    PubMed Central

    Eisenhut, Michael; Hargreaves, Dougal S.; Scott, Anne; Housley, David; Walters, Andrew; Mulla, Rohinton

    2016-01-01

    Background. Biomarkers to distinguish latent from active Mycobacterium (M.) tuberculosis infection in clinical practice are lacking. The urinary neopterin/creatinine ratio can quantify the systemic interferon-gamma effect in patients with M. tuberculosis infection. Methods. In a prospective observational study, urinary neopterin levels were measured by enzyme linked immunosorbent assay in patients with active tuberculosis, in people with latent M. tuberculosis infection, and in healthy controls and the urinary neopterin/creatinine ratio was calculated. Results. We included a total of 44 patients with M. tuberculosis infection and nine controls. 12 patients had active tuberculosis (8 of them culture-confirmed). The median age was 15 years (range 4.5 to 49). Median urinary neopterin/creatinine ratio in patients with active tuberculosis was 374.1 micromol/mol (129.0 to 1072.3), in patients with latent M. tuberculosis infection it was 142.1 (28.0 to 384.1), and in controls it was 146.0 (40.3 to 200.0), with significantly higher levels in patients with active tuberculosis (p < 0.01). The receiver operating characteristics curve had an area under the curve of 0.84 (95% CI 0.70 to 0.97) (p < 0.01). Conclusions. Urinary neopterin/creatinine ratios are significantly higher in patients with active tuberculosis compared to patients with latent infection and may be a significant predictor of active tuberculosis in patients with M. tuberculosis infection. PMID:27433370

  15. Tuberculosis.

    PubMed

    Dheda, Keertan; Barry, Clifton E; Maartens, Gary

    2016-03-19

    Although the worldwide incidence of tuberculosis has been slowly decreasing, the global disease burden remains substantial (∼9 million cases and ∼1·5 million deaths in 2013), and tuberculosis incidence and drug resistance are rising in some parts of the world such as Africa. The modest gains achieved thus far are threatened by high prevalence of HIV, persisting global poverty, and emergence of highly drug-resistant forms of tuberculosis. Tuberculosis is also a major problem in health-care workers in both low-burden and high-burden settings. Although the ideal preventive agent, an effective vaccine, is still some time away, several new diagnostic technologies have emerged, and two new tuberculosis drugs have been licensed after almost 50 years of no tuberculosis drugs being registered. Efforts towards an effective vaccine have been thwarted by poor understanding of what constitutes protective immunity. Although new interventions and investment in control programmes will enable control, eradication will only be possible through substantial reductions in poverty and overcrowding, political will and stability, and containing co-drivers of tuberculosis, such as HIV, smoking, and diabetes. PMID:26377143

  16. An acidic sphingomyelinase Type C activity from Mycobacterium tuberculosis.

    PubMed

    Castro-Garza, Jorge; González-Salazar, Francisco; Quinn, Frederick D; Karls, Russell K; De La Garza-Salinas, Laura Hermila; Guzmán-de la Garza, Francisco J; Vargas-Villarreal, Javier

    2016-01-01

    Sphingomyelinases (SMases) catalyze the hydrolysis of sphingomyelin to ceramide and phosphorylcholine. Sphingolipids are recognized as diverse and dynamic regulators of a multitude of cellular processes mediating cell cycle control, differentiation, stress response, cell migration, adhesion, and apoptosis. Bacterial SMases are virulence factors for several species of pathogens. Whole cell extracts of Mycobacterium tuberculosis strains H37Rv and CDC1551 were assayed using [N-methyl-(14)C]-sphingomyelin as substrate. Acidic Zn(2+)-dependent SMase activity was identified in both strains. Peak SMase activity was observed at pH 5.5. Interestingly, overall SMase activity levels from CDC1551 extracts are approximately 1/3 of those of H37Rv. The presence of exogenous SMase produced by M. tuberculosis during infection may interfere with the normal host inflammatory response thus allowing the establishment of infection and disease development. This Type C activity is different from previously identified M. tuberculosis SMases. Defining the biochemical characteristics of M. tuberculosis SMases helps to elucidate the roles that these enzymes play during infection and disease. PMID:26948102

  17. Novel agents in the management of Mycobacterium tuberculosis disease.

    PubMed

    Barry, P J; O'Connor, T M

    2007-01-01

    The goals of tuberculosis control are to cure active disease, prevent relapse, reduce transmission and avert the emergence of drug resistance. However, since the 1960s, there have been few developments in available therapies. Currently available agents are complicated by numerous side-effects, drug interactions and the need for a long duration of therapy. Rifampicin-containing regimes lead to hepatic enzyme induction which can complicate or preclude the use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors in patients infected with the human immunodeficiency virus. Furthermore, emerging drug resistance has complicated management for many patients and clinicians. Therefore, new chemotherapeutic agents are urgently needed. Existing antimicrobials are emerging as potent antituberculous agents. Recent studies have demonstrated the antituberculous activity of newer fluoroquinolones including levofloxacin, moxifloxacin, and gatifloxacin. Their use as first line antituberculous agents is currently under investigation. Furthermore, the oxazolidinones linezolid and PNU-100480 have been shown to have antituberculous activity in addition to their antibacterial effects. Several other agents are currently being developed for the treatment of tuberculosis. These agents include diarylquinolones (R207910), nitroimidazopyrans (PA-824, OPC-67683), ethambutol analogues (SQ109), cerulenin, trans-cinnamic acid, macrolides, pyrroles (LL3858), long-acting rifamycins and inhaled interferon-gamma. Furthermore, vaccines are being explored for pre-exposure and post-exposure use. This review will describe therapeutic developments in the management of tuberculosis, highlighting mechanisms of action of new pharmacological agents and their potential for clinical use. PMID:17691942

  18. Tuberculosis-associated chronic kidney disease.

    PubMed

    de Oliveira, Jobson Lopes; da Silva Junior, Geraldo Bezerra; Daher, Elizabeth De Francesco

    2011-06-01

    Extrapulmonary tuberculosis (TB) account for approximately 15-20% of TB cases in immunocompetent patients. The genitourinary system is the third most commonly affected site. We report the case of a 20-year-old man admitted with fever, chills, dry cough, right flank pain, and oliguria who developed renal function loss. The pyelogram evidenced silence of the right kidney, and the abdominal and pelvic magnetic resonance showed significant dilation of the right pyelocaliceal system and proximal ureter. Biopsies of renal cortex and retroperitoneal lymph nodes showed caseous granuloma consistent with TB. Treatment was started with rifampicin, isoniazid, pyrazinamide, and ethambutol, and the patient presented a favorable outcome but with non-dialytic chronic kidney disease. This case illustrates a case of chronic kidney disease secondary to TB in a young, otherwise healthy man. PMID:21633015

  19. Native New Zealand plants with inhibitory activity towards Mycobacterium tuberculosis

    PubMed Central

    2010-01-01

    Background Plants have long been investigated as a source of antibiotics and other bioactives for the treatment of human disease. New Zealand contains a diverse and unique flora, however, few of its endemic plants have been used to treat tuberculosis. One plant, Laurelia novae-zelandiae, was reportedly used by indigenous Maori for the treatment of tubercular lesions. Methods Laurelia novae-zelandiae and 44 other native plants were tested for direct anti-bacterial activity. Plants were extracted with different solvents and extracts screened for inhibition of the surrogate species, Mycobacterium smegmatis. Active plant samples were then tested for bacteriostatic activity towards M. tuberculosis and other clinically-important species. Results Extracts of six native plants were active against M. smegmatis. Many of these were also inhibitory towards M. tuberculosis including Laurelia novae-zelandiae (Pukatea). M. excelsa (Pohutukawa) was the only plant extract tested that was active against Staphylococcus aureus. Conclusions Our data provide support for the traditional use of Pukatea in treating tuberculosis. In addition, our analyses indicate that other native plant species possess antibiotic activity. PMID:20537175

  20. LL-37 immunomodulatory activity during Mycobacterium tuberculosis infection in macrophages.

    PubMed

    Torres-Juarez, Flor; Cardenas-Vargas, Albertina; Montoya-Rosales, Alejandra; González-Curiel, Irma; Garcia-Hernandez, Mariana H; Enciso-Moreno, Jose A; Hancock, Robert E W; Rivas-Santiago, Bruno

    2015-12-01

    Tuberculosis is one of the most important infectious diseases worldwide. The susceptibility to this disease depends to a great extent on the innate immune response against mycobacteria. Host defense peptides (HDP) are one of the first barriers to counteract infection. Cathelicidin (LL-37) is an HDP that has many immunomodulatory effects besides its weak antimicrobial activity. Despite advances in the study of the innate immune response in tuberculosis, the immunological role of LL-37 during M. tuberculosis infection has not been clarified. Monocyte-derived macrophages were infected with M. tuberculosis strain H37Rv and then treated with 1, 5, or 15 μg/ml of exogenous LL-37 for 4, 8, and 24 h. Exogenous LL-37 decreased tumor necrosis factor alpha (TNF-α) and interleukin-17 (IL-17) while inducing anti-inflammatory IL-10 and transforming growth factor β (TGF-β) production. Interestingly, the decreased production of anti-inflammatory cytokines did not reduce antimycobacterial activity. These results are consistent with the concept that LL-37 can modulate the expression of cytokines during mycobacterial infection and this activity was independent of the P2X7 receptor. Thus, LL-37 modulates the response of macrophages during infection, controlling the expression of proinflammatory and anti-inflammatory cytokines. PMID:26351280

  1. LL-37 Immunomodulatory Activity during Mycobacterium tuberculosis Infection in Macrophages

    PubMed Central

    Torres-Juarez, Flor; Cardenas-Vargas, Albertina; Montoya-Rosales, Alejandra; González-Curiel, Irma; Garcia-Hernandez, Mariana H.; Enciso-Moreno, Jose A.; Hancock, Robert E. W.

    2015-01-01

    Tuberculosis is one of the most important infectious diseases worldwide. The susceptibility to this disease depends to a great extent on the innate immune response against mycobacteria. Host defense peptides (HDP) are one of the first barriers to counteract infection. Cathelicidin (LL-37) is an HDP that has many immunomodulatory effects besides its weak antimicrobial activity. Despite advances in the study of the innate immune response in tuberculosis, the immunological role of LL-37 during M. tuberculosis infection has not been clarified. Monocyte-derived macrophages were infected with M. tuberculosis strain H37Rv and then treated with 1, 5, or 15 μg/ml of exogenous LL-37 for 4, 8, and 24 h. Exogenous LL-37 decreased tumor necrosis factor alpha (TNF-α) and interleukin-17 (IL-17) while inducing anti-inflammatory IL-10 and transforming growth factor β (TGF-β) production. Interestingly, the decreased production of anti-inflammatory cytokines did not reduce antimycobacterial activity. These results are consistent with the concept that LL-37 can modulate the expression of cytokines during mycobacterial infection and this activity was independent of the P2X7 receptor. Thus, LL-37 modulates the response of macrophages during infection, controlling the expression of proinflammatory and anti-inflammatory cytokines. PMID:26351280

  2. Pulmonary disease due to Mycobacterium tuberculosis in a horse: zoonotic concerns and limitations of antemortem testing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A case of pulmonary tuberculosis caused by Mycobacterium tuberculosis was diagnosed in a horse. Clinical evaluation performed prior to euthanasia did not suggest tuberculosis, but postmortem examination provided pathological and bacteriological evidence of disease. In the lungs, multiple tuberculoid...

  3. [Tuberculosis infection and disease in immigrant children].

    PubMed

    Giacchino, Raffaella; di Martino, Lucio; Losurdo, Giuseppe; Pisanti, Antonello

    2003-06-01

    From the second half of the eighties, the cases of tuberculosis (TBC) in Italy have been constantly increasing. The increase in TBC cases in developed countries is related to different factors, including HIV epidemic and increased number of immigrants from countries with high TBC incidence and important socio-economic problems. Compared with adults few children with TBC were homeless or coinfected with HIV, nonetheless the children lived frequently in low socioeconomic status and consequently high risk of being uninsured and with adults at risk for tuberculosis (immediate relative, household members, or recently immigrated). An epidemiologic study was carried out, in order to evaluate the impact of TBC infection in immigrant children. From January 2001 to December 2002, Mantoux test (5 IU) was performed in immigrant children hospitalized or followed in two children hospitals. They included 228 children: mean age 4 years (range 1 month to 15 years). The patients came from: South America (44%) (especially from Ecuador), from Africa (20%), from Eastern Europe (19%), (especially from Middle East and North Africa), from Far East (17%). In 30 cases (13,2%) Mantoux test was positive. Among these latter, 21 presented latent infection, whereas another 9 had tuberculous disease with pulmonary localization and one of them associated with cervical adenopathy. In the study period, among all children (4426) admitted the two Units, the prevalence of tuberculous disease was 2,5% in immigrant children compared 0.2% in native children. Accurate epidemiologic monitoring, further clinical studies aimed at highlighting TBC peculiar aspects in children, and adequate therapy can lead to TBC control in the immigrant children. PMID:15020852

  4. The relationship between chitotriosidase activity and tuberculosis.

    PubMed

    Chen, M; Deng, J; Li, W; Su, C; Xia, Y; Wang, M; Li, X; Abuaku, B K; Tan, H; Wen, S W

    2015-11-01

    Chitotriosidase, secreted by activated macrophages, is a biomarker of activated macrophages. In this study, we explored whether chitotriosidase could be adopted as a biomarker to evaluate the curative effect on tuberculosis (TB). Five counties were randomly selected out of 122 counties/cities/districts in Hunan Province, China. Our cases were all TB patients who were newly diagnosed or had been receiving treatment at the Centers for Disease Control (CDCs) of these five counties between April and August in 2009. Healthy controls were selected from a community health facility in the Kaifu district of Changsha City after frequency-matching of gender and age with the cases. Chitotriosidase activity was evaluated by a fluorometric assay. Categorical variables were analysed with the χ 2 test. Measurement data in multiple groups were tested with analysis of variance and least significant difference (LSD). Correlation between chitotriosidase activity and the degree of radiological extent (DRE) was examined by Spearman's rank correlation test. The average chitotriosidase activity levels of new TB cases, TB cases with different periods of treatment (6 months) and the control group were 54·47, 34·77, 21·54, 12·73 and 10·53 nmol/h.ml, respectively. Chitotriosidase activity in TB patients declined along with the continuity of treatment. The chitotriosidase activity of both smear-positive and the smear-negative pulmonary TB patients decreased after 6 months' treatment to normal levels (P < 0·05). Moreover, chitotriosidase activity was positively correlated with DRE (r = 0·607, P < 0·001). Our results indicate that chitotriosidase might be a marker of TB treatment effects. However, further follow-up study of TB patients is needed in the future. PMID:26418349

  5. Nutritional supplements for people being treated for active tuberculosis

    PubMed Central

    Grobler, Liesl; Nagpal, Sukrti; Sudarsanam, Thambu D; Sinclair, David

    2016-01-01

    Background Tuberculosis and malnutrition are linked in a complex relationship. Tuberculosis may cause undernutrition through increased metabolic demands and decreased intake, and nutritional deficiencies may worsen the disease, or delay recovery by depressing important immune functions. At present, there is no evidence-based nutritional guidance for adults and children being treated for tuberculosis. Objectives To assess the effects of oral nutritional supplements in people being treated with antituberculous drug therapy for active tuberculosis. Search methods We searched the Cochrane Infectious Disease Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, 2016), MEDLINE (from 1946 to 4 February 2016), EMBASE (from 1980 to 4 February 2016), LILACS (from 1982 to 4 February 2016), the metaRegister of Controlled Trials (mRCT), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and the Indian Journal of Tuberculosis up to 4 February 2016, and checked the reference lists of all included studies. Selection criteria Randomized controlled trials that compared any oral nutritional supplement given for at least four weeks with no nutritional intervention, placebo, or dietary advice only for people being treated for active tuberculosis. The primary outcomes of interest were all-cause death, and cure at six and 12 months. Data collection and analysis Two review authors independently selected trials for inclusion, and extracted data and assessed the risk of bias in the included trials. We presented the results as risk ratios (RR) for dichotomous variables, and mean differences (MD) for continuous variables, with 95% confidence intervals (CIs). Where appropriate, we pooled data from trials with similar interventions and outcomes. We assessed the quality of the evidence using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Main results Thirty-five trials

  6. Diagnostic Utility of QuantiFERON-TB Gold (QFT-G) in Active Pulmonary Tuberculosis

    PubMed Central

    Anwar, Ahmed; Hamdan, AL-Jahdali; Salim, Baharoon; Yosra, Ali; Hani, Mohamed; Abdullah, AL-Harbi

    2015-01-01

    Background: The utility of QuantiFERON-TB Gold In-Tube (QFT-G) test in the diagnosis of tuberculosis disease has been validated in high and low tuberculosis-prevalent (TB) countries. Aim: The aim of this study is to assess the performance of the QFT-G test in the diagnosis of tuberculosis disease among tuberculosis patients in an intermediate prevalent country. Setting and Design: A retrospective study at the King Abdulaziz Medical City-Riyadh (KAMC-R) Materials and Methods: We retrospectively reviewed all the patients with a diagnosis of pneumonia, including tuberculosis, admitted to KAMC-R between 1 January 2009 and 31 December 2013. We included only patients with an available result of the QFT-G test. A total of 142 tuberculosis cases and 226 pneumonia cases were studied, to assess the utility of the QFT-G test in diagnosing tuberculosis cases. Results: Among the tuberculosis (n = 142) cases, the QFT-G tested positive in 68.3%, negative in 23.2%, and indeterminate in 12 cases (8.5%). Of the 226 pneumonia cases, the QFT-G tested positive in only 20.4%, while a majority of 66.4% tested negative, with 30 cases (13.3%) being indeterminate. When we excluded 42 patients with indeterminate results, the QFT-G test achieved a sensitivity of 74.6% [95% CI: 66.09 to 81.65%] and specificity of 76.53 % [95% CI: 69.85 to 82.15%] in the diagnosis of tuberculosis cases. Conclusions: This study concludes that the QFT-G test is a useful tool for detecting tuberculosis disease when used as an adjunct tool for the diagnosis of active TB cases. It certainly cannot be used solely and indiscriminately, separate from other clinical and radiological information, in the diagnosis of active tuberculosis cases. PMID:26392718

  7. Tuberculosis.

    PubMed

    Tiruviluamala, Parvathi; Reichman, Lee B

    2002-01-01

    Tuberculosis is an infectious disease caused by bacteria in the Mycobacterium tuberculosis complex. Of these, the most common species to infect humans is M. tuberculosis. The TB bacillus is an extremely successful human pathogen, infecting two billion persons worldwide; an estimated 2 to 3 million people die from tuberculosis each year. In the United States, TB rates decreased steadily at the rate of 5% per year from 1953 until 1985 when the trend reversed, with the number of TB cases peaking in 1992. Outbreaks of multidrug-resistant TB (MDR TB) were reported, and these cases were documented to be transmitted in nosocomial and congregate settings, including hospitals and prisons. AIDS patients infected with M. tb developed disease rapidly, and case-fatality rates of >80% were noted in those infected with multidrug-resistant M. tb. Intensive intervention, at enormous cost, caused the number of TB cases to decline. This article discusses factors that led to the increase in TB cases, their subsequent decline, and measures needed in the future if TB is to be eliminated in the United States. PMID:11910069

  8. Intestinal tuberculosis versus crohn's disease: Clinical and radiological recommendations

    PubMed Central

    Sharma, Raju; Madhusudhan, Kumble S; Ahuja, Vineet

    2016-01-01

    Intestinal tuberculosis is a common clinical problem in India. The clinical features of this disease are nonspecific and can be very similar to Crohn's disease. Radiological evaluation of the small bowel has undergone a paradigm shift in the last decade. This long tubular organ that has traditionally been difficult to evaluate can now be well-visualized by some innovative imaging and endoscopic techniques. This article highlights the state-of-the-art evaluation of ulceroconstrictive diseases of the bowel and provides recommendations for the differentiation of intestinal tuberculosis from Crohn's disease. PMID:27413261

  9. Intestinal tuberculosis versus crohn's disease: Clinical and radiological recommendations.

    PubMed

    Sharma, Raju; Madhusudhan, Kumble S; Ahuja, Vineet

    2016-01-01

    Intestinal tuberculosis is a common clinical problem in India. The clinical features of this disease are nonspecific and can be very similar to Crohn's disease. Radiological evaluation of the small bowel has undergone a paradigm shift in the last decade. This long tubular organ that has traditionally been difficult to evaluate can now be well-visualized by some innovative imaging and endoscopic techniques. This article highlights the state-of-the-art evaluation of ulceroconstrictive diseases of the bowel and provides recommendations for the differentiation of intestinal tuberculosis from Crohn's disease. PMID:27413261

  10. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... shown by X-ray in active service. 3.370 Section 3.370 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... Rating Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for grant of direct...

  11. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... shown by X-ray in active service. 3.370 Section 3.370 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... Rating Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for grant of direct...

  12. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... shown by X-ray in active service. 3.370 Section 3.370 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... Rating Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for grant of direct...

  13. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... shown by X-ray in active service. 3.370 Section 3.370 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... Rating Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for grant of direct...

  14. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... shown by X-ray in active service. 3.370 Section 3.370 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... Rating Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for grant of direct...

  15. Association Between Tuberculosis and Parkinson Disease

    PubMed Central

    Shen, Chih-Hao; Chou, Chung-Hsing; Liu, Feng-Cheng; Lin, Te-Yu; Huang, Wen-Yen; Wang, Yu-Chiao; Kao, Chia-Hung

    2016-01-01

    Abstract Few studies have investigated the association between tuberculosis (TB) and Parkinson disease (PD). This nationwide, population-based, retrospective cohort study investigated the risk of PD in patients with TB. We selected patients newly diagnosed with TB (International Classification of Diseases, Ninth Revision, Clinical Modification: 011) from 2000 to 2009 in the Taiwan National Health Insurance Database as the TB cohort. The comparison cohort (the non-TB cohort) was frequency matched to the TB cohort at a ratio of 4:1 by sex, age, and the index date. We analyzed the risks of PD by using Cox proportional hazard regression models. A total of 121,951 patients with TB and 487,800 non-TB controls were enrolled in this study. The TB cohort had a 1.38-fold risk of PD compared with the non-TB cohort after adjustment for age, sex, and comorbidities (aHR, 95% CI: 1.30–1.46). The adjusted risk of PD in the TB and non-TB cohorts increased in subgroups regardless of age, sex, and comorbidities. Combined effect of TB and comorbidities on the risk of PD were significant in patients with TB who had diabetes (aHR: 2.26, 95% CI: 2.02–2.52), hypertension (aHR: 2.23, 95% CI: 2.04–2.44), head injury (aHR: 2.32, 95% CI: 1.95–2.77), chronic kidney disease (aHR: 2.02, 95% CI: 1.49–2.72), chronic obstructive pulmonary disease (aHR: 1.84, 95% CI: 1.66–2.05), depression (aHR: 4.66, 95% CI: 3.59–6.05), dementia (aHR: 3.70, 95% CI: 2.99–4.59), and stroke (aHR: 2.56, 95% CI: 2.28–2.87). The risk of PD was higher in a follow-up within 1 year (aHR: 1.78, 95% CI: 1.58–2.00) and decreased with the follow-up period in the TB cohort. Patients with TB have an independently 1.38-fold risk of PD. The risk of PD decreased with the follow-up period in the TB cohort. Physicians should be aware of the risk of PD in patients with TB when treating such patients. PMID:26937925

  16. [Revealing of tuberculosis in an infectious diseases hospital of a megalopolis].

    PubMed

    Malashenkov, E A; Ivanovskiĭ, V B

    2007-01-01

    The advisory work of the phthisiatrician in an infectious diseases hospital was analyzed; the analysis revealed that in 2005 tuberculose changes of various degrees of activity had been revealed in 42.5% of examined patients, and 32.1% of them were subjects in whom tuberculosis of diferent localizations had been revealed for the first time. In 43.2% of the latter subjects, the reasons for hospitalization were "clinical masks" of tuberculose process (influenza, acute respiratory viral disease), while 48.6% were hospitalized for gastrointestinal infections and viral hepatitis. In 20.7% of cases tuberculosis was combined with HIV infection. In the infectious diseases hospital, 16.2% of patients with active tuberculosis died. Among the patients treated in the infectious diseases hospital during one year, the proportion of patients with active tuberculosis was 1.44%, the proportion of those in whom the process was revealed for the first time, was 0.75%. In Botkin infectious diseases hospital, there were approximately 6% of patients in whom tuberculose process was revealed for the first time in Saint Petersburg. The peculiarities of this group of patients in an infectious diseases hospital require not only tuberculose alertness, but also reinforcement of phthisiatric, radiological, and laboratory services. PMID:17926491

  17. Laboratory Diagnosis of Mycobacterium tuberculosis Infection and Disease in Children.

    PubMed

    Dunn, James J; Starke, Jeffrey R; Revell, Paula A

    2016-06-01

    Diagnosis of tuberculosis in children is challenging; even with advanced technologies, the diagnosis is often difficult to confirm microbiologically in part due to the paucibacillary nature of the disease. Clinical diagnosis lacks standardization, and traditional and molecular microbiologic methods lack sensitivity, particularly in children. Immunodiagnostic tests may improve sensitivity, but these tests cannot distinguish tuberculosis disease from latent infection and some lack specificity. While molecular tools like Xpert MTB/RIF have advanced our ability to detect Mycobacterium tuberculosis and to determine antimicrobial resistance, decades old technologies remain the standard in most locales. Today, the battle against this ancient disease still poses one of the primary diagnostic challenges in pediatric laboratory medicine. PMID:26984977

  18. Does M. tuberculosis genomic diversity explain disease diversity?

    PubMed Central

    Coscolla, Mireilla; Gagneux, Sebastien

    2010-01-01

    The outcome of tuberculosis infection and disease is highly variable. This variation has been attributed primarily to host and environmental factors, but better understanding of the global genomic diversity in the M. tuberculosis complex (MTBC) suggests that bacterial factors could also be involved. Review of nearly 100 published reports shows that MTBC strains differ in their virulence and immunogenicity in experimental models, but whether this phenotypic variation plays a role in human disease remains unclear. Given the complex interactions between the host, the pathogen and the environment, linking MTBC genotypic diversity to experimental and clinical phenotypes requires an integrated systems epidemiology approach embedded in a robust evolutionary framework. PMID:21076640

  19. Gene Regulatory Networks Activated during Chronic Tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic tuberculosis represents a burden for most of world’s population. Several genes were found to be up-regulated at the late stage of chronic tuberculosis when DNA microarray protocol was used to analyze murine tuberculosis. Rv0348 is a potential transcriptional regulator that is highly expresse...

  20. Tuberculosis

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Tuberculosis KidsHealth > For Teens > Tuberculosis Print A A A Text Size What's in ... Duration When to Call the Doctor en español Tuberculosis TB Basics Tuberculosis (also known as "TB") is ...

  1. Is tuberculosis a lymphatic disease with a pulmonary portal

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tuberculosis (TB) is commonly viewed as a pulmonary disease, in which infection, persistence, induction of pathology and bacterial expulsion all occur in the lungs. In this model, enlarged lymph nodes represent reactive adenitis and spread of organisms to extrapulmonary sites results in a non-transm...

  2. Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

    PubMed

    Nahid, Payam; Dorman, Susan E; Alipanah, Narges; Barry, Pennan M; Brozek, Jan L; Cattamanchi, Adithya; Chaisson, Lelia H; Chaisson, Richard E; Daley, Charles L; Grzemska, Malgosia; Higashi, Julie M; Ho, Christine S; Hopewell, Philip C; Keshavjee, Salmaan A; Lienhardt, Christian; Menzies, Richard; Merrifield, Cynthia; Narita, Masahiro; O'Brien, Rick; Peloquin, Charles A; Raftery, Ann; Saukkonen, Jussi; Schaaf, H Simon; Sotgiu, Giovanni; Starke, Jeffrey R; Migliori, Giovanni Battista; Vernon, Andrew

    2016-10-01

    The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the

  3. Diseases masking and delaying the diagnosis of urogenital tuberculosis

    PubMed Central

    Kulchavenya, Ekaterina; Kholtobin, Denis

    2015-01-01

    As urogenital tuberculosis (UGTB) has no specific clinical features, it is often overlooked. To identify some of the reasons for misdiagnosing UGTB we performed a systematic review. We searched in Medline/PubMed papers with keywords ‘urogenital tuberculosis, rare’ and ‘urogenital tuberculosis, unusual’. ‘Urogenital tuberculosis, rare’ presented 230 articles and ‘urogenital tuberculosis, unusual’ presented 81 articles only, a total of 311 papers. A total of 34 papers were duplicated and so were excluded from the review. In addition, we excluded from the analysis 33 papers on epidemiological studies and literature reviews, papers describing non-TB cases and cases of TB another than urogenital organs (48 articles), cases of congenital TB (three articles), UGTB as a case of concomitant disease (16 articles), and UGTB as a complication of BCG-therapy (eight articles). We also excluded 22 articles dedicated to complications of the therapy, which made a total of 164 articles. Among the remaining 147 articles we selected 43 which described really unusual, difficult to diagnose cases. We also included in our review a WHO report from 2014, and one scientific monograph on TB urology. The most frequent reasons for delayed diagnosis were absence typical clinical features of UGTB, and the tendency of UGTB to hide behind the mask of another disease. We can conclude that actually UGTB is not rare disease, but it is often an overlooked disease. The main reasons for delayed diagnosis are vague, atypical clinical features and a low index of suspicion. PMID:26622318

  4. Misdiagnosis and Mistherapy of Crohn's Disease as Intestinal Tuberculosis

    PubMed Central

    Wei, Jiang-Peng; Wu, Xiao-Yan; Gao, Sen-Yang; Chen, Qiu-Yu; Liu, Tong; Liu, Gang

    2016-01-01

    Abstract The differential diagnosis of Crohn's disease (CD) and intestinal tuberculosis (ITB) remains difficult as the clinical symptoms of the 2 digestive diseases are so similar. Here we report a case where a patient was initially misdiagnosed with ITB prior to the correct CD diagnosis. The 46-year-old male patient was hospitalized elsewhere for pain in the right lower abdomen and underwent an appendectomy. The pathological diagnosis was ITB and the patient was administered antituberculosis therapy for 1 year. Afterward, the patient was readmitted to the hospital for a right lower abdominal mass. A computed tomography scan revealed intestinal gas, fistula, and abdominal mass. We performed a right hemicolectomy on the patient. Postoperatively, we diagnosed the patient with CD, based on patient history and pathological examination. According to the CD active index (CDAI), the patient was at high risk and began treatment with infliximab. The patient has remained in complete remission and made a good recovery after 8-months follow-up. We compared this case with the results of a literature review on the misdiagnosis between CD and ITB (26 previously reported cases) to determine the characteristics of misdiagnosed cases. We found that distinguishing between ITB and CD is difficult because of their varied clinical presentation, nonspecific investigative tools, and profound similarities even in pathological specimens. Although a CT scan to determine the morphology of the bowel wall is a key for correct diagnosis, each case still poses challenges for diagnosis and administrating the appropriate treatment. PMID:26735549

  5. Update in tuberculosis and nontuberculous mycobacterial disease 2012.

    PubMed

    Menzies, Dick; Nahid, Payam

    2013-10-15

    In 2012, new publications in the Journal described both the predictive value of the new IFN-γ release assays for diagnosis of latent tuberculosis (TB), but also provided evidence that these new tests cannot be interpreted simply as positive or negative, as initially hoped. Surgical masks can reduce transmission of TB infection, but other measures such as state-wide implementation of targeted testing and treatment of latent TB or active case finding require substantial and sustained effort to successfully reduce TB morbidity and mortality. A quasiexperimental study revealed that a package of social interventions could substantially reduce risk of TB disease in heavily exposed (and infected) children in the preantibiotic era. A study in a high-TB burden setting suggested that a new rapid drug-susceptibility test for TB may be more practical for implementation than traditional culture-based phenotypic tests. And two studies of TB vaccines revealed that currently used bacillus Calmette-Guérin strains vary in their ability to affect correlates of immunogenicity, whereas a new candidate vaccine, MVA85A, was safe and immunogenic in adults. Studies of nontuberculous mycobacteria (NTM) described a rapid rise in the prevalence and spatial clustering of NTM in the United States over the past decade. Although risk factors for pulmonary NTM such as advanced age and low BMI are known, the mechanisms underlying infection and disease remain mysterious. Four studies of therapy of NTM disease highlighted the pressing need for well-designed international randomized controlled trials to improve our management of NTM disease. PMID:24127799

  6. Heme Oxygenase-1 Regulation of Matrix Metalloproteinase-1 Expression Underlies Distinct Disease Profiles in Tuberculosis.

    PubMed

    Andrade, Bruno B; Pavan Kumar, Nathella; Amaral, Eduardo P; Riteau, Nicolas; Mayer-Barber, Katrin D; Tosh, Kevin W; Maier, Nolan; Conceição, Elisabete L; Kubler, Andre; Sridhar, Rathinam; Banurekha, Vaithilingam V; Jawahar, Mohideen S; Barbosa, Theolis; Manganiello, Vincent C; Moss, Joel; Fontana, Joseph R; Marciano, Beatriz E; Sampaio, Elizabeth P; Olivier, Kenneth N; Holland, Steven M; Jackson, Sharon H; Moayeri, Mahtab; Leppla, Stephen; Sereti, Irini; Barber, Daniel L; Nutman, Thomas B; Babu, Subash; Sher, Alan

    2015-09-15

    Pulmonary tuberculosis (TB) is characterized by oxidative stress and lung tissue destruction by matrix metalloproteinases (MMPs). The interplay between these distinct pathological processes and the implications for TB diagnosis and disease staging are poorly understood. Heme oxygenase-1 (HO-1) levels were previously shown to distinguish active from latent TB, as well as successfully treated Mycobacterium tuberculosis infection. MMP-1 expression is also associated with active TB. In this study, we measured plasma levels of these two important biomarkers in distinct TB cohorts from India and Brazil. Patients with active TB expressed either very high levels of HO-1 and low levels of MMP-1 or the converse. Moreover, TB patients with either high HO-1 or MMP-1 levels displayed distinct clinical presentations, as well as plasma inflammatory marker profiles. In contrast, in an exploratory North American study, inversely correlated expression of HO-1 and MMP-1 was not observed in patients with other nontuberculous lung diseases. To assess possible regulatory interactions in the biosynthesis of these two enzymes at the cellular level, we studied the expression of HO-1 and MMP-1 in M. tuberculosis-infected human and murine macrophages. We found that infection of macrophages with live virulent M. tuberculosis is required for robust induction of high levels of HO-1 but not MMP-1. In addition, we observed that CO, a product of M. tuberculosis-induced HO-1 activity, inhibits MMP-1 expression by suppressing c-Jun/AP-1 activation. These findings reveal a mechanistic link between oxidative stress and tissue remodeling that may find applicability in the clinical staging of TB patients. PMID:26268658

  7. Novel Cephalosporins Selectively Active on Nonreplicating Mycobacterium tuberculosis

    PubMed Central

    2016-01-01

    We report two series of novel cephalosporins that are bactericidal to Mycobacterium tuberculosis alone of the pathogens tested, which only kill M. tuberculosis when its replication is halted by conditions resembling those believed to pertain in the host, and whose bactericidal activity is not dependent upon or enhanced by clavulanate, a β-lactamase inhibitor. The two classes of cephalosporins bear an ester or alternatively an oxadiazole isostere at C-2 of the cephalosporin ring system, a position that is almost exclusively a carboxylic acid in clinically used agents in the class. Representatives of the series kill M. tuberculosis within macrophages without toxicity to the macrophages or other mammalian cells. PMID:27144688

  8. Novel Cephalosporins Selectively Active on Nonreplicating Mycobacterium tuberculosis.

    PubMed

    Gold, Ben; Smith, Robert; Nguyen, Quyen; Roberts, Julia; Ling, Yan; Lopez Quezada, Landys; Somersan, Selin; Warrier, Thulasi; Little, David; Pingle, Maneesh; Zhang, David; Ballinger, Elaine; Zimmerman, Matthew; Dartois, Véronique; Hanson, Paul; Mitscher, Lester A; Porubsky, Patrick; Rogers, Steven; Schoenen, Frank J; Nathan, Carl; Aubé, Jeffrey

    2016-07-14

    We report two series of novel cephalosporins that are bactericidal to Mycobacterium tuberculosis alone of the pathogens tested, which only kill M. tuberculosis when its replication is halted by conditions resembling those believed to pertain in the host, and whose bactericidal activity is not dependent upon or enhanced by clavulanate, a β-lactamase inhibitor. The two classes of cephalosporins bear an ester or alternatively an oxadiazole isostere at C-2 of the cephalosporin ring system, a position that is almost exclusively a carboxylic acid in clinically used agents in the class. Representatives of the series kill M. tuberculosis within macrophages without toxicity to the macrophages or other mammalian cells. PMID:27144688

  9. HIV-Mycobacterium tuberculosis co-infection: a 'danger-couple model' of disease pathogenesis.

    PubMed

    Shankar, Esaki M; Vignesh, Ramachandran; Ellegård, Rada; Barathan, Muttiah; Chong, Yee K; Bador, M Kahar; Rukumani, Devi V; Sabet, Negar S; Kamarulzaman, Adeeba; Velu, Vijayakumar; Larsson, Marie

    2014-03-01

    Tuberculosis (TB) and human immunodeficiency virus (HIV) infection interfere and impact the pathogenesis phenomena of each other. Owing to atypical clinical presentations and diagnostic complications, HIV/TB co-infection continues to be a menace for healthcare providers. Although the increased access to highly active antiretroviral therapy (HAART) has led to a reduction in HIV-associated opportunistic infections and mortality, the concurrent management of HIV/TB co-infection remains a challenge owing to adverse effects, complex drug interactions, overlapping toxicities and tuberculosis -associated immune reconstitution inflammatory syndrome. Several hypotheses have been put forward for the exacerbation of tuberculosis by HIV and vice versa supported by immunological studies. Discussion on the mechanisms produced by infectious cofactors with impact on disease pathology could shed light on how to design potential interventions that could decelerate disease progression. With no vaccine for HIV and lack of an effective vaccine for tuberculosis, it is essential to design strategies against HIV-TB co-infection. PMID:24214523

  10. Active case finding of tuberculosis: historical perspective and future prospects

    PubMed Central

    Golub, J. E.; Mohan, C. I.; Comstock, G. W.; Chaisson, R. E.

    2015-01-01

    SUMMARY Despite a history of remarkable scientific achievements in microbiology and therapeutics, tuberculosis (TB) continues to pose an extraordinary threat to human health. Case finding and treatment of TB disease are the principal means of controlling transmission and reducing incidence. This review presents a historical perspective of active case finding (ACF) of TB, detailing case detection strategies that have been used over the last century. This review is divided into the following sections: mass radiography, house-to-house surveys, out-patient case detection, enhanced case finding, high-risk populations and cost-effectiveness. The report concludes with a discussion and recommendations for future case finding strategies. Understanding the strengths and weaknesses of these methods will help inform and shape ACF as a TB control policy in the twenty-first century. PMID:16333924

  11. Impaired activation of Stat1 and c-Jun as a possible defect in macrophages of patients with active tuberculosis.

    PubMed

    Esquivel-Solís, H; Quiñones-Falconi, F; Zarain-Herzberg, A; Amieva-Fernández, R I; López-Vidal, Y

    2009-10-01

    Studies of patients with active tuberculosis (TB) and infected healthy individuals have shown that interferon (IFN)-gamma is present in sites of Mycobacterium tuberculosis infection in comparable levels. This suggests that there is a deficiency in the macrophage response to IFN-gamma in TB patients. We used recombinant human IFN-gamma to stimulate adherent monocyte-derived macrophages from three groups of people: patients with active tuberculosis (TBP), their healthy household contacts (HHC) and healthy uninfected controls from the community (CC). We then evaluated the ability of the macrophages to inhibit the growth of M. tuberculosis H37Rv as well as their cytokine profile at early in infection (48 h). After IFN-gamma treatment, macrophages of healthy individuals (HHC and CC) controlled M. tuberculosis growth and produced mainly nitric oxide (NO) and interleukin (IL)-12p70, whereas TBP macrophages did not kill M. tuberculosis. Additionally, TBP macrophages produced low levels of NO and IL-12p70 and high levels of tumour necrosis factor (TNF)-alpha and IL-10. Transforming growth factor (TGF)-beta levels were similar among all three groups. M. tuberculosis infection had little effect on the cytokine response after IFN-gamma stimulus, but infection alone induced more IL-10 and TGF-beta in TBP macrophages. There were no differences in Stat1 nuclear translocation and DNA binding between the groups. However, the phosphorylated Stat1 and c-Jun (AP-1) in nuclear protein extracts was diminished in TBP macrophages compared to macrophages of healthy individuals. These results indicate an impairment of Stat1-dependent and Stat1-independent IFN-gamma signalling in macrophages of people with active tuberculosis, suggesting a different molecular regulation that could impact macrophage functionality and disease outcome. PMID:19737230

  12. Identification of new diamine scaffolds with activity against Mycobacterium tuberculosis

    PubMed Central

    Bogatcheva, Elena; Hanrahan, Colleen; Nikonenko, Boris; Samala, Rowena; Chen, Ping; Gearhart, Jacqueline; Barbosa, Francis; Einck, Leo; Nacy, Carol A.; Protopopova, Marina

    2015-01-01

    A diverse 5,000-compound library was synthesized from commercially available diamines and screened for activity against Mycobacterium tuberculosis in vitro, revealing 143 hits with MIC equal to or less than 12.5 µM. New prospective scaffolds with antitubercular activity derived from homopiperazine, phenyl- and benzyl substituted piperazines, 4-aminomethylpiperidine, 4-aminophenylethylamine, 4,4'-methylenebiscyclohexylamine were identified. Compound SQ775 derived from homopiperazine, and compound SQ786 derived from benzylpiperazine had potent antimicrobial activity against M. tuberculosis in experimental animals in vivo. PMID:16722620

  13. Functional analysis of TPM domain containing Rv2345 of Mycobacterium tuberculosis identifies its phosphatase activity.

    PubMed

    Sinha, Avni; Eniyan, Kandasamy; Sinha, Swati; Lynn, Andrew Michael; Bajpai, Urmi

    2015-07-01

    Mycobacterium tuberculosis (Mtb) is the causal agent of tuberculosis, the second largest infectious disease. With the rise of multi-drug resistant strains of M. tuberculosis, serious challenge lies ahead of us in treating the disease. The availability of complete genome sequence of Mtb has improved the scope for identifying new proteins that would not only further our understanding of biology of the organism but could also serve to discover new drug targets. In this study, Rv2345, a hypothetical membrane protein of M. tuberculosis H37Rv, which is reported to be a putative ortholog of ZipA cell division protein has been assigned function through functional annotation using bioinformatics tools followed by experimental validation. Sequence analysis showed Rv2345 to have a TPM domain at its N-terminal region and predicted it to have phosphatase activity. The TPM domain containing region of Rv2345 was cloned and expressed using pET28a vector in Escherichia coli and purified by Nickel affinity chromatography. The purified TPM domain was tested in vitro and our results confirmed it to have phosphatase activity. The enzyme activity was first checked and optimized with pNPP as substrate, followed by using ATP, which was also found to be used as substrate by the purified protein. Hence sequence analysis followed by in vitro studies characterizes TPM domain of Rv2345 to contain phosphatase activity. PMID:25782739

  14. Gamma interferon release assay for monitoring of treatment response for active tuberculosis: an explosion in the spaghetti factory.

    PubMed

    Denkinger, Claudia M; Pai, Madhukar; Patel, Meena; Menzies, Dick

    2013-02-01

    Few studies have correlated the results of interferon (gamma interferon) release assays (IGRAs) with known markers of tuberculosis (TB) treatment response. We report the results of serial QuantiFERON-TB gold in-tube assay (QFT) testing on 149 patients with active tuberculosis and correlate the results with smear and culture conversion. We show that QFT results do not offer much value for treatment monitoring of TB disease. PMID:23175268

  15. Identification of potential biomarkers of disease progression in bovine tuberculosis.

    PubMed

    Blanco, Federico Carlos; Bigi, Fabiana; Soria, Marcelo Abel

    2014-08-15

    Bovine tuberculosis (bTB) remains an important animal and zoonotic disease in many countries. The diagnosis of bTB is based on tuberculin skin test and IFN-γ release assays (IGRA). Positive animals are separated from the herd and sacrificed. The cost of this procedure is difficult to afford for developing countries with high prevalence of bTB; therefore, the improvement of diagnostic methods and the identification of animals in different stages of the disease will be helpful to control the infection. To identify biomarkers that can discriminate between tuberculin positive cattle with and without tuberculosis lesions (ML+ and ML-, respectively), we assessed a group of immunological parameters with three different classification methods: lineal discriminant analysis (LDA), quadratic discriminant analysis (QDA) and K nearest neighbors (k-nn). For this purpose, we used data from 30 experimentally infected cattle. All the classifiers (LDA, QDA and k-nn) selected IL-2 and IL-17 as the most discriminatory variables. The best classification method was LDA using IL-17 and IL-2 as predictors. The addition of IL-10 to LDA improves the performance of the classifier to discriminate ML-individuals (93.3% vs. 86.7%). Thus, the expression of IL-17, IL-2 and, in some cases, IL-10 would serve as an additional tool to study disease progression in herds with a history of bTB. PMID:24856732

  16. Congenital Tuberculosis as a Result of Disseminated Maternal Disease: Case Report

    PubMed Central

    Trujillo-Honeysberg, Mónica; Diazgranados-Cuenca, Lucy

    2015-01-01

    Although tuberculosis is highly prevalent worldwide, congenital tuberculosis is one of the least common manifestations of the disease. The diagnosis is usually difficult because of the non-specific clinical presentation and the lack of awareness of maternal disease prior to pregnancy and delivery. We present the case of a preterm neonate with congenital tuberculosis, born to a previously healthy mother who had developed severe disseminated tuberculosis during her pregnancy. Once the diagnosis was confirmed in the mother, the congenital infection was confirmed by isolation of Mycobacterium tuberculosis in gastric aspirates, and positive polymerase chain reaction in a cerebrospinal fluid examination. Treatment for tuberculosis with a four-drug regimen resulted in an adequate clinical response in both the mother and infant. PMID:26508944

  17. [Spanish Society for Pediatric Infectious Diseases guidelines on tuberculosis in pregnant women and neonates (i): Epidemiology and diagnosis. Congenital tuberculosis].

    PubMed

    Baquero-Artigao, F; Mellado Peña, M J; Del Rosal Rabes, T; Noguera Julián, A; Goncé Mellgren, A; de la Calle Fernández-Miranda, M; Navarro Gómez, M L

    2015-10-01

    Tuberculosis (TB) screening in pregnancy using tuberculin skin test (TST) is recommended in case of symptoms of TB disease, close contact with a patient with infectious TB, or high risk of developing active disease. The new interferon gamma release assay (IGRA) tests are recommended in BCG-vaccinated pregnant women with positive TST and no known risk factors for TB, and in those immunocompromised, with clinical suspicion of TB but negative TST. TB diagnosis is difficult due to the non-specific symptoms, the increased frequency of extrapulmonary disease, the delay in radiological examinations, and the high rate of tuberculin anergy. Neonatal TB can be acquired in utero (congenital TB), or through airborne transmission after delivery (postnatal TB). Congenital TB is extremely rare and does not cause fetal malformations. It may be evident at birth, although it usually presents after the second week of life. In newborns with no family history of TB, the disease should be considered in cases of miliary pneumonia, hepatosplenomegaly with focal lesions, or lymphocytic meningitis with hypoglycorrhachia, especially in those born to immigrants from high TB-burden countries. TST is usually negative, and IGRAs have lower sensitivity than in older children. However, the yield of acid-fast smear and culture is higher, mostly in congenital TB. Molecular diagnosis techniques enable early diagnosis and detection of drug resistance mutations. There is a substantial risk of disseminated disease and death. PMID:25754313

  18. All-trans retinoic acid triggered antimicrobial activity against Mycobacterium tuberculosis is dependent on NPC2

    PubMed Central

    Inkeles, Megan S.; De Leon, Avelino; Pellegrini, Matteo; Krutzik, Stephan R.; Liu, Philip T.

    2014-01-01

    A role for vitamin A in host defense against Mycobacterium tuberculosis has been suggested through epidemiological and in vitro studies; however, the mechanism is unclear. Here, we demonstrate that vitamin A-triggered antimicrobial activity against M. tuberculosis requires expression of Niemann-Pick disease type C2 (NPC2). Comparison of monocytes stimulated with all-trans retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3 (1,25D3), the biologically active forms of vitamin A and vitamin D, respectively, indicates that ATRA and 1,25D3 induce mechanistically distinct antimicrobial activities. Stimulation of primary human monocytes with ATRA did not result in expression of the antimicrobial peptide cathelicidin, which is required for 1,25D3 antimicrobial activity. In contrast, ATRA triggers a reduction in the total cellular cholesterol concentration, whereas 1,25D3 did not. Blocking ATRA-induced cellular cholesterol reduction inhibits antimicrobial activity as well. Bioinformatic analysis of ATRA and 1,25D3 induced gene profiles suggests Niemann-Pick disease type C2 (NPC2) is a key gene in ATRA-induced cholesterol regulation. Knockdown experiments demonstrate that ATRA-mediated decrease of total cellular cholesterol content and increase in lysosomal acidification are both dependent upon expression of NPC2. Expression of NPC2 was lower in caseous tuberculosis granulomas and M. tuberculosis-infected monocytes compared to normal lung and uninfected cells, respectively. Loss of NPC2 expression ablated ATRA-induced antimicrobial activity. Taken together, these results suggest that the vitamin A-mediated antimicrobial mechanism against M. tuberculosis requires NPC2-dependent expression and function, indicating a key role for cellular cholesterol regulation in the innate immune response. PMID:24501203

  19. Involvement of Antilipoarabinomannan Antibodies in Classical Complement Activation in Tuberculosis

    PubMed Central

    Hetland, Geir; Wiker, Harald G.; Høgåsen, Kolbjørn; Hamasur, Beston; Svenson, Stefan B.; Harboe, Morten

    1998-01-01

    We examined alternative and classical complement activation induced by whole bacilli of Mycobacterium bovis BCG and Mycobacterium tuberculosis products. After exposure to BCG, there were higher levels of the terminal complement complex in sera from Indian tuberculosis patients than in sera from healthy controls. The addition of BCG with or without EGTA to these sera indicated that approximately 70 to 85% of the total levels of the terminal complement complex was formed by classical activation. Sera from Indian tuberculosis patients contained more antibody to lipoarabinomannan (LAM) than sera from healthy Indians. Levels of anti-LAM immunoglobulin G2 (IgG2), but not anti-LAM IgM, correlated positively with classical activation induced by BCG in the sera. By flow cytometry, deposition of C3 and terminal complement complex on bacilli incubated with normal human serum was demonstrated. The anticomplement staining was significantly reduced in the presence of EGTA and EDTA. Flow cytometry also revealed the binding of complement to BCG incubated with rabbit anti-LAM and then with factor B-depleted serum. This indicates that classical activation plays a major role in complement activation induced by mycobacteria and that anti-LAM IgG on the bacilli can mediate this response. Classical complement activation may be important for the extent of phagocytosis of M. tuberculosis by mononuclear phagocytes, which may influence the course after infection. PMID:9521145

  20. Angiotensin-Converting Enzyme Inhibitors and Active Tuberculosis

    PubMed Central

    Wu, Jiunn-Yih; Lee, Meng-Tse Gabriel; Lee, Si-Huei; Lee, Shih-Hao; Tsai, Yi-Wen; Hsu, Shou-Chien; Chang, Shy-Shin; Lee, Chien-Chang

    2016-01-01

    Abstract Numerous epidemiological data suggest that the use of angiotensin-converting enzyme inhibitors (ACEis) can improve the clinical outcomes of pneumonia. Tuberculosis (TB) is an airborne bacteria like pneumonia, and we aimed to find out whether the use of ACEis can decrease the risk of active TB. We conducted a nested case–control analysis by using a 1 million longitudinally followed cohort, from Taiwan national health insurance research database. The rate ratios (RRs) for TB were estimated by conditional logistic regression, and adjusted using a TB-specific disease risk score (DRS) with 71 TB-related covariates. From January, 1997 to December, 2011, a total of 75,536 users of ACEis, and 7720 cases of new active TB were identified. Current use (DRS adjusted RR, 0.87 [95% CI, 0.78–0.97]), but not recent and past use of ACEis, was associated with a decrease in risk of active TB. Interestingly, it was found that chronic use (>90 days) of ACEis was associated with a further decrease in the risk of TB (aRR, 0.74, [95% CI, 0.66–0.83]). There was also a duration response effect, correlating decrease in TB risk with longer duration of ACEis use. The decrease in TB risk was also consistent across all patient subgroups (age, sex, heart failure, cerebrovascular diseases, myocardial infraction, renal diseases, and diabetes) and patients receiving other cardiovascular medicine. In this large population-based study, we found that subjects with recent and chronic use of ACEis were associated with decrease in TB risk. PMID:27175655

  1. Too Busy for TB: Managing a Case of Tuberculosis Disease in the School Setting.

    PubMed

    Galemore, Cynthia A

    2016-03-01

    School nurses actively monitor the school population for signs of communicable disease on a daily basis. State regulations outline reportable diseases and provide guidance to control disease outbreak, including management of disease outbreak in the school setting. The purpose of this article is to review strategies recently used in managing a tuberculosis (TB) outbreak at a large high school in Kansas. A timeline of events is presented along with a discussion of the differences between latent TB infection and TB disease. Partnering across agencies and departments enabled the timely testing of over 400 individuals and subsequent management of individuals testing positive for latent TB infection. Public information officers provided necessary guidance to communicate to audiences both internally and externally. PMID:26822133

  2. MicroRNA-365 in macrophages regulates Mycobacterium tuberculosis-induced active pulmonary tuberculosis via interleukin-6.

    PubMed

    Song, Qingzhang; Li, Hui; Shao, Hua; Li, Chunling; Lu, Xiao

    2015-01-01

    The present study is to investigate the relationship between microRNA (miR)-365 expression and the levels of interleukin (IL)-6 mRNA and protein in patients with active tuberculosis. From June 2011 to June 2014, 48 patients with active pulmonary tuberculosis induced by Mycobacterium tuberculosis were included in the study. In addition, 23 healthy subjects were enrolled as control. Macrophages were collected by pulmonary alveolus lavage. In addition, serum and mononuclear cells were isolated from peripheral blood. The levels of miR-365 and IL-6 in macrophages, mononuclear cells and serum were determined using quantitative real-time polymerase chain reaction. The protein expression of IL-6 in macrophages and mononuclear cells was measured using Western blotting, while that in serum was detected by enzyme-linked immunoabsorbent assay. Expression of IL-6 mRNA and protein was significantly enhanced in patients with active pulmonary tuberculosis. Increase of IL-6 protein concentration in serum was probably due to the release of IL-6 protein from mononuclear cells in the blood. In addition, miR-365 levels were significantly lowered in patients with active pulmonary tuberculosis. Up-regulated IL-6 expression in macrophages, mononuclear cells and serum in patients with active pulmonary tuberculosis is related to the down-regulation of miR-365, suggesting that miR-365 may regulate the occurrence and immune responses of active pulmonary tuberculosis via IL-6. PMID:26629035

  3. MicroRNA-365 in macrophages regulates Mycobacterium tuberculosis-induced active pulmonary tuberculosis via interleukin-6

    PubMed Central

    Song, Qingzhang; Li, Hui; Shao, Hua; Li, Chunling; Lu, Xiao

    2015-01-01

    The present study is to investigate the relationship between microRNA (miR)-365 expression and the levels of interleukin (IL)-6 mRNA and protein in patients with active tuberculosis. From June 2011 to June 2014, 48 patients with active pulmonary tuberculosis induced by Mycobacterium tuberculosis were included in the study. In addition, 23 healthy subjects were enrolled as control. Macrophages were collected by pulmonary alveolus lavage. In addition, serum and mononuclear cells were isolated from peripheral blood. The levels of miR-365 and IL-6 in macrophages, mononuclear cells and serum were determined using quantitative real-time polymerase chain reaction. The protein expression of IL-6 in macrophages and mononuclear cells was measured using Western blotting, while that in serum was detected by enzyme-linked immunoabsorbent assay. Expression of IL-6 mRNA and protein was significantly enhanced in patients with active pulmonary tuberculosis. Increase of IL-6 protein concentration in serum was probably due to the release of IL-6 protein from mononuclear cells in the blood. In addition, miR-365 levels were significantly lowered in patients with active pulmonary tuberculosis. Up-regulated IL-6 expression in macrophages, mononuclear cells and serum in patients with active pulmonary tuberculosis is related to the down-regulation of miR-365, suggesting that miR-365 may regulate the occurrence and immune responses of active pulmonary tuberculosis via IL-6. PMID:26629035

  4. Central Nervous System Tuberculosis: An Imaging-Focused Review of a Reemerging Disease

    PubMed Central

    Sanei Taheri, Morteza; Karimi, Mohammad Ali; Haghighatkhah, Hamidreza; Samadian, Mohammad; Delavar Kasmaei, Hosein

    2015-01-01

    Central nervous system (CNS) tuberculosis is a potentially life threatening condition which is curable if the correct diagnosis is made in the early stages. Its clinical and radiologic manifestations may mimic other infectious and noninfectious neurological conditions. Hence, familiarity with the imaging presentations of various forms of CNS tuberculosis is essential in timely diagnosis, and thereby reducing the morbidity and mortality of this disease. In this review, we describe the imaging characteristics of the different forms of CNS tuberculosis, including meningitis, tuberculoma, miliary tuberculosis, abscess, cerebritis, and encephalopathy. PMID:25653877

  5. Central nervous system tuberculosis: an imaging-focused review of a reemerging disease.

    PubMed

    Sanei Taheri, Morteza; Karimi, Mohammad Ali; Haghighatkhah, Hamidreza; Pourghorban, Ramin; Samadian, Mohammad; Delavar Kasmaei, Hosein

    2015-01-01

    Central nervous system (CNS) tuberculosis is a potentially life threatening condition which is curable if the correct diagnosis is made in the early stages. Its clinical and radiologic manifestations may mimic other infectious and noninfectious neurological conditions. Hence, familiarity with the imaging presentations of various forms of CNS tuberculosis is essential in timely diagnosis, and thereby reducing the morbidity and mortality of this disease. In this review, we describe the imaging characteristics of the different forms of CNS tuberculosis, including meningitis, tuberculoma, miliary tuberculosis, abscess, cerebritis, and encephalopathy. PMID:25653877

  6. Pulmonary Disease due to Mycobacterium tuberculosis in a Horse: Zoonotic Concerns and Limitations of Antemortem Testing

    PubMed Central

    Lyashchenko, Konstantin P.; Greenwald, Rena; Esfandiari, Javan; Lecu, Alexis; Waters, W. Ray; Posthaus, Horst; Bodmer, Thomas; Janssens, Jean-Paul; Aloisio, Fabio; Graubner, Claudia; Grosclaude, Eléonore; Piersigilli, Alessandra; Schiller, Irene

    2012-01-01

    A case of pulmonary tuberculosis caused by Mycobacterium tuberculosis was diagnosed in a horse. Clinical evaluation performed prior to euthanasia did not suggest tuberculosis, but postmortem examination provided pathological and bacteriological evidence of mycobacteriosis. In the lungs, multiple tuberculoid granulomas communicating with the bronchiolar lumen, pleural effusion, and a granulomatous lymphadenitis involving mediastinal and tracheobronchial lymph nodes were found. Serologic response to M. tuberculosis antigens was detected in the infected horse, but not in the group of 42 potentially exposed animals (18 horses, 14 alpacas, 6 donkeys, and 4 dogs) which showed no signs of disease. Diagnosis of tuberculosis in live horses remains extremely difficult. Four of 20 animal handlers at the farm were positive for tuberculous infection upon follow-up testing by interferon-gamma release assay, indicating a possibility of interspecies transmission of M. tuberculosis. PMID:22567544

  7. Pulmonary Disease due to Mycobacterium tuberculosis in a Horse: Zoonotic Concerns and Limitations of Antemortem Testing.

    PubMed

    Lyashchenko, Konstantin P; Greenwald, Rena; Esfandiari, Javan; Lecu, Alexis; Waters, W Ray; Posthaus, Horst; Bodmer, Thomas; Janssens, Jean-Paul; Aloisio, Fabio; Graubner, Claudia; Grosclaude, Eléonore; Piersigilli, Alessandra; Schiller, Irene

    2012-01-01

    A case of pulmonary tuberculosis caused by Mycobacterium tuberculosis was diagnosed in a horse. Clinical evaluation performed prior to euthanasia did not suggest tuberculosis, but postmortem examination provided pathological and bacteriological evidence of mycobacteriosis. In the lungs, multiple tuberculoid granulomas communicating with the bronchiolar lumen, pleural effusion, and a granulomatous lymphadenitis involving mediastinal and tracheobronchial lymph nodes were found. Serologic response to M. tuberculosis antigens was detected in the infected horse, but not in the group of 42 potentially exposed animals (18 horses, 14 alpacas, 6 donkeys, and 4 dogs) which showed no signs of disease. Diagnosis of tuberculosis in live horses remains extremely difficult. Four of 20 animal handlers at the farm were positive for tuberculous infection upon follow-up testing by interferon-gamma release assay, indicating a possibility of interspecies transmission of M. tuberculosis. PMID:22567544

  8. AIDS and multidrug-resistant tuberculosis: an epidemic transforms an old disease.

    PubMed

    Farley, T A

    1992-08-01

    Since 1985, tuberculosis case counts in the United States have increased, primarily because of the influence of the HIV epidemic. In addition, during this time outbreaks of multidrug-resistant tuberculosis among patients with AIDS or HIV infection have been reported in New York City and Florida. These outbreaks have occurred in hospitals and prisons and have been characterized by high case fatality rates, disease transmission within the institutions, and high infection rates in health care workers. The increase in tuberculosis rates and the outbreaks have raised concern that multidrug-resistant tuberculosis could become a widespread problem in the United States. Dealing with tuberculosis in the 1990s will require reconsideration of our current methods of tuberculosis prevention, diagnosis, treatment, and control. PMID:1453093

  9. The outcome of tuberculosis treatment in subjects with chronic kidney disease in Brazil: a multinomial analysis*

    PubMed Central

    Reis-Santos, Barbara; Gomes, Teresa; Horta, Bernardo Lessa; Maciel, Ethel Leonor Noia

    2013-01-01

    OBJECTIVE: To analyze the association between clinical/epidemiological characteristics and outcomes of tuberculosis treatment in patients with concomitant tuberculosis and chronic kidney disease (CKD) in Brazil. METHODS: We used the Brazilian Ministry of Health National Case Registry Database to identify patients with tuberculosis and CKD, treated between 2007 and 2011. The tuberculosis treatment outcomes were compared with epidemiological and clinical characteristics of the subjects using a hierarchical multinomial logistic regression model, in which cure was the reference outcome. RESULTS: The prevalence of CKD among patients with tuberculosis was 0.4% (95% CI: 0.37-0.42%). The sample comprised 1,077 subjects. The outcomes were cure, in 58%; treatment abandonment, in 7%; death from tuberculosis, in 13%; and death from other causes, in 22%. The characteristics that differentiated the ORs for treatment abandonment or death were age; alcoholism; AIDS; previous noncompliance with treatment; transfer to another facility; suspected tuberculosis on chest X-ray; positive results in the first smear microscopy; and indications for/use of directly observed treatment, short-course strategy. CONCLUSIONS: Our data indicate the importance of sociodemographic characteristics for the diagnosis of tuberculosis in patients with CKD and underscore the need for tuberculosis control strategies targeting patients with chronic noncommunicable diseases, such as CKD. PMID:24310632

  10. Tuberculosis

    MedlinePlus

    ... to address TB and HIV coinfection around the world? The President’s U.S. President's Emergency Plan for AIDS ... of those suffering from HIV/AIDS around the world. PEPFAR’s Global Fund to Fight AIDS, Tuberculosis and ...

  11. The Influence of Host and Bacterial Genotype on the Development of Disseminated Disease with Mycobacterium tuberculosis

    PubMed Central

    Caws, Maxine; Thwaites, Guy; Dunstan, Sarah; Hawn, Thomas R.; Thi Ngoc Lan, Nguyen; Thuong, Nguyen Thuy Thuong; Stepniewska, Kasia; Huyen, Mai Nguyet Thu; Bang, Nguyen Duc; Huu Loc, Tran; Gagneux, Sebastien; van Soolingen, Dick; Kremer, Kristin; van der Sande, Marianne; Small, Peter; Thi Hoang Anh, Phan; Chinh, Nguyen Tran; Thi Quy, Hoang; Thi Hong Duyen, Nguyen; Quang Tho, Dau; Hieu, Nguyen T.; Torok, Estee; Hien, Tran Tinh; Dung, Nguyen Huy; Thi Quynh Nhu, Nguyen; Duy, Phan Minh; van Vinh Chau, Nguyen; Farrar, Jeremy

    2008-01-01

    The factors that govern the development of tuberculosis disease are incompletely understood. We hypothesized that some strains of Mycobacterium tuberculosis (M. tuberculosis) are more capable of causing disseminated disease than others and may be associated with polymorphisms in host genes responsible for the innate immune response to infection. We compared the host and bacterial genotype in 187 Vietnamese adults with tuberculous meningitis (TBM) and 237 Vietnamese adults with uncomplicated pulmonary tuberculosis. The host genotype of tuberculosis cases was also compared with the genotype of 392 cord blood controls from the same population. Isolates of M. tuberculosis were genotyped by large sequence polymorphisms. The hosts were defined by polymorphisms in genes encoding Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and Toll-like receptor-2 (TLR-2). We found a significant protective association between the Euro-American lineage of M. tuberculosis and pulmonary rather than meningeal tuberculosis (Odds ratio (OR) for causing TBM 0.395, 95% confidence intervals (C.I.) 0.193–0.806, P = 0.009), suggesting these strains are less capable of extra-pulmonary dissemination than others in the study population. We also found that individuals with the C allele of TLR-2 T597C allele were more likely to have tuberculosis caused by the East-Asian/Beijing genotype (OR = 1.57 [95% C.I. 1.15–2.15]) than other individuals. The study provides evidence that M. tuberculosis genotype influences clinical disease phenotype and demonstrates, for the first time, a significant interaction between host and bacterial genotypes and the development of tuberculosis. PMID:18369480

  12. The International Union Against Tuberculosis and Lung Disease: past, present and future.

    PubMed

    Billo, Nils; Castro, José Luis; Jones, Sinéad; Rusen, I D; Chiang, Chen-Yuan; Fussell, Mark; Fujiwara, Paula I; Harries, Anthony D; Enarson, Donald A

    2009-12-01

    The International Union Against Tuberculosis and Lung Disease (The Union) is the oldest international non-governmental organization involved in the fight against tuberculosis. This review documents the history and structure of The Union up to 2009, and describes the achievements that have taken place in the field of tuberculosis and lung health. The progress made in tackling the major killer (pneumonia) of children less than 5 years of age, the barrier to affordable essential asthma medicines, the complex issue of tobacco control, the move into the realm of HIV and AIDS, and new ideas and activities around the increasingly important domain of operational research are described and discussed. Finally, as with many institutions that have seen a rapid phase of growth, expansion and decentralisation to regional offices around the world, the review highlights the internal strategic initiative that aims to fine-tune the organisational structure, clarify lines of authority, create more efficient business, human resource and financial systems and revise, where necessary, The Union's guiding mission, vision and values for the future. PMID:24036555

  13. Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

    PubMed Central

    Monin, Leticia; Griffiths, Kristin L.; Lam, Wing Y.; Gopal, Radha; Kang, Dongwan D.; Ahmed, Mushtaq; Rajamanickam, Anuradha; Cruz-Lagunas, Alfredo; Zúñiga, Joaquín; Babu, Subash; Kolls, Jay K.; Mitreva, Makedonka; Rosa, Bruce A.; Ramos-Payan, Rosalio; Morrison, Thomas E.; Murray, Peter J.; Rangel-Moreno, Javier; Pearce, Edward J.; Khader, Shabaana A.

    2015-01-01

    Parasitic helminth worms, such as Schistosoma mansoni, are endemic in regions with a high prevalence of tuberculosis (TB) among the population. Human studies suggest that helminth coinfections contribute to increased TB susceptibility and increased rates of TB reactivation. Prevailing models suggest that T helper type 2 (Th2) responses induced by helminth infection impair Th1 immune responses and thereby limit Mycobacterium tuberculosis (Mtb) control. Using a pulmonary mouse model of Mtb infection, we demonstrated that S. mansoni coinfection or immunization with S. mansoni egg antigens can reversibly impair Mtb-specific T cell responses without affecting macrophage-mediated Mtb control. Instead, S. mansoni infection resulted in accumulation of high arginase-1–expressing macrophages in the lung, which formed type 2 granulomas and exacerbated inflammation in Mtb-infected mice. Treatment of coinfected animals with an antihelminthic improved Mtb-specific Th1 responses and reduced disease severity. In a genetically diverse mouse population infected with Mtb, enhanced arginase-1 activity was associated with increased lung inflammation. Moreover, in patients with pulmonary TB, lung damage correlated with increased serum activity of arginase-1, which was elevated in TB patients coinfected with helminths. Together, our data indicate that helminth coinfection induces arginase-1–expressing type 2 granulomas, thereby increasing inflammation and TB disease severity. These results also provide insight into the mechanisms by which helminth coinfections drive increased susceptibility, disease progression, and severity in TB. PMID:26571397

  14. LAG3 Expression in Active Mycobacterium tuberculosis Infections

    PubMed Central

    Phillips, Bonnie L.; Mehra, Smriti; Ahsan, Muhammad H.; Selman, Moises; Khader, Shabaana A.; Kaushal, Deepak

    2016-01-01

    Mycobacterium tuberculosis (MTB) is a highly successful pathogen because of its ability to persist in human lungs for long periods of time. MTB modulates several aspects of the host immune response. Lymphocyte-activation gene 3 (LAG3) is a protein with a high affinity for the CD4 receptor and is expressed mainly by regulatory T cells with immunomodulatory functions. To understand the function of LAG3 during MTB infection, a nonhuman primate model of tuberculosis, which recapitulates key aspects of natural human infection in rhesus macaques (Macaca mulatta), was used. We show that the expression of LAG3 is highly induced in the lungs and particularly in the granulomatous lesions of macaques experimentally infected with MTB. Furthermore, we show that LAG3 expression is not induced in the lungs and lung granulomas of animals exhibiting latent tuberculosis infection. However, simian immunodeficiency virus–induced reactivation of latent tuberculosis infection results in an increased expression of LAG3 in the lungs. This response is not observed in nonhuman primates infected with non-MTB bacterial pathogens, nor with simian immunodeficiency virus alone. Our data show that LAG3 was expressed primarily on CD4+ T cells, presumably by regulatory T cells but also by natural killer cells. The expression of LAG3 coincides with high bacterial burdens and changes in the host type 1 helper T-cell response. PMID:25549835

  15. EFFECT OF PYRAZINAMIDASE ACTIVITY ON PYRAZINAMIDE RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS

    PubMed Central

    Sheen, Patricia; Ferrer, Patricia; Gilman, Robert H.; López-Llano, Jon; Fuentes, Patricia; Valencia, Eddy; Zimic, Mirko J.

    2009-01-01

    Resistance of Mycobacterium tuberculosis to pyrazinamide is associated with mutations in the pncA gene, which codes for pyrazinamidase. The association between the enzymatic activity of mutated pyrazinamidases and the level of pyrazinamide resistance remains poorly understood. Twelve M. tuberculosis clinical isolates resistant to pyrazinamide were selected based on Wayne activity and localization of pyrazinamidase mutation. Recombinant pyrazinamidases were expressed and tested for their kinetic parameters (activity, kcat, Km, and efficiency). Pyrazinamide resistance level was measured by Bactec-460TB and 7H9 culture. The linear correlation between the resistance level and the kinetic parameters of the corresponding mutated pyrazinamidase was calculated. The enzymatic activity and efficiency of the mutated pyrazinamidases varied with the site of mutation and ranged widely from low to high levels close to the corresponding of the wild-type enzyme. The level of resistance was significantly associated with pyrazinamidase activity and efficiency, but only 27.3% of its statistical variability was explained. Although pyrazinamidase mutations are indeed associated with resistance, the loss of pyrazinamidase activity and efficiency as assessed in the recombinant mutated enzymes is not sufficient to explain a high variability of the level of pyrazinamide resistance, suggesting that complementary mechanisms for pyrazinamide resistance in M. tuberculosis with mutations in pncA are more important than currently thought. PMID:19249243

  16. Coincident Helminth Infection Modulates Systemic Inflammation and Immune Activation in Active Pulmonary Tuberculosis

    PubMed Central

    George, Parakkal Jovvian; Kumar, Nathella Pavan; Sridhar, Rathinam; Hanna, Luke E.; Nair, Dina; Banurekha, Vaithilingam V.; Nutman, Thomas B.; Babu, Subash

    2014-01-01

    Background Helminth infections are known to modulate innate and adaptive immune responses in active and latent tuberculosis (TB). However, the role of helminth infections in modulating responses associated with inflammation and immune activation (reflecting disease activity and/or severity) in TB is not known. Methodology We measured markers of inflammation and immune activation in active pulmonary TB individuals (ATB) with co-incidental Strongyloides stercoralis (Ss) infection. These included systemic levels of acute phase proteins, matrix metalloproteinases and their endogenous inhibitors and immune activation markers. As a control, we measured the systemic levels of the same molecules in TB-uninfected individuals (NTB) with or without Ss infection. Principal Findings Our data confirm that ATB is associated with elevated levels of the various measured molecules when compared to those seen in NTB. Our data also reveal that co-incident Ss infection in ATB individuals is associated with significantly decreased circulating levels of acute phase proteins, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases as well as the systemic immune activation markers, sCD14 and sCD163. These changes are specific to ATB since they are absent in NTB individuals with Ss infection. Conclusions Our data therefore reveal a profound effect of Ss infection on the markers associated with TB disease activity and severity and indicate that co-incidental helminth infections might dampen the severity of TB disease. PMID:25375117

  17. Interleukin 12 at the site of disease in tuberculosis.

    PubMed Central

    Zhang, M; Gately, M K; Wang, E; Gong, J; Wolf, S F; Lu, S; Modlin, R L; Barnes, P F

    1994-01-01

    Interleukin 12 (IL-12), a heterodimeric cytokine composed of p40 and p35 chains, has potent immunologic effects in vitro. We used tuberculous pleuritis as a model to study the immunoregulatory potential of IL-12 in vivo at the site of human infectious disease. Messenger RNAs for p40 and p35 were detected in pleural fluid from six of six patients by reverse-transcription polymerase chain reaction. By using an ELISA that detected both free p40 and heterodimeric IL-12, we found that mean concentrations were 585 +/- 89 pg/ml in pleural fluid of patients with tuberculous pleuritis, which were significantly higher than those in serum of the same patients (54 +/- 36 pg/ml), or in malignant pleural effusions (123 +/- 35 pg/ml). By using an ELISA specific for heterodimeric IL-12, we found that mean concentrations in pleural fluid of patients with tuberculous pleuritis were 165 +/- 28 pg/ml and undetectable in serum of the same patients, or in malignant pleural effusions. Bioactive IL-12 was detectable in five of five supernatants of pleural fluid cells stimulated with Mycobacterium tuberculosis. Addition of anti-IL-12 antibodies suppressed proliferative responses of pleural fluid cells to M. tuberculosis by 36 +/- 7%. These data indicate that IL-12 may play a role in the human immune response to infectious agents in vivo. We hypothesize that IL-12 contributes to the antimycobacterial immune response by enhancing production of interferon-gamma, facilitating development of Th1 cells and augmenting cytotoxicity of antigen-specific T cells and natural killer cells. Images PMID:7909320

  18. Target prediction for an open access set of compounds active against Mycobacterium tuberculosis.

    PubMed

    Martínez-Jiménez, Francisco; Papadatos, George; Yang, Lun; Wallace, Iain M; Kumar, Vinod; Pieper, Ursula; Sali, Andrej; Brown, James R; Overington, John P; Marti-Renom, Marc A

    2013-01-01

    Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects an estimated two billion people worldwide and is the leading cause of mortality due to infectious disease. The development of new anti-TB therapeutics is required, because of the emergence of multi-drug resistance strains as well as co-infection with other pathogens, especially HIV. Recently, the pharmaceutical company GlaxoSmithKline published the results of a high-throughput screen (HTS) of their two million compound library for anti-mycobacterial phenotypes. The screen revealed 776 compounds with significant activity against the M. tuberculosis H37Rv strain, including a subset of 177 prioritized compounds with high potency and low in vitro cytotoxicity. The next major challenge is the identification of the target proteins. Here, we use a computational approach that integrates historical bioassay data, chemical properties and structural comparisons of selected compounds to propose their potential targets in M. tuberculosis. We predicted 139 target--compound links, providing a necessary basis for further studies to characterize the mode of action of these compounds. The results from our analysis, including the predicted structural models, are available to the wider scientific community in the open source mode, to encourage further development of novel TB therapeutics. PMID:24098102

  19. Target Prediction for an Open Access Set of Compounds Active against Mycobacterium tuberculosis

    PubMed Central

    Martínez-Jiménez, Francisco; Papadatos, George; Yang, Lun; Wallace, Iain M.; Kumar, Vinod; Pieper, Ursula; Sali, Andrej; Brown, James R.; Overington, John P.; Marti-Renom, Marc A.

    2013-01-01

    Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects an estimated two billion people worldwide and is the leading cause of mortality due to infectious disease. The development of new anti-TB therapeutics is required, because of the emergence of multi-drug resistance strains as well as co-infection with other pathogens, especially HIV. Recently, the pharmaceutical company GlaxoSmithKline published the results of a high-throughput screen (HTS) of their two million compound library for anti-mycobacterial phenotypes. The screen revealed 776 compounds with significant activity against the M. tuberculosis H37Rv strain, including a subset of 177 prioritized compounds with high potency and low in vitro cytotoxicity. The next major challenge is the identification of the target proteins. Here, we use a computational approach that integrates historical bioassay data, chemical properties and structural comparisons of selected compounds to propose their potential targets in M. tuberculosis. We predicted 139 target - compound links, providing a necessary basis for further studies to characterize the mode of action of these compounds. The results from our analysis, including the predicted structural models, are available to the wider scientific community in the open source mode, to encourage further development of novel TB therapeutics. PMID:24098102

  20. Turning off the tap: stopping tuberculosis transmission through active case-finding and prompt effective treatment.

    PubMed

    Yuen, Courtney M; Amanullah, Farhana; Dharmadhikari, Ashwin; Nardell, Edward A; Seddon, James A; Vasilyeva, Irina; Zhao, Yanlin; Keshavjee, Salmaan; Becerra, Mercedes C

    2015-12-01

    To halt the global tuberculosis epidemic, transmission must be stopped to prevent new infections and new cases. Identification of individuals with tuberculosis and prompt initiation of effective treatment to rapidly render them non-infectious is crucial to this task. However, in settings of high tuberculosis burden, active case-finding is often not implemented, resulting in long delays in diagnosis and treatment. A range of strategies to find cases and ensure prompt and correct treatment have been shown to be effective in high tuberculosis-burden settings. The population-level effect of targeted active case-finding on reducing tuberculosis incidence has been shown by studies and projected by mathematical modelling. The inclusion of targeted active case-finding in a comprehensive epidemic-control strategy for tuberculosis should contribute substantially to a decrease in tuberculosis incidence. PMID:26515675

  1. Intestinal tuberculosis and Crohn's disease: challenging differential diagnosis.

    PubMed

    Ma, Jia Yi; Tong, Jin Lu; Ran, Zhi Hua

    2016-03-01

    Along with epidemiological changes in tuberculosis (TB) and an increased incidence of Crohn's disease (CD), the differential diagnosis of intestinal TB (ITB) and CD is of vital importance and has become a clinical challenge because treatment based on misdiagnosis may lead to fatal outcomes. In this study, we reviewed the similarities and differences in clinical, endoscopic, radiological and histological features of these two diseases. Concomitant pulmonary TB, ascites, night sweats, involvement of fewer than four segments of the bowel, patulous ileocecal valve, transverse ulcers, scars or pseudopolyps strongly indicate ITB. Bloody stools, perianal signs, chronic diarrhea, extraintestinal manifestations, anorectal lesions, longitudinal ulcers and a cobblestone appearance are all suggestive of CD. Significant differences in the size, number, location and patterns of granulomas in ITB and CD with regard to their histopathologic features have been noted. Immune stain of cell surface markers is also helpful. Interferon-γ release assay and polymerase chain reaction analysis have achieved satisfactory sensitivity and specificity in the diagnosis of ITB. Computed tomography enterographic findings of segmental small bowel or left colon involvement, mural stratification, the comb sign and fibrofatty proliferation are significantly more common in CD, whereas mesenteric lymph node changes (calcification or central necrosis) and focal ileocecal lesions are more frequently seen in ITB. A diagnosis should be carefully established before the initiation of the therapy. In suspicious cases, short-term empirical anti-TB therapy is quite efficient to further confirm the diagnosis. PMID:26854750

  2. Diagnostic value of antibody responses to multiple antigens from Mycobacterium tuberculosis in active and latent tuberculosis.

    PubMed

    Senoputra, Muhammad Andrian; Shiratori, Beata; Hasibuan, Fakhrial Mirwan; Koesoemadinata, Raspati Cundarani; Apriani, Lika; Ashino, Yugo; Ono, Kenji; Oda, Tetsuya; Matsumoto, Makoto; Suzuki, Yasuhiko; Alisjahbana, Bachti; Hattori, Toshio

    2015-11-01

    We investigated the antibody responses to 10 prospective Mycobacterium tuberculosis (MTB) antigens and evaluated their ability to discriminate between latent (LTBI) and active pulmonary tuberculosis (TB). Our results indicate that plasma levels of anti-α-crystallin (ACR), antilipoarabinomannan, anti-trehalose 6,6'-dimycolate, and anti-tubercular-glycolipid antigen antibodies were higher in patients with active TB, compared to those in the LTBI and control subjects. No differences in the antibodies were observed between the control and LTBI subjects. Antibodies against the glycolipid antigens could not distinguish between Mycobacterium avium complex (MAC)-negative TB patients and MAC-infected LTBI individuals. The most useful serological marker was antibodies to ACR, with MAC-negative TB patients having higher titers than those observed in MAC-positive LTBI and control subjects. Our data indicate that antibody to ACR is a promising target for the serological diagnosis of patients with active TB patients. When dealing with antiglycolipid antibodies, MAC coinfection should always be considered in serological studies. PMID:26307672

  3. Circulatory disease mortality in the Massachusetts tuberculosis fluoroscopy cohort study.

    PubMed

    Little, Mark P; Zablotska, Lydia B; Brenner, Alina V; Lipshultz, Steven E

    2016-03-01

    High-dose ionizing radiation is associated with circulatory disease. Risks from lower-dose fractionated exposures, such as from diagnostic radiation procedures, remain unclear. In this study we aimed to ascertain the relationship between fractionated low-to-medium dose radiation exposure and circulatory disease mortality in a cohort of 13,568 tuberculosis patients in Massachusetts, some with fluoroscopy screenings, between 1916 and 1961 and follow-up until the end of 2002. Analysis of mortality was in relation to cumulative thyroid (cerebrovascular) or lung (all other circulatory disease) radiation dose via Poisson regression. Over the full dose range, there was no overall radiation-related excess risk of death from circulatory disease (n = 3221; excess relative risk/Gy -0.023; 95% CI -0.067, 0.028; p = 0.3574). Risk was somewhat elevated in hypertensive heart disease (n = 89; excess relative risk/Gy 0.357; 95% CI -0.043, 1.030, p = 0.0907) and slightly decreased in ischemic heart disease (n = 1950; excess relative risk/Gy -0.077; 95% CI -0.130, -0.012; p = 0.0211). However, under 0.5 Gy, there was a borderline significant increasing trend for all circulatory disease (excess relative risk/Gy 0.345; 95% CI -0.032, 0.764; p = 0.0743) and for ischemic heart disease (excess relative risk/Gy 0.465; 95% CI, -0.032, 1.034, p = 0.0682). Pneumolobectomy increased radiation-associated risk (excess relative risk/Gy 0.252; 95% CI 0.024, 0.579). Fractionation of dose did not modify excess risk. In summary, we found no evidence of radiation-associated excess circulatory death risk overall, but there are indications of excess circulatory death risk at lower doses (<0.5 Gy). Although consistent with other radiation-exposed groups, the indications of higher risk at lower doses are unusual and should be confirmed against other data. PMID:26255039

  4. Direct inhibitors of InhA active against Mycobacterium tuberculosis

    PubMed Central

    Manjunatha, Ujjini H.; Rao, Srinivasa P. S.; Kondreddi, Ravinder Reddy; Noble, Christian G.; Camacho, Luis R.; Tan, Bee H.; Ng, Seow H.; Ng, Pearly Shuyi; Ma, N. L.; Lakshminarayana, Suresh B.; Herve, Maxime; Barnes, S. Whitney; Yu, Weixuan; Kuhen, Kelli; Blasco, Francesca; Beer, David; Walker, John R.; Tonge, Peter J.; Glynne, Richard; Smith, Paul W.; Diagana, Thierry T.

    2015-01-01

    New chemotherapeutic agents are urgently required to combat the global spread of multi-drug resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase, InhA, is one of the few clinically-validated targets in tuberculosis drug discovery. Here, we report the identification of a new class of direct InhA inhibitors, the 4-hydroxy-2-pyridones, using phenotypic high-throughput whole-cell screening. This class of orally-active compounds showed potent bactericidal activity against common isoniazid-resistant TB clinical isolates. Biophysical studies revealed that 4-hydroxy-2-pyridones bound specifically to InhA in an NADH-dependent manner and blocked the enoyl-substrate binding pocket. The lead compound NITD-916 directly blocked InhA in a dose-dependent manner and showed in vivo efficacy in acute and established mouse models of infection by Mycobacterium tuberculosis. Collectively, our structural and biochemical data open up new avenues for rational structure-guided optimization of the 4-hydroxy-2-pyridone class of compounds for the treatment of MDR-TB. PMID:25568071

  5. Controlling the seedbeds of tuberculosis: diagnosis and treatment of tuberculosis infection.

    PubMed

    Rangaka, Molebogeng X; Cavalcante, Solange C; Marais, Ben J; Thim, Sok; Martinson, Neil A; Swaminathan, Soumya; Chaisson, Richard E

    2015-12-01

    The billions of people with latent tuberculosis infection serve as the seedbeds for future cases of active tuberculosis. Virtually all episodes of tuberculosis disease are preceded by a period of asymptomatic Mycobacterium tuberculosis infection; therefore, identifying infected individuals most likely to progress to disease and treating such subclinical infections to prevent future disease provides a crucial opportunity to interrupt tuberculosis transmission and reduce the global burden of tuberculosis disease. Programmes focusing on single strategies rather than comprehensive programmes that deliver an integrated arsenal for tuberculosis control might continue to struggle. Tuberculosis preventive therapy is a poorly used method that is essential for controlling the reservoirs of disease that drive the epidemic. Comprehensive control strategies that combine preventive therapy for the most high-risk populations and communities with improved case-finding and treatment, control of transmission, and health systems strengthening could ultimately lead to worldwide tuberculosis elimination. In this Series paper we outline challenges to implementation of preventive therapy and provide pragmatic suggestions for overcoming them. We further advocate for tuberculosis preventive therapy as the core of a renewed worldwide focus to implement a comprehensive epidemic control strategy that would reduce new tuberculosis cases to elimination targets. This strategy would be underpinned by accelerated research to further understand the biology of subclinical tuberculosis infections, develop novel diagnostics and drug regimens specifically for subclinical tuberculosis infection, strengthen health systems and community engagement, and enhance sustainable large scale implementation of preventive therapy programmes. PMID:26515679

  6. Anti-Mycobacterium tuberculosis activity of fungus Phomopsis stipata

    PubMed Central

    de Prince, Karina Andrade; Sordi, Renata; Pavan, Fernando Rogério; Barreto Santos, Adolfo Carlos; Araujo, Angela R.; Leite, Sergio R.A.; Leite, Clarice Q. F.

    2012-01-01

    Our purpose was to determine the anti-Mycobacterium tuberculosis activity of the metabolites produced by the endophitic fungus Phomopsis stipata (Lib.) B. Sutton, (Diaporthaceae), cultivated in different media. The antimycobacterial activity was assessed through the Resazurin Microtiter Assay (REMA) and the cytotoxicity test performed on macrophage cell line. The extracts derived from fungi grown on Corn Medium and Potato Dextrose Broth presented the smallest values of Minimum Inhibitory Concentration (MIC) and low cytotoxicity, which implies a high selectivity index. This is the first report on the chemical composition and antitubercular activity of metabolites of P. stipata, as well as the influence of culture medium on these properties. PMID:24031821

  7. Tuberculosis and Leprosy: Classical Granulomatous Diseases in the Twenty-First Century.

    PubMed

    Scollard, David M; Dacso, Mara M; Abad-Venida, Ma Luisa

    2015-07-01

    Leprosy and tuberculosis are chronic mycobacterial infections that elicit granulomatous inflammation. Both infections are curable, but granulomatous injury to cutaneous structures, including cutaneous nerves in leprosy, may cause permanent damage. Both diseases are major global concerns: tuberculosis for its high prevalence and mortality, and leprosy for its persistent global presence and high rate of neuropathic disability. Cutaneous manifestations of both leprosy and tuberculosis are frequently subtle and challenging in dermatologic practice and often require a careful travel and social history and a high index of suspicion. PMID:26143431

  8. Cat scratch disease and lymph node tuberculosis in a colon patient with cancer.

    PubMed

    Matias, M; Marques, T; Ferreira, M A; Ribeiro, L

    2013-01-01

    A 71-year-old man operated for a sigmoid tumour remained in the surveillance after adjuvant chemotherapy. After 3 years, a left axillary lymph node was visible on CT scan. The biopsy revealed a necrotising and abscessed granulomatous lymphadenitis, suggestive of cat scratch disease. The patient confirmed having been scratched by a cat and the serology for Bartonella henselae was IgM+/IgG-. Direct and culture examinations for tuberculosis were negative. The patient was treated for cat scratch disease. One year later, the CT scan showed increased left axillary lymph nodes and a left pleural effusion. Direct and cultural examinations to exclude tuberculosis were again negative. Interferon-γ release assay testing for tuberculosis was undetermined and then positive. Lymph node and pleural tuberculosis were diagnosed and treated with a good radiological response. This article has provides evidence of the importance of continued search for the right diagnosis and that two diagnoses can happen in the same patient. PMID:24334464

  9. Differences in clinical features of Crohn's disease and intestinal tuberculosis

    PubMed Central

    Huang, Xin; Liao, Wang-Di; Yu, Chen; Tu, Yi; Pan, Xiao-Lin; Chen, You-Xiang; Lv, Nong-Hua; Zhu, Xuan

    2015-01-01

    AIM: To investigate the clinical features of Crohn’s disease (CD) and intestinal tuberculosis (ITB) with a scoring system that we have developed. METHODS: A total of 25 CD and 40 ITB patients were prospectively enrolled from August 2011 to July 2012. Their characteristics and clinical features were recorded. Laboratory, endoscopic, histologic and radiographic features were determined. The features with a high specificity were selected to establish a scoring system. The features supporting CD scored +1, and those supporting ITB scored -1; each patient received a final total score. A receiver operating characteristic (ROC) curve was used to determine the best cut-off value for distinguishing CD from ITB. RESULTS: Based on a high specificity of differentiating between CD and ITB, 12 features, including longitudinal ulcers, nodular hyperplasia, cobblestone-like mucosa, intestinal diseases, intestinal fistula, the target sign, the comb sign, night sweats, the purified protein derivative test, the interferon-γ release assay (T-SPOT.TB), ring ulcers and ulcer scars, were selected for the scoring system. The results showed that the average total score of the CD group was 3.12 ± 1.740, the average total score of the ITB group was -2.58 ± 0.984, the best cutoff value for the ROC curve was -0.5, and the diagnostic area under the curve was 0.997, which was statistically significant (P < 0.001). The patients whose total scores were higher than -0.5 were diagnosed with CD; otherwise, patients were diagnosed with ITB. Overall, the diagnostic accuracy rate and misdiagnosis rate of this scoring system were 97% and 3%, respectively. CONCLUSION: Some clinical features are valuable for CD and ITB diagnosis. The described scoring system is key to differentiating between CD and ITB. PMID:25834333

  10. Effects of genetic variability of Mycobacterium tuberculosis strains on the presentation of disease.

    PubMed

    Malik, Aeesha N J; Godfrey-Faussett, Peter

    2005-03-01

    The nature of the variability in the clinical and epidemiological consequences of Mycobacterium tuberculosis infection remains poorly understood. Environmental and host factors that contribute to the outcome of infection and disease presentation are well recognised, but the role of bacterial factors has been more elusive. The rapid increase in the understanding of the molecular basis of M tuberculosis over the past decades has revived research into its pathogenesis. DNA fingerprinting techniques have been used to distinguish between strains of M tuberculosis, and efforts to characterise the strains present within populations have led to increased understanding of their global distribution. This research has shown that in certain areas a small number of strains are causing a disproportionate number of cases of the disease. The sequencing of the complete genome of M tuberculosis has accelerated the development of molecular techniques to differentiate strains according to their genetic polymorphisms. Investigation into the reasons why some strains are predominant by genetic strain-typing techniques may clarify which bacterial factors contribute to disease. This knowledge has the potential to influence control and prevention strategies for tuberculosis in the future. However, there are still limitations in these techniques and their results. This review discusses molecular epidemiology and genetic studies, and their contribution to the understanding of the links between genotypic and phenotypic characteristics of M tuberculosis strains. PMID:15766652

  11. Humoral immunity in tuberculin skin test anergy and its role in high-risk persons exposed to active tuberculosis.

    PubMed

    Encinales, Liliana; Zuñiga, Joaquin; Granados-Montiel, Julio; Yunis, Maria; Granados, Julio; Almeciga, Ingrid; Clavijo, Olga; Awad, Carlos; Collazos, Vilma; Vargas-Rojas, María Inés; Bañales-Mendez, José Luis; Vazquez-Castañeda, Lilia; Stern, Joel N; Romero, Viviana; Fridkis-Hareli, Masha; Frindkis-Hareli, Masha; Terreros, Daniel; Fernandez-Viña, Marcelo; Yunis, Edmond J

    2010-02-01

    The most common test to identify latent tuberculosis is the tuberculin skin test that detects T cell responses of delayed type hypersensitivity type IV. Since it produces false negative reactions in active tuberculosis or in high-risk persons exposed to tuberculosis patients as shown in this report, we studied antibody profiles to explain the anergy of such responses in high-risk individuals without active infection. Our results showed that humoral immunity against tuberculin, regardless of the result of the tuberculin skin test is important for protection from active tuberculosis and that the presence of high antibody titers is a more reliable indicator of infection latency suggesting that latency can be based on the levels of antibodies together with in vitro proliferation of peripheral blood mononuclear cells in the presence of the purified protein derivative. Importantly, anti-tuberculin IgG antibody levels mediate the anergy described herein, which could also prevent reactivation of disease in high-risk individuals with high antibody titers. Such anti-tuberculin IgG antibodies were also found associated with blocking and/or stimulation of in vitro cultures of PBMC with tuberculin. In this regard, future studies need to establish if immune responses to Mycobacterium tuberculosis can generate a broad spectrum of reactions either toward Th1 responses favoring stimulation by cytokines or by antibodies and those toward diminished responses by Th2 cytokines or blocking by antibodies; possibly involving mechanisms of antibody dependent protection from Mtb by different subclasses of IgG. PMID:20004475

  12. Humoral immunity in tuberculin skin test anergy and its role in high-risk persons exposed to active tuberculosis

    PubMed Central

    Encinales, Liliana; Zuñiga, Joaquin; Yunis, Maria; Granados-Montiel, Julio; Granados, Julio; Almeciga, Ingrid; Clavijo, Olga; Awad, Carlos; Collazos, Vilma; Vargas-Rojas, María Inés; Bañales-Mendez, José Luis; Vazquez-Castañeda, Lilia; Stern, Joel N.; Romero, Viviana; Frindkis-Hareli, Masha; Terreros, Daniel; Fernandez-Viña, Marcelo; Yunis, Edmond J.

    2009-01-01

    The most common test to identify latent tuberculosis is the Tuberculin skin test that detects T cell responses of delayed type hypersensitivity type IV. Since it produces false negative reactions in active tuberculosis or in high-risk persons exposed to tuberculosis patients as shown in this report, we studied antibody profiles to explain the anergy of such responses in high-risk individuals without active infection. Our results showed that humoral immunity against Tuberculin, regardless of the result of the Tuberculin skin test is important for protection from active tuberculosis and that the presence of high antibody titers is a more reliable indicator of infection latency suggesting that latency can be based on the levels of antibodies together with in vitro proliferation of peripheral blood mononuclear cells in the presence of the purified protein derivative. Importantly, anti-Tuberculin IgG antibody levels mediate the anergy described herein, which could also prevent reactivation of disease in high-risk individuals with high antibody titers. Such IgG Tuberculin antibodies were also found associated with blocking and/or stimulation of in vitro cultures of PBMC with Tuberculin. In this regard, future studies need to establish if immune responses to Mycobacterium tuberculosis can generate a broad spectrum of reactions either toward Th1 responses favoring stimulation by cytokines or by antibodies and those toward diminished responses by Th2 cytokines or blocking by antibodies; possibly involving mechanisms of antibody dependent protection from Mtb by different subclasses of IgG. PMID:20004475

  13. Granzyme A as a potential biomarker of Mycobacterium tuberculosis infection and disease.

    PubMed

    Guggino, Giuliana; Orlando, Valentina; Cutrera, Stella; La Manna, Marco P; Di Liberto, Diana; Vanini, Valentina; Petruccioli, Elisa; Dieli, Francesco; Goletti, Delia; Caccamo, Nadia

    2015-08-01

    Cytotoxic molecules such as granulysin, perforin and granzymes produced by cytolytic T cells directly contribute to immune defense against tuberculosis (TB). In search for novel TB biomarkers, we have evaluated the levels of granzyme A in plasma obtained from QuantiFERON-TB Gold In tube (QFT-IT) assays from patients with active TB disease and subjects with latent TB infection (LTBI). Granzyme A serum levels in TB patients were significantly lower than values found in LTBI subjects even after subtraction of the unstimulated levels from the antigen-stimulated responses. The receiver operator characteristics (ROC) curve analysis comparing TB patients and LTBI groups, showed that at a cut-off value of granzyme A of <3.425pg/ml, the sensitivity and the specificity of the assay were 29.41% and 94.74%, respectively. Our results suggest that granzyme A could be considered another biomarker of TB, that can be used, other than IFN-γ, to discriminate between patients with active TB and LTBI subjects in a well characterized cohort of confirmed Mycobacterium tuberculosis-infected individuals. PMID:26051682

  14. HIV and AIDS, other sexually transmitted diseases, and tuberculosis in ethnic minorities in United Kingdom: is surveillance serving its purpose?

    PubMed Central

    De Cock, K. M.; Low, N.

    1997-01-01

    Experience of disease differs across ethnic groups, and ethnicity is a relevant personal characteristic for descriptive epidemiology. Information about ethnicity and country of birth is omitted from the routine notification of many diseases. HIV infection and AIDS, other sexually transmitted diseases, and tuberculosis have different incidence rates in different ethnic groups in the United Kingdom. Omission of ethnic data from surveillance activities allows such differences in incidence to go undetected and unaddressed. Surveillance data that included ethnic details could guide interventions to reduce inequalities in health between different subpopulations. PMID:9202508

  15. The Risk of Tuberculosis Reinfection Soon after Cure of a First Disease Episode Is Extremely High in a Hyperendemic Community.

    PubMed

    Uys, Pieter; Brand, Hilmarie; Warren, Robin; van der Spuy, Gian; Hoal, Eileen G; van Helden, Paul D

    2015-01-01

    Elevated rates of reinfection tuberculosis in various hyperendemic regions have been reported and, in particular, it has been shown that in a high-incidence setting near Cape Town, South Africa, the rate of reinfection tuberculosis (TB) disease after cure of a previous TB disease episode is about four times greater than the rate of first-time TB disease. It is not known whether this elevated rate is caused by a high reinfection rate due, for instance, to living circumstances, or a high rate of progress to disease specific to the patients, or both. In order to address that question we analysed an extensive data set from clinics attended by TB patients in the high-incidence setting near Cape Town, South Africa and found that, in fact, the (average) rate of reinfection (as opposed to the rate of reinfection disease) after cure of a previous TB disease episode is initially about 0.85 per annum. This rate diminishes rapidly over time and after about ten years this rate is similar to the rate of infection in the general population. Also, the rate of progress to disease after reinfection is initially high but declines in subsequent years down to the figure typical for the general population. These findings suggest that the first few months after cure of a TB disease episode form a critical period for controlling reinfection disease in a hyperendemic setting and that monitoring such cured patients could pre-empt a reinfection progressing to active disease. PMID:26649422

  16. The Risk of Tuberculosis Reinfection Soon after Cure of a First Disease Episode Is Extremely High in a Hyperendemic Community

    PubMed Central

    Warren, Robin; van der Spuy, Gian; Hoal, Eileen G.; van Helden, Paul D

    2015-01-01

    Elevated rates of reinfection tuberculosis in various hyperendemic regions have been reported and, in particular, it has been shown that in a high-incidence setting near Cape Town, South Africa, the rate of reinfection tuberculosis (TB) disease after cure of a previous TB disease episode is about four times greater than the rate of first-time TB disease. It is not known whether this elevated rate is caused by a high reinfection rate due, for instance, to living circumstances, or a high rate of progress to disease specific to the patients, or both. In order to address that question we analysed an extensive data set from clinics attended by TB patients in the high-incidence setting near Cape Town, South Africa and found that, in fact, the (average) rate of reinfection (as opposed to the rate of reinfection disease) after cure of a previous TB disease episode is initially about 0.85 per annum. This rate diminishes rapidly over time and after about ten years this rate is similar to the rate of infection in the general population. Also, the rate of progress to disease after reinfection is initially high but declines in subsequent years down to the figure typical for the general population. These findings suggest that the first few months after cure of a TB disease episode form a critical period for controlling reinfection disease in a hyperendemic setting and that monitoring such cured patients could pre-empt a reinfection progressing to active disease. PMID:26649422

  17. New 2-Thiopyridines as Potential Candidates for Killing both Actively Growing and Dormant Mycobacterium tuberculosis Cells

    PubMed Central

    Ryabova, Olga; Kaprelyants, Arseny; Makarov, Vadim

    2014-01-01

    From in vivo observations, a majority of M. tuberculosis cells in latently infected individuals are in a dormant and probably nonculturable state, display little metabolic activity, and are phenotypically resistant to antibiotics. Despite many attempts, no specific antimicrobials effective against latent tuberculosis have yet been found, partly because of a lack of reliable and adequate in vitro models for screening of drug candidates. We propose here a novel in vitro model of M. tuberculosis dormancy that meets the important criteria of latency, namely, nonculturability of cells, considerable reduction of metabolic activity, and significant phenotypic resistance to the first-line antibiotics rifampin and isoniazid. Using this model, we found a new group of 2-thiopyridine derivatives that had potent antibacterial activity against both actively growing and dormant M. tuberculosis cells. By means of the model of M. tuberculosis nonculturability, several new 2-thiopyridine derivatives were found to have potent antitubercular activity. The compounds are effective against both active and dormant M. tuberculosis cells. The bactericidal effects of compounds against dormant M. tuberculosis was confirmed by using three different in vitro models of tuberculosis dormancy. The model of nonculturability could be used as a reliable tool for screening drug candidates, and 2-thiopyridine derivatives may be regarded as prominent compounds for further development of new drugs for curing latent M. tuberculosis infection. PMID:24126578

  18. [What Hansen's disease research learned from tuberculosis research: from molecular biological aspect].

    PubMed

    Suzuki, Yasuhiko; Yamaguchi, Tomoyuki; Kim, Hyun; Yokoyama, Kazumasa; Nakajima, Chie

    2014-12-01

    As for the Mycobacterium leprae which is a causative agent of Hansen's disease, many studies had been done since it was identified in 1873. However, those studies, at the same time, experienced many struggles because of the difficulty of culture of M. leprae on the artificial growth media. Hence, the study of Hansen's disease progressed by taking the knowledge from the study of tuberculosis caused by the bacteria belonging to the same genus, genus Mycobacterium. For instance, the knowledge of mutations in specific genes responsible for rifampicin- and quinolone-resistance in M. tuberculosis led the elucidation of drug-resistant acquisition mechanism of M. leprae. Similarly, it is necessary for the researcher of Hansen's disease to get important information from the latest topic of the tuberculosis study and utilize them to the study of the disease. PMID:25826852

  19. Evaluation of disease patterns, treatment and prognosis of tuberculosis in AIDS patient.

    PubMed

    Atomiya, Angela Naomi; Uip, David Emerson; Leite, Olavo Henrique Munhoz

    2002-02-01

    Patterns of disease, diagnosis, treatment and prognosis of tuberculosis in 100 patients co-infected with AIDS at Casa da AIDS clinic was studied. Demographic characteristics were as follows: 76 male patients, 24 female patients, 67 caucasian, average 35.8 years-old (SD +/- 8.5). Sexual transmission of HIV was reported in 68 patients. Pulmonary tuberculosis was seen in 40 patients, extrapulmonary in 11, and combined in 49 patients. In 63 patients, TCD(4)(+) counts were below 200/mm(3) when tuberculosis was diagnosed. Fifty-five patients had their diagnoses confirmed by bacteriological identification of Mycobacterium; either through direct observation and/or culture. Tuberculosis was treated with rifampin, isoniazid and pyrazinamide in 60 patients, reinforced treatment in 14 and alternative treatment in the other 13 patients. Tuberculosis therapy lasted up to 9 months in 66% of the patients. Fifty-four patients were treated with a two-drug antiretroviral regimen and the remaining 46 patients received a triple regimen, which included a protease inhibitor. Among the latter, 35 patients were co-treated with rifampin. The occurrence of hepatic liver enzyme abnormalities was statistically related to alternative antiretroviral regimens (p = 0.01) and to the co-administration of rifampin and protease inhibitor (p = 0.019). Clinical resolution of tuberculosis was obtained in 74 patients. Twelve patients died during tuberculosis treatment. Resolution of tuberculosis was statistically significant related to antituberculosis treatment adherence (p = 0.001). The risk of no response to the treatment was 1.84 times more frequent among patients treated with alternative regimens regardless of the duration of the therapy. We conclude that the characteristics of tuberculosis in HIV infected patients requires that special attention be directed to the types and duration of both antiretroviral and anti-TB therapy in order to achieve the highest level of care. PMID:11980601

  20. Performance of the Interferon Gamma Release Assays in Tuberculosis Disease in Children Five Years Old or Less

    PubMed Central

    Yin, Qing-qin; Xiao, Jing; Li, Jie-qiong; Guo, Ya-jie; Feng, Guo-shuang; Peng, Xiao-xia; Qi, Hui; Xu, Fang; Jiao, Wei-wei; Shen, Chen; Shen, A-dong

    2015-01-01

    Interferon Gamma Release Assays (IGRAs) were developed for the indirect or immunologic diagnosis of tuberculosis infection; however, they have also been used to assist in difficult to diagnose cases of tuberculosis disease in adults, and to a lesser extent, in children, especially in those under 5 years old. We evaluated the utility of using an IGRA in pediatric tuberculosis in younger children in a hospital setting. The diagnostic accuracy of T-SPOT.TB and TST was assessed in 117 children with active tuberculosis and 413 children with respiratory tract infection. Sensitivity and specificity were calculated for the tests used individually and together. Concordance was also calculated. Sensitivity of T-SPOT.TB (82.9%) was higher than TST (78.6% using a 5mm cut-off), especially in children confirmed to have TB. T-SPOT.TB was more specific than TST using a 5mm cut-off (96.1% vs. 70.9%). Combining T-SPOT.TB and TST results improved the sensitivity to 96.6%. In conclusion, the results of the current study indicate that T-SPOT.TB has good sensitivity and specificity, supporting its use among patients of this age. A combination of IGRA and TST would be useful additions to assist in the diagnosis of childhood TB. PMID:26640948

  1. Micrococcin P1 - A bactericidal thiopeptide active against Mycobacterium tuberculosis.

    PubMed

    Degiacomi, Giulia; Personne, Yoann; Mondésert, Guillaume; Ge, Xueliang; Mandava, Chandra Sekhar; Hartkoorn, Ruben C; Boldrin, Francesca; Goel, Pavitra; Peisker, Kristin; Benjak, Andrej; Barrio, Maria Belén; Ventura, Marcello; Brown, Amanda C; Leblanc, Véronique; Bauer, Armin; Sanyal, Suparna; Cole, Stewart T; Lagrange, Sophie; Parish, Tanya; Manganelli, Riccardo

    2016-09-01

    The lack of proper treatment for serious infectious diseases due to the emergence of multidrug resistance reinforces the need for the discovery of novel antibiotics. This is particularly true for tuberculosis (TB) for which 3.7% of new cases and 20% of previously treated cases are estimated to be caused by multi-drug resistant strains. In addition, in the case of TB, which claimed 1.5 million lives in 2014, the treatment of the least complicated, drug sensitive cases is lengthy and disagreeable. Therefore, new drugs with novel targets are urgently needed to control resistant Mycobacterium tuberculosis strains. In this manuscript we report the characterization of the thiopeptide micrococcin P1 as an anti-tubercular agent. Our biochemical experiments show that this antibiotic inhibits the elongation step of protein synthesis in mycobacteria. We have further identified micrococcin resistant mutations in the ribosomal protein L11 (RplK); the mutations were located in the proline loop at the N-terminus. Reintroduction of the mutations into a clean genetic background, confirmed that they conferred resistance, while introduction of the wild type RplK allele into resistant strains re-established sensitivity. We also identified a mutation in the 23S rRNA gene. These data, in good agreement with previous structural studies suggest that also in M. tuberculosis micrococcin P1 functions by binding to the cleft between the 23S rRNA and the L11 protein loop, thus interfering with the binding of elongation factors Tu and G (EF-Tu and EF-G) and inhibiting protein translocation. PMID:27553416

  2. Immunopathogenesis of tuberculosis and novel mechanisms of vaccine activity.

    PubMed

    Schrager, Lewis K; Izzo, Angelo; Velmurugan, Kamalakannan

    2016-08-01

    The 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 - 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on Immunopathogenesis of Tuberculosis, and Immunopathogenesis and Novel Mechanisms of Vaccine Activity. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis. PMID:27450395

  3. The burden of disease due to tuberculosis in the state of Santa Catarina, Brazil*, **

    PubMed Central

    Ferrer, Glênio César Nunes; da Silva, Rosemeri Maurici; Ferrer, Kelian Tenfen; Traebert, Jefferson

    2014-01-01

    OBJECTIVE: To estimate the burden of disease due to tuberculosis in the state of Santa Catarina, Brazil, in 2009. METHODS: This was an epidemiological study with an ecological design. Data on tuberculosis incidence and mortality were collected from specific Brazilian National Ministry of Health databases. The burden of disease due to tuberculosis was based on the calculation of disability-adjusted life years (DALYs). The DALYs were estimated by adding the years of life lost (YLLs) and years lived with disability (YLDs). Absolute values were transformed into rates per 100,000 population. The rates were calculated by gender, age group, and health care macroregion. RESULTS: The burden of disease due to tuberculosis was 5,644.27 DALYs (92.25 DALYs/100,000 population), YLLs and YLDs respectively accounting for 78.77% and 21.23% of that total. The highest rates were found in males in the 30-44 and 45-59 year age brackets, although that was not true in every health care macroregion. Overall, the highest estimated burden was in the Planalto Norte macroregion (179.56 DALYs/100,000 population), followed by the Nordeste macroregion (167.07 DALYs/100,000 population). CONCLUSIONS: In the majority of the health care macroregions of Santa Catarina, the burden of disease due to tuberculosis was concentrated in adult males, the level of that concentration varying among the various macroregions. PMID:24626271

  4. Tuberculosis: General Information

    MedlinePlus

    TB Elimination Tuberculosis: General Information What is TB? Tuberculosis (TB) is a disease caused by germs that are spread from person ... Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination CS227840_A What Does a Positive Test ...

  5. The Small Breathing Amplitude at the Upper Lobes Favors the Attraction of Polymorphonuclear Neutrophils to Mycobacterium tuberculosis Lesions and Helps to Understand the Evolution toward Active Disease in An Individual-Based Model

    PubMed Central

    Cardona, Pere-Joan; Prats, Clara

    2016-01-01

    Infection with Mycobacterium tuberculosis (Mtb) can induce two kinds of lesions, namely proliferative and exudative. The former are based on the presence of macrophages with controlled induction of intragranulomatous necrosis, and are even able to stop its physical progression, thus avoiding the induction of active tuberculosis (TB). In contrast, the most significant characteristic of exudative lesions is their massive infiltration with polymorphonuclear neutrophils (PMNs), which favor enlargement of the lesions and extracellular growth of the bacilli. We have built an individual-based model (IBM) (known as “TBPATCH”) using the NetLogo interface to better understand the progression from Mtb infection to TB. We have tested four main factors previously identified as being able to favor the infiltration of Mtb-infected lesions with PMNs, namely the tolerability of infected macrophages to the bacillary load; the capacity to modulate the Th17 response; the breathing amplitude (BAM) (large or small in the lower and upper lobes respectively), which influences bacillary drainage at the alveoli; and the encapsulation of Mtb-infected lesions by the interlobular septae that structure the pulmonary parenchyma into secondary lobes. Overall, although all the factors analyzed play some role, the small BAM is the major factor determining whether Mtb-infected lesions become exudative, and thus induce TB, thereby helping to understand why this usually takes place in the upper lobes. This information will be very useful for the design of future prophylactic and therapeutic approaches against TB. PMID:27065951

  6. Mycobacterium tuberculosis Lipolytic Enzymes as Potential Biomarkers for the Diagnosis of Active Tuberculosis

    PubMed Central

    Brust, Belinda; Lecoufle, Mélanie; Tuaillon, Edouard; Dedieu, Luc; Canaan, Stéphane; Valverde, Viviane; Kremer, Laurent

    2011-01-01

    Background New diagnosis tests are urgently needed to address the global tuberculosis (TB) burden and to improve control programs especially in resource-limited settings. An effective in vitro diagnostic of TB based on serological methods would be regarded as an attractive progress because immunoassays are simple, rapid, inexpensive, and may offer the possibility to detect cases missed by standard sputum smear microscopy. However, currently available serology tests for TB are highly variable in sensitivity and specificity. Lipolytic enzymes have recently emerged as key factors in lipid metabolization during dormancy and/or exit of the non-replicating growth phase, a prerequisite step of TB reactivation. The focus of this study was to analyze and compare the potential of four Mycobacterium tuberculosis lipolytic enzymes (LipY, Rv0183, Rv1984c and Rv3452) as new markers in the serodiagnosis of active TB. Methods Recombinant proteins were produced and used in optimized ELISA aimed to detect IgG and IgM serum antibodies against the four lipolytic enzymes. The capacity of the assays to identify infection was evaluated in patients with either active TB or latent TB and compared with two distinct control groups consisting of BCG-vaccinated blood donors and hospitalized non-TB individuals. Results A robust humoral response was detected in patients with active TB whereas antibodies against lipolytic enzymes were infrequently detected in either uninfected groups or in subjects with latent infection. High specifity levels, ranging from 93.9% to 97.5%, were obtained for all four antigens with sensitivity values ranging from 73.4% to 90.5%, with Rv3452 displaying the highest performances. Patients with active TB usually exhibited strong IgG responses but poor IgM responses. Conclusion These results clearly indicate that the lipolytic enzymes tested are strongly immunogenic allowing to distinguish active from latent TB infections. They appear as potent biomarkers providing high

  7. Determinants of active pulmonary tuberculosis in Ambo Hospital, West Ethiopia

    PubMed Central

    Mengiste, Bezatu; Mesfin, Frehiwot; Godana, Wanzahun

    2015-01-01

    Objectives The aim of this study was to determine factors associated with active pulmonary tuberculosis seen in cases in Ambo Hospital, Ethiopia. Design A facility-based prospective case-control study. Setting Patients attending Ambo Hospital from 01 December 2011 to 29 March 2012. Participants The sample included 312 adult patients attending Ambo Hospital. The main outcome measure was presence of active pulmonary tuberculosis (TB). Explanatory measures Age, gender, occupation, educational status, marital status, place of residence, patient history of TB, family history of TB, human immunodeficiency virus (HIV) infection, smoking, alcohol intake, khat chewing, body mass index (BMI), employment, diabetes, history of asthma, previous history of worm infestation, history of hospitalisation, number of adults living in the household (HH), person per room, housing condition. Results A total of 312 study participants, including 104 active pulmonary tuberculosis (PTB) cases (cases) and 208 non-active PTB cases (controls), were recruited for the present study. Having one or more family member with a history of TB (OR = 4.4; 95% CI: 1.50–12.90), marital status (OR = 7.6; 95% CI: 2.2–12.6), male gender (OR = 3.2; 95% CI: 1.4–7), rural residence (OR = 3.3; P = 0.012), being a current or past smoker (OR = 2.8; 95% CI: 1.1–7.2), BMI < 18.5 (OR = 2.1; 95% CI: 1.03–4.2), HIV infection (OR = 8.8; 95% CI: 2.4–23.8) and a history of worm infestation (OR = 6.4; 95% CI: 2.6–15.4) remained significant independent host-related factors for active PTB. Conclusion Patients who came from a compound with more than two HHs were more likely to develop active PTB than those who came from a compound with only one HH. Those who lived in houses with no windows were more likely to develop active PTB than those who lived in houses with one or more windows, had a family history of TB, lived in rural areas. Sex of the patient was a predicting factor. Not being the owner of the house was

  8. Identifying an active case of tuberculosis.

    PubMed

    Williams, G; Alarcon, E; Jittimanee, S; Walusimbi, M; Sebek, M; Berga, E; Villa, T S

    2008-04-01

    The best practice standards set out in chapter 2 of the Best Practice guide focus on the various aspects of identifying an active case of TB and aim to address some of the challenges associated with case detection. The importance of developing a good relationship with the patient from the start, when he or she is often most vulnerable, is emphasised. The first standard focuses on the assessment of someone who might have TB and the second gives detailed guidance about the collection of sputum for diagnosis. The standards are aimed at the health care worker, who assesses the patient when he or she presents at a health care facility and therefore needs to be familiar with the signs, symptoms and risk factors associated with TB. Having suspected TB, the health care worker then needs to ensure that the correct tests are ordered and procedures are followed so that the best quality samples possible are sent to the laboratory and all documentation is filled out clearly and correctly. The successful implementation of these standards can be measured by the accurate and prompt reporting of results, the registration of every case detected and the continued attendance of every patient who needs treatment. PMID:18371262

  9. Mefloquine and its oxazolidine derivative compound are active against drug-resistant Mycobacterium tuberculosis strains and in a murine model of tuberculosis infection.

    PubMed

    Rodrigues-Junior, Valnês S; Villela, Anne D; Gonçalves, Raoni S B; Abbadi, Bruno Lopes; Trindade, Rogério Valim; López-Gavín, Alexandre; Tudó, Griselda; González-Martín, Julian; Basso, Luiz Augusto; de Souza, Marcus V N; Campos, Maria Martha; Santos, Diógenes Santiago

    2016-08-01

    Repurposing of drugs to treat tuberculosis (TB) has been considered an alternative to overcome the global TB epidemic, especially to combat drug-resistant forms of the disease. Mefloquine has been reported as a potent drug to kill drug-resistant strains of Mycobacterium tuberculosis. In addition, mefloquine-derived molecules have been synthesised and their effectiveness against mycobacteria has been assessed. In this work, we demonstrate for the first time the activities of mefloquine and its oxazolidine derivative compound 1E in a murine model of TB infection following administration of both drugs by the oral route. The effects of associations between mefloquine or 1E with the clinically used antituberculosis drugs isoniazid, rifampicin, ethambutol, moxifloxacin and streptomycin were also investigated. Importantly, combination of mefloquine with isoniazid and of 1E with streptomycin showed a two-fold decrease in their minimum inhibitory concentrations (MICs). Moreover, no tested combinations demonstrated antagonist interactions. Here we describe novel evidence on the activity of mefloquine and 1E against a series of quinolone-resistant M. tuberculosis strains. These data show MICs against quinolone-resistant strains (0.5-8 µg/mL) similar to or lower than those previously reported for multidrug-resistant strains. Taking these results together, we can suggest the use of mefloquine or 1E in combination with clinically available drugs, especially in the case of resistant forms of TB. PMID:27364701

  10. Mechanism of action of the tuberculosis and Crohn disease risk factor IRGM in autophagy.

    PubMed

    Chauhan, Santosh; Mandell, Michael A; Deretic, Vojo

    2016-01-01

    Polymorphisms in the IRGM gene, associated with Crohn disease (CD) and tuberculosis, are among the earliest identified examples documenting the role of autophagy in human disease. Functional studies have shown that IRGM protects against these diseases by modulating autophagy, yet the exact molecular mechanism of IRGM's activity has remained unknown. We have recently elucidated IRGM's mechanism of action. IRGM functions as a platform for assembling, stabilizing, and activating the core autophagic machinery, while at the same time physically coupling it to conventional innate immunity receptors. Exposure to microbial products or bacterial invasion increases IRGM expression, which leads to stabilization of AMPK. Specific protein-protein interactions and post-translational modifications such as ubiquitination of IRGM, lead to a co-assembly with IRGM of the key autophagy regulators ULK1 and BECN1 in their activated forms. IRGM physically interacts with 2 other CD risk factors, ATG16L1 and NOD2, placing these 3 principal players in CD within the same molecular complex. This explains how polymorphisms altering expression or function of any of the 3 factors individually can affect the same process-autophagy. Furthermore, IRGM's interaction with NOD2, and additional pattern recognition receptors such as NOD1, RIG-I, and select TLRs, transduces microbial signals to the core autophagy apparatus. This work solves the long-standing enigma of how IRGM controls autophagy. PMID:26313894

  11. Tuberculosis Diagnosis: Relevancy of Veterinary Applications to Human Disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Veterinary applications of tuberculosis (TB) tests may provide insight into the diagnostic potential and technical development of emerging tests for human TB. Interferon (IFN)-gamma release assays (IGRA) were developed initially for bovine TB eradication programs. As the test relies on functional le...

  12. Drug Resistance Mechanisms in Mycobacterium tuberculosis

    PubMed Central

    Palomino, Juan Carlos; Martin, Anandi

    2014-01-01

    Tuberculosis (TB) is a serious public health problem worldwide. Its situation is worsened by the presence of multidrug resistant (MDR) strains of Mycobacterium tuberculosis, the causative agent of the disease. In recent years, even more serious forms of drug resistance have been reported. A better knowledge of the mechanisms of drug resistance of M. tuberculosis and the relevant molecular mechanisms involved will improve the available techniques for rapid drug resistance detection and will help to explore new targets for drug activity and development. This review article discusses the mechanisms of action of anti-tuberculosis drugs and the molecular basis of drug resistance in M. tuberculosis. PMID:27025748

  13. Analysis of Immune Responses against a Wide Range of Mycobacterium tuberculosis Antigens in Patients with Active Pulmonary Tuberculosis

    PubMed Central

    Kassa, Desta; Ran, Leonie; Geberemeskel, Wudneh; Tebeje, Mekashaw; Alemu, Amelewerk; Selase, Alemayehu; Tegbaru, Belete; Franken, Kees L. M. C.; Friggen, Annemieke H.; van Meijgaarden, Krista E.; Ottenhoff, Tom H. M.; Wolday, Dawit; Messele, Tsehaynesh

    2012-01-01

    Characterizing host immune responses to molecular targets of Mycobacterium tuberculosis is essential to develop effective immunodiagnostics and better vaccines. We investigated the immune response against a large series of M. tuberculosis antigens, including 5 classical and 64 nonclassical (39 DosR regulon-encoded, 4 resuscitation-promoting factor [RPF], and 21 reactivation-associated) antigens in active-pulmonary-tuberculosis (TB) patients. Whole blood from TB patients (n = 34) was stimulated in vitro with M. tuberculosis antigens. Gamma interferon (IFN-γ) was measured after 7 days of stimulation, using an enzyme-linked immunosorbent assay (ELISA). The majority of the study participants responded to the classical M. tuberculosis antigens TB10.4 (84.8%), early secreted antigenic target-6 kDa (ESAT-6)/CFP-10 (70.6%), and purified protein derivative (PPD) (55.9%). However, only 26.5% and 24.2% responded to HSP65 and Ag85A/B, respectively. Of the 64 nonclassical antigens, 23 (33.3%) were immunogenic (IFN-γ levels, >62 pg/ml) and 8 were strong inducers of IFN-γ (IFN-γ levels, ≥100 pg/ml). The RPF antigens were the most immunogenic. In addition, we observed distinct cytokine expression profiles in response to several M. tuberculosis antigens by multiplex immunoassay. Tumor necrosis factor alpha (TNF-α), interleukin 10 (IL-10), and IL-6 were commonly detected at high levels after stimulation with 4/15 latency antigens (Rv0081, Rv2006, Rv2629, and Rv1733c) and were found especially in supernatants of the three strong IFN-γ inducers (Rv2629, Rv1009, and Rv2389c). IL-8, IL-6, and IL-17 were exclusively detected after stimulation with Rv0574c, Rv2630, Rv1998, Rv054c, and Rv2028c. In conclusion, in active-pulmonary-TB patients, we identified 23 new immunogenic M. tuberculosis antigens. The distinct expression levels of IFN-γ, TNF-α, IL-6, and IL-10 in response to specific subsets of M. tuberculosis antigens may be promising for the development of immunodiagnostics

  14. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... tuberculosis pension cases. A permanent and total disability rating in effect during hospitalization will...

  15. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... tuberculosis pension cases. A permanent and total disability rating in effect during hospitalization will...

  16. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2014-07-01 2014-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... tuberculosis pension cases. A permanent and total disability rating in effect during hospitalization will...

  17. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... tuberculosis pension cases. A permanent and total disability rating in effect during hospitalization will...

  18. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2012-07-01 2012-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... tuberculosis pension cases. A permanent and total disability rating in effect during hospitalization will...

  19. MEROPENEM INHIBITS D,D-CARBOXYPEPTIDASE ACTIVITY IN MYCOBACTERIUM TUBERCULOSIS

    PubMed Central

    Kumar, Pradeep; Arora, Kriti; Lloyd, John R.; Lee, Ill Young; Nair, Vinod; Fischer, Elizabeth; Boshoff, Helena I.M.; Barry, Clifton E.

    2012-01-01

    Summary Carbapenems such as meropenem are being investigated for their potential therapeutic utility against highly drug-resistant tuberculosis. These β-lactams target the transpeptidases that introduce interpeptide cross-links into bacterial peptidoglycan thereby controlling rigidity of the bacterial envelope. Treatment of M. tuberculosis (Mtb) with the β-lactamase inhibitor clavulanate together with meropenem resulted in rapid, polar, cell lysis releasing cytoplasmic contents. In Mtb it has been previously demonstrated that 3-3 cross-linkages (involving two diaminopimelate (DAP) molecules) predominate over 4-3 cross-linkages (involving one DAP and one D-alanine) in stationary-phase cells. We purified and analyzed peptidoglycan from Mtb and found that 3-3 cross-linkages predominate throughout all growth phases and the ratio of 4-3/3-3 linkages does not vary significantly under any growth condition. Meropenem treatment was accompanied by a dramatic accumulation of unlinked pentapeptide stems with no change in the tetrapeptide pools, suggesting that meropenem inhibits both a D,D-carboxypeptidase and an L,D-transpeptidase. We purified a candidate D,D-carboxypeptidase DacB2 and showed that meropenem indeed directly inhibits this enzyme by forming a stable adduct at the enzyme active site. These results suggest that the rapid lysis of meropenem-treated cells is the result of synergistically inhibiting the transpeptidases that introduce 3,3-cross-links while simultaneously limiting the pool of available substrates available for cross-linking. PMID:22906310

  20. Meropenem inhibits D,D-carboxypeptidase activity in Mycobacterium tuberculosis.

    PubMed

    Kumar, Pradeep; Arora, Kriti; Lloyd, John R; Lee, Ill Y; Nair, Vinod; Fischer, Elizabeth; Boshoff, Helena I M; Barry, Clifton E

    2012-10-01

    Carbapenems such as meropenem are being investigated for their potential therapeutic utility against highly drug-resistant tuberculosis. These β-lactams target the transpeptidases that introduce interpeptide cross-links into bacterial peptidoglycan thereby controlling rigidity of the bacterial envelope. Treatment of Mycobacterium tuberculosis (Mtb) with the β-lactamase inhibitor clavulanate together with meropenem resulted in rapid, polar, cell lysis releasing cytoplasmic contents. In Mtb it has been previously demonstrated that 3-3 cross-linkages [involving two diaminopimelate (DAP) molecules] predominate over 4-3 cross-linkages (involving one DAP and one D-alanine) in stationary-phase cells. We purified and analysed peptidoglycan from Mtb and found that 3-3 cross-linkages predominate throughout all growth phases and the ratio of 4-3/3-3 linkages does not vary significantly under any growth condition. Meropenem treatment was accompanied by a dramatic accumulation of unlinked pentapeptide stems with no change in the tetrapeptide pools, suggesting that meropenem inhibits both a D,D-carboxypeptidase and an L,D-transpeptidase. We purified a candidate D,D-carboxypeptidase DacB2 and showed that meropenem indeed directly inhibits this enzyme by forming a stable adduct at the enzyme active site. These results suggest that the rapid lysis of meropenem-treated cells is the result of synergistically inhibiting the transpeptidases that introduce 3,3-cross-links while simultaneously limiting the pool of available substrates available for cross-linking. PMID:22906310

  1. Cytokine Response to Antigen Stimulation of Whole Blood from Patients with Mycobacterium ulcerans Disease Compared to That from Patients with Tuberculosis

    PubMed Central

    Phillips, R.; Horsfield, C.; Kuijper, S.; Sarfo, S. F.; Obeng-Baah, J.; Etuaful, S.; Nyamekye, B.; Awuah, P.; Nyarko, K. M.; Osei-Sarpong, F.; Lucas, S.; Kolk, A. H. J.; Wansbrough-Jones, M.

    2006-01-01

    Mycobacterium ulcerans disease (Buruli ulcer) is a skin-ulcerating infection common in some parts of the tropics. We have investigated cytokine secretion after stimulation of whole blood from Buruli ulcer (BU) patients in a region of endemicity in Ghana with M. ulcerans sonicate or culture filtrate antigens to investigate the development of the response over time and its specificity by comparison with the response to Mycobacterium tuberculosis sonicate in human immunodeficiency virus-negative tuberculosis patients. Significant gamma interferon (IFN-γ) production in response to whole-blood stimulation with M. ulcerans sonicate was detected in patients with ulcers, which was higher than that in patients with nodules but similar to subjects with healed BU. The mean IFN-γ response in household contacts of BU patients was not significantly different from that in healthy control subjects from an area of nonendemicity. Results in patients with untreated, smear-positive pulmonary tuberculosis and tuberculosis patients on treatment for more than 2 weeks showed that BU patients responded better to M. ulcerans antigens than tuberculosis patients. In contrast, interleukin-10 results were higher in patients with active M. ulcerans disease than in those with healed lesions, but the pattern of response was similar to that seen in tuberculosis. A similar pattern of cytokine secretion was found using M. tuberculosis sonicate as an antigen. Neither of the two culture filtrate antigens of M. ulcerans appeared to be more specific than M. ulcerans sonicate. In the early stages of M. ulcerans disease there was a mixed Th1 and Th2 cytokine response, but the Th1 response emerged as the dominant type. PMID:16467334

  2. A Microbiological Revolution Meets an Ancient Disease: Improving the Management of Tuberculosis with Genomics

    PubMed Central

    Wlodarska, Marta; Johnston, James C.; Gardy, Jennifer L.

    2015-01-01

    SUMMARY Tuberculosis (TB) is an ancient disease with an enormous global impact. Despite declining global incidence, the diagnosis, phenotyping, and epidemiological investigation of TB require significant clinical microbiology laboratory resources. Current methods for the detection and characterization of Mycobacterium tuberculosis consist of a series of laboratory tests varying in speed and performance, each of which yields incremental information about the disease. Since the sequencing of the first M. tuberculosis genome in 1998, genomic tools have aided in the diagnosis, treatment, and control of TB. Here we summarize genomics-based methods that are positioned to be introduced in the modern clinical TB laboratory, and we highlight how recent advances in genomics will improve the detection of antibiotic resistance-conferring mutations and the understanding of M. tuberculosis transmission dynamics and epidemiology. We imagine the future TB clinic as one that relies heavily on genomic interrogation of the M. tuberculosis isolate, allowing for more rapid diagnosis of TB and real-time monitoring of outbreak emergence. PMID:25810419

  3. Bronchocentric granulomatosis with extensive cystic lung disease in tuberculosis: An unusual presentation

    PubMed Central

    Periwal, Pallavi; Khanna, Arjun; Gothi, Rajesh; Talwar, Deepak

    2016-01-01

    Tuberculosis is known to cause both cystic lung disease and bronchocentric granulomatosis (BCG). However, both are rare manifestations of this common disease. We report a case of BCG with extensive cystic lung disease in a young female who presented with fever, weight loss, and recurrent pneumothoraces with respiratory failure. Early diagnosis and treatment are imperative, as appropriate therapy may be life-saving in such cases. PMID:27185999

  4. Adverse neuro-immune-endocrine interactions in patients with active tuberculosis.

    PubMed

    Bottasso, Oscar; Bay, María Luisa; Besedovsky, Hugo; Del Rey, Adriana

    2013-03-01

    The nervous, endocrine and immune systems play a crucial role in maintaining homeostasis and interact with each other for a successful defensive strategy against injurious agents. However, the situation is different in long-term diseases with marked inflammation, in which defensive mechanisms become altered. In the case of tuberculosis (TB), this is highlighted by several facts: an imbalance of plasma immune and endocrine mediators, that results in an adverse environment for mounting an adequate response against mycobacteria and controlling inflammation; the demonstration that dehidroepiandrosterone (DHEA) secretion by a human adrenal cell line can be inhibited by culture supernatants from Mycobacterium tuberculosis-stimulated peripheral blood mononuclear cells - PBMC - of TB patients, with this effect being partly reverted when neutralizing transforming growth factor-β in such supernantants; the in vitro effects of adrenal steroids on the specific immune response of PBMC from TB patients, that is a cortisol inhibition of mycobacterial antigen-driven lymphoproliferation and interferon-γ production as well as a suppression of TGF-β production in DHEA-treated PBMC; and lastly the demonstration that immune and endocrine compounds participating in the regulation of energy sources and immune activity correlated with the consumption state of TB patients. Collectively, immune-endocrine disturbances of TB patients are involved in critical components of disease pathology with implications in the impaired clinical status and unfavorable disease outcome. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'. PMID:23147110

  5. Active and latent tuberculosis among HIV-positive injecting drug users in Indonesia

    PubMed Central

    Meijerink, Hinta; Wisaksana, Rudi; Lestari, Mery; Meilana, Intan; Chaidir, Lydia; van der Ven, Andre JAM; Alisjahbana, Bachti; van Crevel, Reinout

    2015-01-01

    Introduction Injecting drug use (IDU) is associated with tuberculosis but few data are available from low-income settings. We examined IDU in relation to active and latent tuberculosis (LTBI) among HIV-positive individuals in Indonesia, which has a high burden of tuberculosis and a rapidly growing HIV epidemic strongly driven by IDU. Methods Active tuberculosis was measured prospectively among 1900 consecutive antiretroviral treatment (ART)-naïve adult patients entering care in a clinic in West Java. Prevalence of LTBI was determined cross-sectionally in a subset of 518 ART-experienced patients using an interferon-gamma release assay. Results Patients with a history of IDU (53.1%) more often reported a history of tuberculosis treatment (34.8% vs. 21.9%, p<0.001), more often received tuberculosis treatment during follow-up (adjusted HR=1.71; 95% CI: 1.25–2.35) and more often had bacteriologically confirmed tuberculosis (OR=1.67; 95% CI: 0.94–2.96). LTBI was equally prevalent among people with and without a history of IDU (29.1 vs. 30.4%, NS). The risk estimates did not change after adjustment for CD4 cell count or ART. Conclusions HIV-positive individuals with a history of IDU in Indonesia have more active tuberculosis, with similar rates of LTBI. Within the HIV clinic, LTBI screening and isoniazid preventive therapy may be prioritized to patients with a history of IDU. PMID:25690530

  6. Discriminating Active Tuberculosis from Latent Tuberculosis Infection by flow cytometric measurement of CD161-expressing T cells

    PubMed Central

    Yang, Qianting; Xu, Qian; Chen, Qi; Li, Jin; Zhang, Mingxia; Cai, Yi; Liu, Haiying; Zhou, Yiping; Deng, Guofang; Deng, Qunyi; Zhou, Boping; Kornfeld, Hardy; Chen, Xinchun

    2015-01-01

    Interferon-gamma Release Assays (IGRAs) significantly increases the possibility for early diagnosis of tuberculosis, but IGRAs alone cannot discriminate active TB from LTBI. Therefore, fast and reliable discrimination of active tuberculosis, especially bacteriology negative tuberculosis, from LTBI is a great necessity. Here we established an assay based on flow cytometric multiparameter assay assessing expression of CD161 along with CD3, CD4, and CD8, whereby a set of indices formulated by the percentages of CD3+CD161+, CD3+CD4+CD161+ and CD3+CD8+CD161+ T cells multiplied with lymphocyte/monocyte ratio were established. Application of the CD3+CD8+CD161+ index to compare a cohort of active tuberculosis with a cohort of LTBI or health control yielded 0.7662 (95% confidence interval [CI] 0.6559–0.8552) or 0.7922 (95%  CI 0.6846–0.8763) for sensitivity and 0.9048 (95%  CI 0.8209–0.9580) or 0.8939 (95% CI 0.8392–0.9349) for specificity when the TB cohort was AFB+; the corresponding results were 0.7481 (95%  CI 0.6648–0.8198) or 0.7557 (95%  CI 0.6730–0.8265) for sensitivity and 0.8571 (95%  CI 0.7637–0.9239) or 0.8603 (95%  CI 0.8008–0.9075) for specificity when the TB cohort was AFB−. Our results reveal that in combination with IGRAs, CD161-based indices provide a novel, fast diagnostic solution addressing the limitation of current tuberculosis diagnostics. PMID:26643453

  7. US College and University Student Health Screening Requirements for Tuberculosis and Vaccine-Preventable Diseases, 2012

    ERIC Educational Resources Information Center

    Jewett, Amy; Bell, Teal; Cohen, Nicole J.; Buckley, Kirsten; Leino, E. Victor; Even, Susan; Beavers, Suzanne; Brown, Clive; Marano, Nina

    2016-01-01

    Objective: Colleges are at risk for communicable disease outbreaks because of the high degree of person-to-person interactions and relatively crowded dormitory settings. This report describes the US college student health screening requirements among US resident and international students for tuberculosis (TB) and vaccine-preventable diseases…

  8. Characterization of Antibacterial and Hemolytic Activity of Synthetic Pandinin 2 Variants and Their Inhibition against Mycobacterium tuberculosis

    PubMed Central

    Rodríguez, Alexis; Villegas, Elba; Montoya-Rosales, Alejandra; Rivas-Santiago, Bruno; Corzo, Gerardo

    2014-01-01

    The contention and treatment of Mycobacterium tuberculosis and other bacteria that cause infectious diseases require the use of new type of antibiotics. Pandinin 2 (Pin2) is a scorpion venom antimicrobial peptide highly hemolytic that has a central proline residue. This residue forms a structural “kink” linked to its pore-forming activity towards human erythrocytes. In this work, the residue Pro14 of Pin2 was both substituted and flanked using glycine residues (P14G and P14GPG) based on the low hemolytic activities of antimicrobial peptides with structural motifs Gly and GlyProGly such as magainin 2 and ponericin G1, respectively. The two Pin2 variants showed antimicrobial activity against E. coli, S. aureus, and M. tuberculosis. However, Pin2 [GPG] was less hemolytic (30%) than that of Pin2 [G] variant. In addition, based on the primary structure of Pin2 [G] and Pin2 [GPG], two short peptide variants were designed and chemically synthesized keeping attention to their physicochemical properties such as hydrophobicity and propensity to adopt alpha-helical conformations. The aim to design these two short antimicrobial peptides was to avoid the drawback cost associated to the synthesis of peptides with large sequences. The short Pin2 variants named Pin2 [14] and Pin2 [17] showed antibiotic activity against E. coli and M. tuberculosis. Besides, Pin2 [14] presented only 25% of hemolysis toward human erythrocytes at concentrations as high as 100 µM, while the peptide Pin2 [17] did not show any hemolytic effect at the same concentration. Furthermore, these short antimicrobial peptides had better activity at molar concentrations against multidrug resistance M. tuberculosis than that of the conventional antibiotics ethambutol, isoniazid and rifampicin. Therefore, Pin2 [14] and Pin2 [17] have the potential to be used as an alternative antibiotics and anti-tuberculosis agents with reduced hemolytic effects. PMID:25019413

  9. [Spanish Society for Pediatric Infectious Diseases guidelines on tuberculosis in pregnant women and neonates (ii): Prophylaxis and treatment].

    PubMed

    Baquero-Artigao, F; Mellado Peña, M J; del Rosal Rabes, T; Noguera Julián, A; Goncé Mellgren, A; de la Calle Fernández-Miranda, M; Navarro Gómez, M L

    2015-10-01

    In pregnant women who have been exposed to tuberculosis (TB), primary isoniazid prophylaxis is only recommended in cases of immunosuppression, chronic medical conditions or obstetric risk factors, and close and sustained contact with a patient with infectious TB. Isoniazid prophylaxis for latent tuberculosis infection (LTBI) is recommended in women who have close contact with an infectious TB patient or have risk factors for progression to active disease. Otherwise, it should be delayed until at least three weeks after delivery. Treatment of TB disease during pregnancy is the same as for the general adult population. Infants born to mothers with disseminated or extrapulmonary TB in pregnancy, with active TB at delivery, or with postnatal exposure to TB, should undergo a complete diagnostic evaluation. Primary isoniazid prophylaxis for at least 12 weeks is recommended for those with negative diagnostic tests and no evidence of disease. Repeated negative diagnostic tests are mandatory before interrupting prophylaxis. Isoniazid for 9 months is recommended in LTBI. Treatment of neonatal TB disease is similar to that of older children, but should be maintained for at least 9 months. Respiratory isolation is recommended in congenital TB, and in postnatal TB with positive gastric or bronchial aspirate acid-fast smears. Separation of mother and infant is only necessary when the mother has received treatment for less than 2 weeks, is sputum smear-positive, or has drug-resistant TB. Breastfeeding is not contraindicated, and in case of mother-infant separation expressed breast milk feeding is recommended. PMID:25754314

  10. Leveraging Advances in Tuberculosis Diagnosis and Treatment to Address Nontuberculous Mycobacterial Disease

    PubMed Central

    Zhao, Yanlin; Rubin, Eric J.

    2016-01-01

    The nontuberculous mycobacteria (NTM), defined as any mycobacterial pathogen other than Mycobacterium tuberculosis or Mycobacterium leprae, are a diverse group of pathogens that collectively cause a substantive but often unappreciated worldwide burden of illness. Although NTMs may cause illness similar to M. tuberculosis, these pathogens generally do not respond to classic tuberculosis (TB) drug regimens, resulting in misdiagnosis and poor treatment, particularly in resource-poor settings. Although a few high-quality epidemiologic surveys have been made on the topic, existing evidence suggests that NTM-associated disease is much more common than previously thought: more common than TB in the industrialized world and likely increasing in prevalence globally. Despite this evidence, these organisms remain markedly understudied, and few international grants support basic science and clinical research. Here we suggest that the considerable efforts in developing new treatments and diagnostics for TB can be harnessed in the fight against NTM-associated illnesses. PMID:26886068

  11. Leveraging Advances in Tuberculosis Diagnosis and Treatment to Address Nontuberculous Mycobacterial Disease.

    PubMed

    Raju, Ravikiran M; Raju, Sagar M; Zhao, Yanlin; Rubin, Eric J

    2016-03-01

    The nontuberculous mycobacteria (NTM), defined as any mycobacterial pathogen other than Mycobacterium tuberculosis or Mycobacterium leprae, are a diverse group of pathogens that collectively cause a substantive but often unappreciated worldwide burden of illness. Although NTMs may cause illness similar to M. tuberculosis, these pathogens generally do not respond to classic tuberculosis (TB) drug regimens, resulting in misdiagnosis and poor treatment, particularly in resource-poor settings. Although a few high-quality epidemiologic surveys have been made on the topic, existing evidence suggests that NTM-associated disease is much more common than previously thought: more common than TB in the industrialized world and likely increasing in prevalence globally. Despite this evidence, these organisms remain markedly understudied, and few international grants support basic science and clinical research. Here we suggest that the considerable efforts in developing new treatments and diagnostics for TB can be harnessed in the fight against NTM-associated illnesses. PMID:26886068

  12. Mycobacterium tuberculosis induces apoptosis in gamma/delta T lymphocytes from patients with advanced clinical forms of active tuberculosis.

    PubMed Central

    Duarte, R; Kindlelán, J M; Carracedo, J; Sánchez-Guijo, P; Ramírez, R

    1997-01-01

    Antigens from inactivated Mycobacterium tuberculosis H37Ra induce activation in a subpopulation of gamma/delta (gamma/delta) T lymphocytes in a manner that resembles that of superantigens from alpha/beta T cells. After culture in vitro with H37Ra proteins, gamma/delta T lymphocytes from patients with advanced clinical forms of active tuberculosis (ACF-TBC) display cytotoxic activity against homotypic target cells exposed to H37Ra. Cytotoxicity by gamma/delta T lymphocytes from ACF-TBC patients occurs in a range similar to that observed in healthy subjects. Following activation, H37Ra-stimulated gamma/delta T lymphocytes from healthy subjects did proliferate in the presence of exogenous recombinant human interleukin 2. However, under the same conditions, gamma/delta T lymphocytes from ACF-TBC patients not only did not proliferate but died by apoptosis. These results suggest that in gamma/delta T lymphocytes from patients with ACF-TBC, antigens from M. tuberculosis may induce cell activation that leads to apoptotic cell death. PMID:9008275

  13. The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

    PubMed Central

    Gao, Wei; Kim, Jin-Yong; Anderson, Jeffrey R.; Akopian, Tatos; Hong, Seungpyo; Jin, Ying-Yu; Kandror, Olga; Kim, Jong-Woo; Lee, In-Ae; Lee, Sun-Young; McAlpine, James B.; Mulugeta, Surafel; Sunoqrot, Suhair; Wang, Yuehong; Yang, Seung-Hwan; Yoon, Tae-Mi; Goldberg, Alfred L.; Pauli, Guido F.; Cho, Sanghyun

    2014-01-01

    Drug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action. A high-throughput screening campaign of >65,000 actinomycete extracts for inhibition of Mycobacterium tuberculosis viability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity against M. tuberculosis in vitro, including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. The subcutaneous administration to mice of ecumicin in a micellar formulation at 20 mg/kg body weight resulted in plasma and lung exposures exceeding the MIC. Complete inhibition of M. tuberculosis growth in the lungs of mice was achieved following 12 doses at 20 or 32 mg/kg. Genome mining of lab-generated, spontaneous ecumicin-resistant M. tuberculosis strains identified the ClpC1 ATPase complex as the putative target, and this was confirmed by a drug affinity response test. ClpC1 functions in protein breakdown with the ClpP1P2 protease complex. Ecumicin markedly enhanced the ATPase activity of wild-type (WT) ClpC1 but prevented activation of proteolysis by ClpC1. Less stimulation was observed with ClpC1 from ecumicin-resistant mutants. Thus, ClpC1 is a valid drug target against M. tuberculosis, and ecumicin may serve as a lead compound for anti-TB drug development. PMID:25421483

  14. Mechanistic insights on immunosenescence and chronic immune activation in HIV-tuberculosis co-infection.

    PubMed

    Shankar, Esaki M; Velu, Vijayakumar; Kamarulzaman, Adeeba; Larsson, Marie

    2015-02-12

    Immunosenescence is marked by accelerated degradation of host immune responses leading to the onset of opportunistic infections, where senescent T cells show remarkably higher ontogenic defects as compared to healthy T cells. The mechanistic association between T-cell immunosenescence and human immunodeficiency virus (HIV) disease progression, and functional T-cell responses in HIV-tuberculosis (HIV-TB) co-infection remains to be elaborately discussed. Here, we discussed the association of immunosenescence and chronic immune activation in HIV-TB co-infection and reviewed the role played by mediators of immune deterioration in HIV-TB co-infection necessitating the importance of designing therapeutic strategies against HIV disease progression and pathogenesis. PMID:25674514

  15. Feasibility, Yield, and Cost of Active Tuberculosis Case Finding Linked to a Mobile HIV Service in Cape Town, South Africa: A Cross-sectional Study

    PubMed Central

    Kranzer, Katharina; Lawn, Stephen D.; Meyer-Rath, Gesine; Vassall, Anna; Raditlhalo, Eudoxia; Govindasamy, Darshini; van Schaik, Nienke; Wood, Robin; Bekker, Linda-Gail

    2012-01-01

    Background The World Health Organization is currently developing guidelines on screening for tuberculosis disease to inform national screening strategies. This process is complicated by significant gaps in knowledge regarding mass screening. This study aimed to assess feasibility, uptake, yield, treatment outcomes, and costs of adding an active tuberculosis case-finding program to an existing mobile HIV testing service. Methods and Findings The study was conducted at a mobile HIV testing service operating in deprived communities in Cape Town, South Africa. All HIV-negative individuals with symptoms suggestive of tuberculosis, and all HIV-positive individuals regardless of symptoms were eligible for participation and referred for sputum induction. Samples were examined by microscopy and culture. Active tuberculosis case finding was conducted on 181 days at 58 different sites. Of the 6,309 adults who accessed the mobile clinic, 1,385 were eligible and 1,130 (81.6%) were enrolled. The prevalence of smear-positive tuberculosis was 2.2% (95% CI 1.1–4.0), 3.3% (95% CI 1.4–6.4), and 0.4% (95% CI 1.4 015–6.4) in HIV-negative individuals, individuals newly diagnosed with HIV, and known HIV, respectively. The corresponding prevalence of culture-positive tuberculosis was 5.3% (95% CI 3.5–7.7), 7.4% (95% CI 4.5–11.5), 4.3% (95% CI 2.3–7.4), respectively. Of the 56 new tuberculosis cases detected, 42 started tuberculosis treatment and 34 (81.0%) completed treatment. The cost of the intervention was US$1,117 per tuberculosis case detected and US$2,458 per tuberculosis case cured. The generalisability of the study is limited to similar settings with comparable levels of deprivation and TB and HIV prevalence. Conclusions Mobile active tuberculosis case finding in deprived populations with a high burden of HIV and tuberculosis is feasible, has a high uptake, yield, and treatment success. Further work is now required to examine cost-effectiveness and affordability and

  16. Disease Activity Measures in Paediatric Rheumatic Diseases

    PubMed Central

    Luca, Nadia J.; Feldman, Brian M.

    2013-01-01

    Disease activity refers to potentially reversible aspects of a disease. Measurement of disease activity in paediatric rheumatic diseases is a critical component of patient care and clinical research. Disease activity measures are developed systematically, often involving consensus methods. To be useful, a disease activity measure must be feasible, valid, and interpretable. There are several challenges in quantifying disease activity in paediatric rheumatology; namely, the conditions are multidimensional, the level of activity must be valuated in the context of treatment being received, there is no gold standard for disease activity, and it is often difficult to incorporate the patient's perspective of their disease activity. To date, core sets of response variables are defined for juvenile idiopathic arthritis, juvenile systemic lupus erythematosus, and juvenile dermatomyositis, as well as definitions for improvement in response to therapy. Several specific absolute disease activity measures also exist for each condition. Further work is required to determine the optimal disease activity measures in paediatric rheumatology. PMID:24089617

  17. Detection of lipoarabinomannan as a diagnostic test for tuberculosis.

    PubMed Central

    Sada, E; Aguilar, D; Torres, M; Herrera, T

    1992-01-01

    A coagglutination technique was established for the detection of lipoarabinomannan of Mycobacterium tuberculosis in human serum samples and evaluated for its utility in the diagnosis of tuberculosis at the Instituto Nacional de Enfermedades Respiratorias in Mexico City. The test had a sensitivity of 88% in patients with sputum-smear-positive active pulmonary tuberculosis. The sensitivity in patients with active pulmonary tuberculosis negative for acid-fast bacilli in sputum was 67%. Less favorable results were obtained for patients with AIDS and tuberculosis, with a sensitivity of 57%. The specificity in control patients with lung diseases different from tuberculosis and in healthy subjects was 100%. The positive predictive value was 100%, and the negative predictive value for patients with sputum-positive active pulmonary tuberculosis was 97%. The results of this study suggest that the detection of lipoarabinomannan is an accurate test for the diagnosis of pulmonary tuberculosis. PMID:1401008

  18. Safety of Resuming Tumor Necrosis Factor Inhibitors in Ankylosing Spondylitis Patients Concomitant with the Treatment of Active Tuberculosis: A Retrospective Nationwide Registry of the Korean Society of Spondyloarthritis Research

    PubMed Central

    Kim, Hye Won; Kwon, Seong Ryul; Jung, Kyong-Hee; Kim, Seong-Kyu; Baek, Han Joo; Seo, Mi Ryung; Bang, So-Young; Lee, Hye-Soon; Suh, Chang-Hee; Jung, Ju Yang; Son, Chang-Nam; Shim, Seung Cheol; Lee, Sang-Hoon; Lee, Seung-Geun; Lee, Yeon-Ah; Lee, Eun Young; Kim, Tae-Hwan

    2016-01-01

    Backgrounds Patients who develop an active tuberculosis infection during tumor necrosis factor (TNF) inhibitor treatment typically discontinue TNF inhibitor and receive standard anti-tuberculosis treatment. However, there is currently insufficient information on patient outcomes following resumption of TNF inhibitor treatment during ongoing anti- tuberculosis treatment. Our study was designed to investigate the safety of resuming TNF inhibitors in ankylosing spondylitis (AS) patients who developed tuberculosis as a complication of the use of TNF inhibitors. Methods Through the nationwide registry of the Korean Society of Spondyloarthritis Research, 3929 AS patients who were prescribed TNF inhibitors were recruited between June 2003 and June 2014 at fourteen referral hospitals. Clinical information was analyzed about the patients who experienced tuberculosis after exposure to TNF inhibitors. The clinical features of resumers and non-resumers of TNF inhibitors were compared and the outcomes of tuberculosis were surveyed individually. Findings Fifty-six AS patients were treated for tuberculosis associated with TNF inhibitors. Among them, 23 patients resumed TNF inhibitors, and these patients were found to be exposed to TNF inhibitors for a longer period of time and experienced more frequent disease flare-up after discontinuation of TNF inhibitors compared with those who did not resume. Fifteen patients resumed TNF inhibitors during anti-tuberculosis treatment (early resumers) and 8 after completion of anti-tuberculosis treatment (late resumers). Median time to resuming TNF inhibitor from tuberculosis was 3.3 and 9.0 months in the early and late resumers, respectively. Tuberculosis was treated successfully in all resumers and did not relapse in any of them during follow-up (median 33.8 [IQR; 20.8–66.7] months). Conclusions Instances of tuberculosis were treated successfully in our AS patients, even when given concomitantly with TNF inhibitors. We suggest that early

  19. High Affinity Inha Inhibitors with Activity Against Drug-Resistant Strains of Mycobacterium Tuberculosis

    SciTech Connect

    Sullivan,T.; Truglio, J.; Boyne, M.; Novichenok, P.; Zhang, X.; Stratton, C.; Li, H.; Kaur, T.; Amin, A.; et al.

    2006-01-01

    Novel chemotherapeutics for treating multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) are required to combat the spread of tuberculosis, a disease that kills more than 2 million people annually. Using structure-based drug design, we have developed a series of alkyl diphenyl ethers that are uncompetitive inhibitors of InhA, the enoyl reductase enzyme in the MTB fatty acid biosynthesis pathway. The most potent compound has a Ki{prime} value of 1 nM for InhA and MIC{sub 99} values of 2-3 {micro}g mL{sup -1} (6-10 {micro}M) for both drug-sensitive and drug-resistant strains of MTB. Overexpression of InhA in MTB results in a 9-12-fold increase in MIC{sub 99}, consistent with the belief that these compounds target InhA within the cell. In addition, transcriptional response studies reveal that the alkyl diphenyl ethers fail to upregulate a putative efflux pump and aromatic dioxygenase, detoxification mechanisms that are triggered by the lead compound triclosan. These diphenyl ether-based InhA inhibitors do not require activation by the mycobacterial KatG enzyme, thereby circumventing the normal mechanism of resistance to the front line drug isoniazid (INH) and thus accounting for their activity against INH-resistant strains of MTB.

  20. Risk of tuberculosis during infliximab therapy for inflammatory bowel disease, rheumatoid arthritis, and spondyloarthropathy: A meta-analysis

    PubMed Central

    Wang, Qiang; Wen, Zhenzhen; Cao, Qian

    2016-01-01

    Infliximab is a promising drug with good outcomes demonstrated for diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and spondyloarthropathy (SpA). However, treatment with this drug may increase the risk of tuberculosis infection. The aim of the present study was to investigate infliximab-associated tuberculosis infection. Literature searches in PubMed, MEDLINE and EMBASE databases were performed. Randomized controlled trials with >95% of the patients >18 years-old were included. Meta-analysis was performed to investigate the incidence of tuberculosis infection after infliximab infusion. A total of 24 RCTs were included in the present meta-analysis. In total, 21 (0.51%) tuberculosis infections were detected among 4,111 patients administered infliximab therapy, compared with 0 (0%) among 2,229 patients assigned to the placebo group. Pooled odds ratio (OR) of developing tuberculosis infection was significantly higher with infliximab therapy than with placebo [2.86; 95% confidence interval (CI), 1.09–7.52]. The OR of tuberculosis infection was 3.93 (95% CI, 0.91–16.91) in RA, 2.46 (95% CI, 0.38–15.92) in SpA and 1.66 (95% CI, 0.26–10.57) in IBD. Rates of tuberculosis infection with infliximab therapy in RA, SpA and IBD were 0.70, 0.22 and 0.52%, respectively. Compared with placebo, infliximab therapy may increase the risk of developing tuberculosis. However, the ORs for the risk of infliximab-associated tuberculosis were not demonstrated to be significant in IBD, RA and SpA; therefore, these findings should be interpreted with caution. The risk of developing tuberculosis demonstrates the importance of the prevention and management of tuberculosis infection with infliximab therapy. PMID:27588089

  1. Differential influence of nutrient-starved Mycobacterium tuberculosis on adaptive immunity results in progressive tuberculosis disease and pathology.

    PubMed

    Dietrich, Jes; Roy, Sugata; Rosenkrands, Ida; Lindenstrøm, Thomas; Filskov, Jonathan; Rasmussen, Erik Michael; Cassidy, Joseph; Andersen, Peter

    2015-12-01

    When infected with Mycobacterium tuberculosis, most individuals will remain clinically healthy but latently infected. Latent infection has been proposed to partially involve M. tuberculosis in a nonreplicating stage, which therefore represents an M. tuberculosis phenotype that the immune system most likely will encounter during latency. It is therefore relevant to examine how this particular nonreplicating form of M. tuberculosis interacts with the host immune system. To study this, we first induced a state of nonreplication through prolonged nutrient starvation of M. tuberculosis in vitro. This resulted in nonreplicating persistence even after prolonged culture in phosphate-buffered saline. Infection with either exponentially growing M. tuberculosis or nutrient-starved M. tuberculosis resulted in similar lung CFU levels in the first phase of the infection. However, between week 3 and 6 postinfection, there was a very pronounced increase in bacterial levels and associated lung pathology in nutrient-starved-M. tuberculosis-infected mice. This was associated with a shift from CD4 T cells that coexpressed gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) or IFN-γ, TNF-α, and interleukin-2 to T cells that only expressed IFN-γ. Thus, nonreplicating M. tuberculosis induced through nutrient starvation promotes a bacterial form that is genetically identical to exponentially growing M. tuberculosis yet characterized by a differential impact on the immune system that may be involved in undermining host antimycobacterial immunity and facilitate increased pathology and transmission. PMID:26416911

  2. The Mycobacterium tuberculosis PPE protein Rv1168c induces stronger B cell response than Rv0256c in active TB patients.

    PubMed

    Abraham, Philip Raj; Udgata, Atul; Latha, Gaddam Suman; Mukhopadhyay, Sangita

    2016-06-01

    Tuberculosis (TB) caused by Mycobacterium tuberculosis is a serious global health problem and is responsible for millions of deaths every year. For effective control of this dreadful disease, it is necessary to diagnose TB cases at the initial stages of infection. The serodiagnosis of disease represents simple, rapid and inexpensive method that can be used at the primary health care levels. In this study we have compared sensitivity of two PPE proteins of M. tuberculosis, i.e., Rv0256c and Rv1168c for their use as serodiagnostic markers in active tuberculosis patients. Employing a standardized enzyme immunoassay with these PPE proteins as candidate antigens we were able to successfully discriminate the TB patients' sera from the BCG-vaccinated healthy controls. Further, we observed that Rv1168c displayed higher sensitivity in detecting extrapulmonary and smear negative pulmonary TB cases which are difficult to diagnose by available diagnostic methods. Overall the study highlights that Rv1168c can be used as a potential serodiagnostic marker for the diagnosis of active tuberculosis disease. PMID:26364913

  3. Low nutrient intake among adult women and patients with severe tuberculosis disease in Uganda: a cross-sectional study

    PubMed Central

    2012-01-01

    Background Information regarding dietary nutrient intake during tuberculosis disease is lacking. We established the relationship between disease severity or wasting during pulmonary tuberculosis and nutrient intake. Methods In a cross-sectional study of 131 adults with or without pulmonary tuberculosis were screened for human immune-deficiency virus (HIV), wasting, disease severity using 13 item validated clinical TBscore, and 24-hour dietary intake recall. Results Of the 131 participants, 61 were males and 70 females. Overall men and women had similar age. In average 24-hour nutrient intake, the following nutrients: energy, protein, total fat, carbohydrate, calcium, vitamin A, and folate were low among patients with severe tuberculosis disease. Patients with moderate-to-severe clinical TBscore had lower average energy intake than patients with mild TBscores (6.11 vs. 9.27 MJ, respectively) (p<0.05). The average 24-hour nutrient intakes between wasted and non-wasted tuberculosis patients were comparable. Nutrient intake among men was higher when compared to women regardless of wasting and severity of tuberculosis. Among those with wasting, men had higher average energy intake than women (8.87 vs. 5.81 MJ, respectively) (p<0.05). Among patients with mild disease, men had higher average energy intake than women with mild disease (12.83 vs. 7.49 kcal, respectively) (p<0.001). Conclusions Findings suggest that severity of pulmonary tuberculosis and female gender had reduced nutrient intake. Early tuberculosis diagnosis and nutritional support may be important in management of tuberculosis patients. PMID:23217171

  4. Bovine tuberculosis: an old disease but a new threat to Africa.

    PubMed

    Ayele, W Y; Neill, S D; Zinsstag, J; Weiss, M G; Pavlik, I

    2004-08-01

    Bovine tuberculosis (TB) is a disease characterised by progressive development of specific granulomatous lesions or tubercles in lung tissue, lymph nodes or other organs. Mycobacterium bovis is the causative agent of the disease. Bovine species, including bison and buffaloes, are susceptible to the disease, but nearly all warm-blooded animals can be affected. All species are not equally susceptible to the disease; some are spill-over (end) hosts and others maintenance hosts. In Africa, bovine TB primarily affects cattle; however, infection in other farm and domestic animals, such as sheep, goats, pigs, dogs and cats, is not uncommon. Wild ruminants and carnivores are also affected and are the natural reservoirs of the infectious agent in the wild. Man is also susceptible to the disease, the highest risk groups being individuals with concomitant HIV/AIDS infection. In Africa, human TB is widely known to be caused by M. tuberculosis; however, an unknown proportion of cases are due to M. bovis. This infection in humans is under-reported as a result of the diagnostic limitations of many laboratories in distinguishing M. bovis from M. tuberculosis. None of the national reports submitted to the OIE and WHO by African member states mention the importance of M. bovis in human TB cases. Consumption of unpasteurised milk and poorly heat-treated meat and close contact with infected animals represent the main sources of infection for humans. This review attempts to examine the impact of bovine TB on the health of animals and humans. PMID:15305473

  5. International union against tuberculosis and lung disease (IUATLD): initiatives in non-tuberculous lung disease.

    PubMed

    Becklake, M R

    1995-12-01

    IUATLD initiatives in non-tuberculous lung disease developed in the late 1970s, coincident with improving tuberculosis control, and have targeted acute respiratory infections in children and chronic airways disease in adults and in children. The focus has been on methodology and the tools required to document the distribution and determinants of disease, and is illustrated in data gathered in African populations. Instruments developed include a simplified method of measuring bronchial hyper-reactivity and an asthma questionnaire Non-standard methods of questionnaire administration have also been validated, methods which are appropriate for use in the burgeoning urban communities and workforces of sub-Saharan Africa made up of rural migrants from different tribes and language groups. In addition, a review of reference values available for interpreting lung function in sub-Saharan African populations indicates a need to take into account a secular trend over the last two decades towards higher spirometric values. In the published data from Africa, not inconsiderable between-country differences are evident in the prevalence of chronic bronchitis in adults and of asthma in children. In addition, rates for childhood asthma were consistently higher in urban vs rural communities, with environmental factors playing an important role as well as being locally specific. Not only does the burden of morbidity attributable to both the chronic airway diseases reviewed justify past IUATLD initiatives in non-tuberculous lung disease, but it also argues that future initiatives should focus on investigating between- and within-country differences using a standardized methodology, with a view to identifying local environmental determinants susceptible to intervention and control. Curbing tobacco use is clearly important, not only to benefit the health of adult smokers for whom the ill-health consequences have long been recognized, but, and more important, to protect the health of

  6. Burden of tuberculosis in Kampala, Uganda.

    PubMed Central

    Guwatudde, David; Zalwango, Sarah; Kamya, Moses R.; Debanne, Sara M.; Diaz, Mireya I.; Okwera, Alphonse; Mugerwa, Roy D.; King, Charles; Whalen, Christopher C.

    2003-01-01

    OBJECTIVE: To determine the prevalence and incidence of tuberculosis in one of Uganda's poor peri-urban areas. METHODS: Multi-stage sampling was used to select a sample of households whose members were evaluated for presence of signs and/or symptoms of active tuberculosis; history of tuberculosis treatment; and relevant demographic, socioeconomic, and household environment characteristics. Patients with suspected tuberculosis underwent standardized evaluation for active disease. FINDINGS: A sample of 263 households with 1142 individuals was evaluated. Nineteen people were classified as having had tuberculosis during the one-year reference period (May 2001-April 2002): nine (47%) cases already had been diagnosed through the health care system, while 10 cases (53%) were diagnosed through the survey. The prevalences for all forms of tuberculosis and for sputum smear-positive tuberculosis were 14.0 (95% confidence interval (CI) 7.8-20.3) and 4.4 (CI = 0.83-7.89) per thousand, respectively. The incidences for all forms of tuberculosis and for sputum smear-positive tuberculosis were 9.2 (CI = 3.97-14.4) and 3.7 (CI = 0.39-6.95) per thousand per year, respectively. CONCLUSION: The rate of tuberculosis in this peri-urban community was exceptionally high and may be underestimated by current surveillance systems. The need for interventions aimed at reducing tuberculosis transmission in this, and other similar communities with high case rates, is urgent. PMID:14758406

  7. Tuberculosis (For Parents)

    MedlinePlus

    ... Story" 5 Things to Know About Zika & Pregnancy Tuberculosis KidsHealth > For Parents > Tuberculosis Print A A A Text Size What's in ... When to You Call the Doctor en español Tuberculosis Tuberculosis (popularly known as "TB") is a disease ...

  8. Predictive value of the tuberculin skin test and QuantiFERON-tuberculosis Gold In-Tube test for development of active tuberculosis in hemodialysis patients

    PubMed Central

    Seyhan, Ekrem Cengiz; Gunluoglu, Gulşah; Gunluoglu, Mehmet Zeki; Tural, Seda; Sökücü, Sinem

    2016-01-01

    BACKGROUND: Hemodialysis (HD) patients are at increased risk of reactivation of latent tuberculosis infection (LTBI) compared with the general population. QuantiFERON-TB Gold (QFT-G) for LTBI detection is more promising than tuberculin skin test (TST) in HD patients. AIM: In our study, we evaluated the value of the TST and QFT-G In-Tube (QFG-IT) test in the development of active tuberculosis (TB), in the HD patients, and in healthy controls. METHODS: The study enrolled 95 HD patients and ninety age-matched, healthy controls. The TST and QFG-IT were performed. All the subjects were followed up 5 years for active TB disease. RESULTS: Compared to the healthy controls, a high prevalence of LTBI was found in the HD patients by QFG-IT (41% vs. 25%). However, no significant difference was detected by TST (32% vs. 31%). Four HD patients and one healthy control progressed to active TB disease within the 5-year follow-up. For active TB discovered subjects, QFG-IT was positive in all, but TST was positive in two (one patient and one healthy control). In HD patients; sensitivity, specificity, positive and negative predictive values of QFG-IT, and TST for active TB was 100% and 25%, 62% and 67%, 10%, and 3%, and 100% and 95%, respectively. Receiver operating curve analysis revealed that the results are significantly different (P = 0.04). CONCLUSION: QFG-IT test is a more useful diagnostic method than TST for detecting those who will progress to active TB in HD patients. PMID:27168859

  9. Host Protein Biomarkers Identify Active Tuberculosis in HIV Uninfected and Co-infected Individuals

    PubMed Central

    Achkar, Jacqueline M.; Cortes, Laetitia; Croteau, Pascal; Yanofsky, Corey; Mentinova, Marija; Rajotte, Isabelle; Schirm, Michael; Zhou, Yiyong; Junqueira-Kipnis, Ana Paula; Kasprowicz, Victoria O.; Larsen, Michelle; Allard, René; Hunter, Joanna; Paramithiotis, Eustache

    2015-01-01

    Biomarkers for active tuberculosis (TB) are urgently needed to improve rapid TB diagnosis. The objective of this study was to identify serum protein expression changes associated with TB but not latent Mycobacterium tuberculosis infection (LTBI), uninfected states, or respiratory diseases other than TB (ORD). Serum samples from 209 HIV uninfected (HIV−) and co-infected (HIV+) individuals were studied. In the discovery phase samples were analyzed via liquid chromatography and mass spectrometry, and in the verification phase biologically independent samples were analyzed via a multiplex multiple reaction monitoring mass spectrometry (MRM-MS) assay. Compared to LTBI and ORD, host proteins were significantly differentially expressed in TB, and involved in the immune response, tissue repair, and lipid metabolism. Biomarker panels whose composition differed according to HIV status, and consisted of 8 host proteins in HIV− individuals (CD14, SEPP1, SELL, TNXB, LUM, PEPD, QSOX1, COMP, APOC1), or 10 host proteins in HIV+ individuals (CD14, SEPP1, PGLYRP2, PFN1, VASN, CPN2, TAGLN2, IGFBP6), respectively, distinguished TB from ORD with excellent accuracy (AUC = 0.96 for HIV− TB, 0.95 for HIV+ TB). These results warrant validation in larger studies but provide promise that host protein biomarkers could be the basis for a rapid, blood-based test for TB. PMID:26501113

  10. Host Protein Biomarkers Identify Active Tuberculosis in HIV Uninfected and Co-infected Individuals.

    PubMed

    Achkar, Jacqueline M; Cortes, Laetitia; Croteau, Pascal; Yanofsky, Corey; Mentinova, Marija; Rajotte, Isabelle; Schirm, Michael; Zhou, Yiyong; Junqueira-Kipnis, Ana Paula; Kasprowicz, Victoria O; Larsen, Michelle; Allard, René; Hunter, Joanna; Paramithiotis, Eustache

    2015-09-01

    Biomarkers for active tuberculosis (TB) are urgently needed to improve rapid TB diagnosis. The objective of this study was to identify serum protein expression changes associated with TB but not latent Mycobacterium tuberculosis infection (LTBI), uninfected states, or respiratory diseases other than TB (ORD). Serum samples from 209 HIV uninfected (HIV(-)) and co-infected (HIV(+)) individuals were studied. In the discovery phase samples were analyzed via liquid chromatography and mass spectrometry, and in the verification phase biologically independent samples were analyzed via a multiplex multiple reaction monitoring mass spectrometry (MRM-MS) assay. Compared to LTBI and ORD, host proteins were significantly differentially expressed in TB, and involved in the immune response, tissue repair, and lipid metabolism. Biomarker panels whose composition differed according to HIV status, and consisted of 8 host proteins in HIV(-) individuals (CD14, SEPP1, SELL, TNXB, LUM, PEPD, QSOX1, COMP, APOC1), or 10 host proteins in HIV(+) individuals (CD14, SEPP1, PGLYRP2, PFN1, VASN, CPN2, TAGLN2, IGFBP6), respectively, distinguished TB from ORD with excellent accuracy (AUC = 0.96 for HIV(-) TB, 0.95 for HIV(+) TB). These results warrant validation in larger studies but provide promise that host protein biomarkers could be the basis for a rapid, blood-based test for TB. PMID:26501113

  11. A mathematical representation of the development of Mycobacterium tuberculosis active, latent and dormant stages.

    PubMed

    Magombedze, Gesham; Mulder, Nicola

    2012-01-01

    The majority of individuals infected with Mycobacterium tuberculosis (Mtb) bacilli develop latent infection. Mtb becomes dormant and phenotypically drug resistant when it encounters multiple stresses within the host, and expresses a set of genes, known as the dormancy regulon, in vivo. These genes are expressed in vitro in response to nitric oxide (NO), hypoxia (oxygen deprivation), and nutrient starvation. The occurrence and reactivation of latent tuberculosis (TB) is not clearly understood. The ability of the pathogen to enter and exit from different states is associated with its ability to cause persistent infection. During infection it is not known whether the organism is in a persistent slow replicating state or a dormant non-replicating state, with the latter ultimately causing a latent infection with the potential to reactivate to active disease. We collected gene expression data for Mtb bacilli under different stress conditions that simulate latency or dormancy. Time course experiments were selected and differentially expressed gene profiles were determined at each time point. A mathematical model was then developed to show the dynamics of Mtb latency based on the profile of differentially expressed genes. Analysis of the time course data show the dynamics of latency occurrence in vitro and the mathematical model reveals all possible scenarios of Mtb latency development with respect to the different conditions that may be produced by the immune response in vivo. The mathematical model provides a biological explanation of how Mtb latency occurs based on observed gene expression changes in in vitro latency models. PMID:21968442

  12. Potential novel markers to discriminate between active and latent tuberculosis infection in Chinese individuals.

    PubMed

    Bai, Xue-juan; Liang, Yan; Yang, You-rong; Feng, Jin-dong; Luo, Zhan-peng; Zhang, Jun-Xian; Wu, Xue-qiong

    2016-02-01

    Latent tuberculosis infection (LTBI) constitutes the main reservoir for reactivation tuberculosis. The finding of potential biomarkers for differentiating between TB and LTBI is very necessary. In this study, the immunological characteristics and potential diagnostic utility of Rv2029c, Rv2628 and Rv1813c proteins were assessed. These three proteins stimulated PBMCs from ELISPOT-positive LTBI subjects produced higher levels of IFN-γ in comparison with TB patients and ELISPOT-negative healthy subjects (p<0.05). BCG vaccination and non-TB respiratory disease had little influence on the immunological responses of Rv2029c and Rv2628 proteins (p>0.05). The LTBI diagnostic performance of Rv2029c was higher than Rv2628 and Rv1813c by ROC evaluation. But Rv2628 had much higher specificity than Rv2029c in active TB patients and uninfected healthy subjects. The IgG level against Rv1813c was higher in the TB group than in LTBI and uninfected healthy subjects (p<0.05). These results suggest that T cell response to Rv2628 and antibody against Rv1813c might be applicable as biomarkers to distinguish TB from LTBI and uninfected individuals. PMID:26851588

  13. In Vivo Molecular Dissection of the Effects of HIV-1 in Active Tuberculosis

    PubMed Central

    Bell, Lucy C. K.; Pollara, Gabriele; Pascoe, Mellissa; Tomlinson, Gillian S.; Lehloenya, Rannakoe J.; Roe, Jennifer; Meldau, Richard; Miller, Robert F.; Ramsay, Alan; Chain, Benjamin M.; Dheda, Keertan; Noursadeghi, Mahdad

    2016-01-01

    Increased risk of tuberculosis (TB) associated with HIV-1 infection is primarily attributed to deficient T helper (Th)1 immune responses, but most people with active TB have robust Th1 responses, indicating that these are not sufficient to protect against disease. Recent findings suggest that favourable outcomes following Mycobacterium tuberculosis infection arise from finely balanced inflammatory and regulatory pathways, achieving pathogen control without immunopathology. We hypothesised that HIV-1 and antiretroviral therapy (ART) exert widespread changes to cell mediated immunity, which may compromise the optimal host protective response to TB and provide novel insights into the correlates of immune protection and pathogenesis. We sought to define these effects in patients with active TB by transcriptional profiling of tuberculin skin tests (TST) to make comprehensive molecular level assessments of in vivo human immune responses at the site of a standardised mycobacterial challenge. We showed that the TST transcriptome accurately reflects the molecular pathology at the site of human pulmonary TB, and used this approach to investigate immune dysregulation in HIV-1/TB co-infected patients with distinct clinical phenotypes associated with TST reactivity or anergy and unmasking TB immune reconstitution inflammatory syndrome (IRIS) after initiation of ART. HIV-1 infected patients with positive TSTs exhibited preserved Th1 responses but deficient immunoregulatory IL10-inducible responses. Those with clinically negative TSTs revealed profound anergy of innate as well as adaptive immune responses, except for preservation of type 1 interferon activity, implicated in impaired anti-mycobacterial immunity. Patients with unmasking TB IRIS showed recovery of Th1 immunity to normal levels, but exaggerated Th2-associated responses specifically. These mechanisms of immune dysregulation were localised to the tissue microenvironment and not evident in peripheral blood. TST

  14. In Vivo Molecular Dissection of the Effects of HIV-1 in Active Tuberculosis.

    PubMed

    Bell, Lucy C K; Pollara, Gabriele; Pascoe, Mellissa; Tomlinson, Gillian S; Lehloenya, Rannakoe J; Roe, Jennifer; Meldau, Richard; Miller, Robert F; Ramsay, Alan; Chain, Benjamin M; Dheda, Keertan; Noursadeghi, Mahdad

    2016-03-01

    Increased risk of tuberculosis (TB) associated with HIV-1 infection is primarily attributed to deficient T helper (Th)1 immune responses, but most people with active TB have robust Th1 responses, indicating that these are not sufficient to protect against disease. Recent findings suggest that favourable outcomes following Mycobacterium tuberculosis infection arise from finely balanced inflammatory and regulatory pathways, achieving pathogen control without immunopathology. We hypothesised that HIV-1 and antiretroviral therapy (ART) exert widespread changes to cell mediated immunity, which may compromise the optimal host protective response to TB and provide novel insights into the correlates of immune protection and pathogenesis. We sought to define these effects in patients with active TB by transcriptional profiling of tuberculin skin tests (TST) to make comprehensive molecular level assessments of in vivo human immune responses at the site of a standardised mycobacterial challenge. We showed that the TST transcriptome accurately reflects the molecular pathology at the site of human pulmonary TB, and used this approach to investigate immune dysregulation in HIV-1/TB co-infected patients with distinct clinical phenotypes associated with TST reactivity or anergy and unmasking TB immune reconstitution inflammatory syndrome (IRIS) after initiation of ART. HIV-1 infected patients with positive TSTs exhibited preserved Th1 responses but deficient immunoregulatory IL10-inducible responses. Those with clinically negative TSTs revealed profound anergy of innate as well as adaptive immune responses, except for preservation of type 1 interferon activity, implicated in impaired anti-mycobacterial immunity. Patients with unmasking TB IRIS showed recovery of Th1 immunity to normal levels, but exaggerated Th2-associated responses specifically. These mechanisms of immune dysregulation were localised to the tissue microenvironment and not evident in peripheral blood. TST

  15. [Clinical practice guidelines from the Andalusian Society of Infectious Diseases (SAEI) for the treatment of tuberculosis].

    PubMed

    Domínguez-Castellano, Angel; Del Arco, Alfonso; Canueto-Quintero, Jesús; Rivero-Román, Antonio; Kindelán, José María; Creagh, Ricardo; Díez-García, Felipe

    2007-10-01

    The therapeutic scheme for initial pulmonary tuberculosis recommended by the SAEI is as follows: Initial phase, isoniazid, rifampin and pyrazinamide given daily for 2 months. In HIV(+) patients and immigrants from areas with a rate of primary resistance to isoniazid > 4%, ethambutol should be added until susceptibility studies are available. Second phase (continuation phase): rifampin and isoniazid, given daily or intermittently for 4 months in the general population. HIV(+) patients (< or = 200 CD4) and culture-positive patients after 2 months of treatment should receive a 7-month continuation phase. A 6-month regimen is recommended for extrapulmonary tuberculosis, with the exception of tuberculous meningitis, which should be treated for a minimum of 12 months and bone/joint tuberculosis, treated for a minimum of 9 months. Treatment regimens for multidrug resistant tuberculosis are based on expert opinion. These would include a combination of still-useful first-line drugs, injectable agents, and alternative agents, such as quinolones. Patients who present a special risk of transmitting the disease or of non-adherence should be treated with directly observed therapy. PMID:17915111

  16. Screening strategies for active tuberculosis: focus on cost-effectiveness

    PubMed Central

    Dobler, Claudia Caroline

    2016-01-01

    In recent years, there has been renewed interest in screening for active tuberculosis (TB), also called active case-finding (ACF), as a possible means to achieve control of the global TB epidemic. ACF aims to increase the detection of TB, in order to diagnose and treat patients with TB earlier than if they had been diagnosed and treated only at the time when they sought health care because of symptoms. This will reduce or avoid secondary transmission of TB to other people, with the long-term goal of reducing the incidence of TB. Here, the history of screening for active TB, current screening practices, and the role of TB-diagnostic tools are summarized and the literature on cost-effectiveness of screening for active TB reviewed. Cost-effectiveness analyses indicate that community-wide ACF can be cost-effective in settings with a high incidence of TB. ACF among close TB contacts is cost-effective in settings with a low as well as a high incidence of TB. The evidence for cost-effectiveness of screening among HIV-infected persons is not as strong as for TB contacts, but the reviewed studies suggest that the intervention can be cost-effective depending on the background prevalence of TB and test volume. None of the cost-effectiveness analyses were informed by data from randomized controlled trials. As the results of randomized controlled trials evaluating different ACF strategies will become available in future, we will hopefully gain a better understanding of the role that ACF can play in achieving global TB control. PMID:27418848

  17. Preventive therapy for tuberculosis in Maryland.

    PubMed

    Rabindran, E; Matuszak, D L; Israel, E; Woodall, H; Highsmith, H; Flynn, J

    1991-09-01

    Maryland data substantiate the safety of isoniazid therapy in preventing tuberculosis. To eradicate tuberculosis in the U.S., private physicians must play an active role by offering preventive therapy to patients at high risk of developing the disease. PMID:1921656

  18. Can stress cause disease? Revisiting the tuberculosis research of Thomas Holmes, 1949-1961.

    PubMed

    Lerner, B H

    1996-04-01

    The increasing emphasis in medicine on treating the whole patient has focused attention of the association between emotions and disease. However, physicians have long studied the connection between mind and body. One particularly interesting researcher in this area was Thomas Holmes, a charismatic and iconoclastic Seattle physician who studied the association between stress and tuberculosis in the 1950s. Although lacking the sophistication of modern biostatistics, several of Holmes' studies suggested that persons who had experienced stressful situations, such as divorce, death of a spouse, or loss of a job, were more likely to develop tuberculosis and less likely to recover from it. Holmes consciously used the same scientific methods as his peers, devising a numeric scale that quantified stressful events and doing prospective studies with control groups. Yet, he also emphasized the need to understand each patient's story and to view his or her tuberculosis as the culmination of a life of emotional hardship. Although Holmes' work was rudimentary, his basic supposition may have been correct. Recent research, benefiting from advances in both immunology and biostatistics, suggests that stress may lead to decreased immune function and thus to clinical disease. As studies of stress and disease become more statistically sophisticated, it will be important to retain Holmes' emphasis on understanding the lives of individual patients. PMID:8607596

  19. Activity of 5-chloro-pyrazinamide in mice infected with Mycobacterium tuberculosis or Mycobacterium bovis

    PubMed Central

    Ahmad, Zahoor; Tyagi, Sandeep; Minkowski, Austin; Almeida, Deepak; Nuermberger, Eric L.; Peck, Kaitlin M.; Welch, John T.; Baughn, Anthony D.; Jacobs, Williams R.; Grosset, Jacques H.

    2012-01-01

    Background & objectives: Pyrazinamide is an essential component of first line anti-tuberculosis regimen as well as most of the second line regimens. This drug has a unique sterilizing activity against Mycobacterium tuberculosis. Its unique role in tuberculosis treatment has lead to the search and development of its structural analogues. One such analogue is 5-chloro-pyrazinamide (5-Cl-PZA) that has been tested under in vitro conditions against M. tuberculosis. The present study was designed with an aim to assess the activity of 5-Cl-PZA, alone and in combination with first-line drugs, against murine tuberculosis. Methods: The minimum inhibitory concentration (MIC) of 5-Cl-PZA in Middlebrook 7H9 broth (neutral pH) and the inhibitory titre of serum from mice that received a 300 mg/kg oral dose of 5-Cl-PZA 30 min before cardiac puncture were determined. To test the tolerability of orally administered 5-Cl-PZA, uninfected mice received doses up to 300 mg/kg for 2 wk. Four weeks after low-dose aerosol infection either with M. tuberculosis or M. bovis, mice were treated 5 days/wk with 5-Cl-PZA, at doses ranging from 37.5 to 150 mg/kg, either alone or in combination with isoniazid and rifampicin. Antimicrobial activity was assessed by colony-forming unit counts in lungs after 4 and 8 wk of treatment. Results: The MIC of 5-Cl-PZA against M. tuberculosis was between 12.5 and 25 μg/ml and the serum inhibitory titre was 1:4. Under the same experimental conditions, the MIC of pyrazinamide was >100 μg/ml and mouse serum had no inhibitory activity after a 300 mg/kg dose; 5-Cl-PZA was well tolerated in uninfected and infected mice up to 300 and 150 mg/kg, respectively. While PZA alone and in combination exhibited its usual antimicrobial activity in mice infected with M. tuberculosis and no activity in mice infected with M. bovis, 5-Cl-PZA exhibited antimicrobial activity neither in mice infected with M. tuberculosis nor in mice infected with M. bovis. Interpretation

  20. Shared risk factors for multiple livestock diseases: a case study of bovine tuberculosis and brucellosis.

    PubMed

    Cowie, C E; Marreos, N; Gortázar, C; Jaroso, R; White, P C L; Balseiro, A

    2014-12-01

    Livestock diseases can result in reduced farm productivity. The bacterial diseases tuberculosis (TB) and brucellosis may share some transmission characteristics which, if managed in common, would result in more cost-effective management. Here, we identify risk factors shared between these diseases using a case-control approach and information theoretic modelling. One-hundred cattle farmers in Atlantic Spain were interviewed about farm characteristics and management practices. The risk factor shared between both diseases was intra- and inter-herd contact between cattle. Disease-specific risk factors were the presence of wildlife for TB, and cattle movement between farms for brucellosis. An integrated approach to disease management needs to consider cattle movement and farm biosecurity, reinforced by an education campaign to increase farmer awareness. This would be likely to bring benefits in reducing both diseases and improve the efficiency of any interventions. PMID:25267287

  1. Tuberculosis Facts - Testing for TB

    MedlinePlus

    Tuberculosis (TB) Facts Testing for TB What is TB? “TB” is short for a disease called tuberculosis. TB is spread through the air from one ... Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination

  2. Tuberculosis Facts - Exposure to TB

    MedlinePlus

    Tuberculosis (TB) Facts Exposure to TB What is TB? “TB” is short for a disease called tuberculosis. TB is spread through the air from one ... Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination

  3. Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response

    PubMed Central

    Adekambi, Toidi; Ibegbu, Chris C.; Cagle, Stephanie; Kalokhe, Ameeta S.; Wang, Yun F.; Hu, Yijuan; Day, Cheryl L.; Ray, Susan M.; Rengarajan, Jyothi

    2015-01-01

    BACKGROUND. The identification and treatment of individuals with tuberculosis (TB) is a global public health priority. Accurate diagnosis of pulmonary active TB (ATB) disease remains challenging and relies on extensive medical evaluation and detection of Mycobacterium tuberculosis (Mtb) in the patient’s sputum. Further, the response to treatment is monitored by sputum culture conversion, which takes several weeks for results. Here, we sought to identify blood-based host biomarkers associated with ATB and hypothesized that immune activation markers on Mtb-specific CD4+ T cells would be associated with Mtb load in vivo and could thus provide a gauge of Mtb infection. METHODS. Using polychromatic flow cytometry, we evaluated the expression of immune activation markers on Mtb-specific CD4+ T cells from individuals with asymptomatic latent Mtb infection (LTBI) and ATB as well as from ATB patients undergoing anti-TB treatment. RESULTS. Frequencies of Mtb-specific IFN-γ+CD4+ T cells that expressed immune activation markers CD38 and HLA-DR as well as intracellular proliferation marker Ki-67 were substantially higher in subjects with ATB compared with those with LTBI. These markers accurately classified ATB and LTBI status, with cutoff values of 18%, 60%, and 5% for CD38+IFN-γ+, HLA-DR+IFN-γ+, and Ki-67+IFN-γ+, respectively, with 100% specificity and greater than 96% sensitivity. These markers also distinguished individuals with untreated ATB from those who had successfully completed anti-TB treatment and correlated with decreasing mycobacterial loads during treatment. CONCLUSION. We have identified host blood-based biomarkers on Mtb-specific CD4+ T cells that discriminate between ATB and LTBI and provide a set of tools for monitoring treatment response and cure. TRIAL REGISTRATION. Registration is not required for observational studies. FUNDING. This study was funded by Emory University, the NIH, and the Yerkes National Primate Center. PMID:25822019

  4. Evaluation of tuberculosis treatment results in Italy, report 1998. Tuberculosis section of the National AIPO Study Group on Infectious Disease and the SMIRA Group.

    PubMed

    Centis, R; Ianni, A; Migliori, G B

    2000-08-01

    In Italy no national data on tuberculosis (TB) treatment results were available. In 1995 the AIPO (Italian Association of Hospital Pneumologists) TB Study Group, in collaboration with the Istituto Superiore di Sanità (technical branch of the Ministry of Health), started a prospective monitoring activity based on World Health Organization (WHO) and International Union against Tuberculosis and Lung Disease (IUATLD) recommendations. Data were collected from a representative network of TB units nationwide, managing a significant proportion of all TB cases notified in Italy each year. The aim of this study was to analyse the case findings and treatment results for the year 1998. The number of TB cases reported was 1162 (61.7% males; 28.2% immigrants), 888 (76.6%) being new cases. Of these cases, 1,001 (86.4%) were pulmonary, 132 (11.4%) extrapulmonary and 26 (2.2%) both pulmonary and extrapulmonary. The main risk factors for TB were a history of recent contact, diabetes and alcohol abuse among native Italians and human immunodeficiency virus-seropositive status and history of recent contact among immigrants. The majority of immigrants were from Africa and South America, and had been in Italy > 24 months before diagnosis of TB. Forty-seven per cent (552 of 1,162) of patients had a positive direct sputum smear examination for alcohol acidfast bacilli; 30% were resistant to any drug (combined monoresistance (the sum of primary and acquired drug resistance) to rifampicin 2.3%; combined multidrug resistance 11.4%). In 97% of cases, the duration of treatment was < 12 months. The overall success rate (cured plus treatment completed excluding transferred out from the denominator) was 83%. A significantly higher percentage of deaths was found in native Italians (being age-related; p < 0.001), whereas immigrants had a higher default rate. PMID:11057082

  5. Comparative Study of Activities of a Diverse Set of Antimycobacterial Agents against Mycobacterium tuberculosis and Mycobacterium ulcerans.

    PubMed

    Scherr, Nicole; Pluschke, Gerd; Panda, Manoranjan

    2016-05-01

    A library of compounds covering a broad chemical space was selected from a tuberculosis drug development program and was screened in a whole-cell assay against Mycobacterium ulcerans, the causative agent of the necrotizing skin disease Buruli ulcer. While a number of potent antitubercular agents were only weakly active or inactive against M. ulcerans, five compounds showed high activity (90% inhibitory concentration [IC90], ≤1 μM), making screening of focused antitubercular libraries a good starting point for lead generation against M. ulcerans. PMID:26883701

  6. MHEALTH INTERVENTION DEVELOPMENT TO SUPPORT PATIENTS WITH ACTIVE TUBERCULOSIS

    PubMed Central

    Iribarren, Sarah J.; Beck, Susan L.; Pearce, Patricia F.; Chirico, Cristina; Etchevarria, Mirta; Rubinstein, Fernando

    2015-01-01

    Background Mobile Health (mHealth) based interventions have been increasingly used to improve a broad range of health outcomes. However, few researchers have reported on the process or the application of theory to guide the development of mHealth based interventions, or specifically for tuberculosis (TB) treatment management. Aims To describe the steps, process, and considerations in developing a text messaging-based intervention to promote treatment adherence and provide support to patients with active TB. Methods Traditional qualitative techniques, including semi-structured interviews, field notes, content analysis, iterative coding, and thematic analysis, were used to design and document the intervention development with a multidisciplinary team of researchers, clinicians, administrators, and patients who were in active TB treatment. The Information-Motivation-Behavioral Skills (IMB) model was used to guide the coding scheme for content analysis of patient-directed TB educational material and intervention development. Results The development steps included: a) establishing intervention components, including justifications, considerations, timing and frequency of components; b) developing educational messages, including cultural adaption, text or short message service (SMS) formatting, and prioritizing message delivery order; and c) determining implementation protocol. A set of 16 IMB-based messages were developed for the educational component. Final intervention development was achieved in 3 months. Conclusion A collaborative approach and application of a theory to guide the intervention design and development is supported. Although a collaborative approach was more time consuming, it resulted in a more responsive, culturally appropriate, and comprehensive intervention. Considerations for developing a text messaging based intervention are provided and may serve as a guide for similar interventions. Further empirical evidence is needed for applying the IMB model

  7. Highly active antiretroviral therapy and tuberculosis control in Africa: synergies and potential.

    PubMed Central

    Harries, Anthony D.; Hargreaves, Nicola J.; Chimzizi, Rehab; Salaniponi, Felix M.

    2002-01-01

    HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) and TB (tuberculosis) are two of the world's major pandemics, the brunt of which falls on sub-Saharan Africa. Efforts aimed at controlling HIV/AIDS have largely focused on prevention, little attention having been paid to care. Work on TB control has concentrated on case detection and treatment. HIV infection has complicated the control of tuberculosis. There is unlikely to be a decline in the number of cases of TB unless additional strategies are developed to control both this disease and HIV simultaneously. Such strategies would include active case-finding in situations where TB transmission is high, the provision of a package of care for HIV-related illness, and the application of highly active antiretroviral therapy. The latter is likely to have the greatest impact, but for this therapy to become more accessible in Africa the drugs would have to be made available through international support and a programme structure would have to be developed for its administration. It could be delivered by means of a structure based on the five-point strategy called DOTS, which has been adopted for TB control. However, it may be unrealistic to give TB control programmes the responsibility for running such a programme. A better approach might be to deliver highly active antiretroviral therapy within a comprehensive HIV/AIDS management strategy complementing the preventive work already being undertaken by AIDS control programmes. TB programmes could contribute towards the development and implementation of this strategy. PMID:12132003

  8. Predominance of interleukin-22 over interleukin-17 at the site of disease in human tuberculosis

    PubMed Central

    Matthews, Kerryn; Wilkinson, Katalin A.; Kalsdorf, Barbara; Roberts, Teri; Diacon, Andreas; Walzl, Gerhard; Wolske, Janine; Ntsekhe, Mpiko; Syed, Faisal; Russell, James; Mayosi, Bongani M.; Dawson, Rodney; Dheda, Keertan; Wilkinson, Robert J.; Hanekom, Willem A.; Scriba, Thomas J.

    2011-01-01

    Summary The inflammatory response to Mycobacterium tuberculosis (M.tb) at the site of disease is Th1 driven. Whether the Th17 cytokines, IL-17 and IL-22, contribute to this response in humans is unknown. We hypothesized that IL-17 and IL-22 contribute to the inflammatory response in pleural and pericardial disease sites of human tuberculosis (TB). We studied pleural and pericardial effusions, established TB disease sites, from HIV-uninfected TB patients. Levels of soluble cytokines were measured by ELISA and MMP-9 by luminex. Bronchoalveolar lavage or pericardial mycobacteria-specific T cell cytokine expression was analyzed by intracellular cytokine staining. IL-17 was not abundant in pleural or pericardial fluid. IL-17 expression by mycobacteria-specific disease site T cells was not detected in healthy, M.tb-infected persons, or patients with TB pericarditis. These data do not support a major role for IL-17 at established TB disease sites in humans. IL-22 was readily detected in fluid from both disease sites. These IL-22 levels exceeded matching peripheral blood levels. Further, IL-22 levels in pericardial fluid correlated positively with MMP-9, an enzyme known to degrade the pulmonary extracellular matrix. We propose that our findings support a role for IL-22 in TB-induced pathology or the resulting repair process. PMID:21767990

  9. Central pontine myelinolysis in advanced HIV infection with tuberculosis and multicentric Castleman's disease.

    PubMed

    Katchanov, J; Branding, G; Stocker, H

    2013-07-01

    We present a case of central pontine myelinolysis (CPM) in a patient with advanced HIV infection and miliary tuberculosis. While hospitalized the patient developed an unusual ataxic variant of CPM with full clinical recovery. Follow-up imaging revealed resolution of pontine lesions. To our knowledge, this is the first report of a clinical and radiological recovery from CPM in advanced HIV disease. Our report extends our knowledge of neurological presentations in patients with advanced HIV infection. It highlights the importance of considering CPM in patients with advanced HIV disease presenting with an ataxic syndrome, even in the absence of an electrolyte derangement. PMID:23970776

  10. Characteristics of Active Tuberculosis Patients Requiring Intensive Care Monitoring and Factors Affecting Mortality

    PubMed Central

    Levent, Dalar; Emel, Eryüksel; Pelin, Uysal; Turkay, Akbaş; Aybüke, Kekeçoğlu

    2016-01-01

    Background One to three percent of cases of acute tuberculosis (TB) require monitoring in the intensive care unit (ICU). The purpose of this study is to establish and determine the mortality rate and discuss the causes of high mortality in these cases, and to evaluate the clinical and laboratory findings of TB patients admitted to the pulmonary ICU. Methods The data of patients admitted to the ICU of Yedikule Chest Diseases and Chest Surgery Education and Research Hospital due to active TB were retrospectively evaluated. Demographic characteristics, medical history, and clinical and laboratory findings were evaluated. Results Thirty-five TB patients (27 males) with a median age of 47 years were included, of whom 20 died within 30 days (57%). The Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were significantly higher, and albumin and PaO2/FIO2 levels were significantly lower, and shock, multiple organ failure, the need for invasive mechanical ventilation and drug resistance were more common in the patients who died. The mortality risk was 7.58 times higher in the patients requiring invasive mechanical ventilation. The SOFA score alone was a significant risk factor affecting survival. Conclusion The survival rate is low in cases of tuberculosis treated in an ICU. The predictors of mortality include the requirement of invasive mechanical ventilation and multiple organ failure. Another factor specific to TB patients is the presence of drug resistance, which should be taken seriously in countries where there is a high incidence of the disease. Finding new variables that can be established with new prospective studies may help to decrease the high mortality rate. PMID:27433176

  11. In Vitro and In Vivo Activities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis

    PubMed Central

    Cho, S.; Yang, T. J.; Kim, Y.; Wang, Y.; Lu, Y.; Wang, B.; Xu, J.; Mdluli, K.; Ma, Z.; Franzblau, S. G.

    2014-01-01

    Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10−7. In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole. PMID:25331696

  12. IFNG-mediated immune responses enhance autophagy against Mycobacterium tuberculosis antigens in patients with active tuberculosis

    PubMed Central

    Rovetta, Ana I; Peña, Delfina; Hernández Del Pino, Rodrigo E; Recalde, Gabriela M; Pellegrini, Joaquín; Bigi, Fabiana; Musella, Rosa M; Palmero, Domingo J; Gutierrez, Marisa; Colombo, María I; García, Verónica E

    2015-01-01

    Protective immunity against Mycobacterium tuberculosis (Mtb) requires IFNG. Besides, IFNG-mediated induction of autophagy suppresses survival of virulent Mtb in macrophage cell lines. We investigated the contribution of autophagy to the defense against Mtb antigen (Mtb-Ag) in cells from tuberculosis patients and healthy donors (HD). Patients were classified as high responders (HR) if their T cells produced significant IFNG against Mtb-Ag; and low responders (LR) when patients showed weak or no T cell responses to Mtb-Ag. The highest autophagy levels were detected in HD cells whereas the lowest quantities were observed in LR patients. Interestingly, upon Mtb-Ag stimulation, we detected a positive correlation between IFNG and MAP1LC3B-II/LC3-II levels. Actually, blockage of Mtb-Ag-induced IFNG markedly reduced autophagy in HR patients whereas addition of limited amounts of IFNG significantly increased autophagy in LR patients. Therefore, autophagy collaborates with human immune responses against Mtb in close association with specific IFNG secreted against the pathogen. PMID:25426782

  13. The Structure Activity Relationship of Urea Derivatives as Anti-Tuberculosis Agents

    PubMed Central

    Brown, Joshua R.; North, Elton J.; Hurdle, Julian G.; Morisseau, Christophe; Scarborough, Jerrod S.; Sun, Dianqing; Korduláková, Jana; Scherman, Michael S.; Jones, Victoria; Grzegorzewicz, Anna; Crew, Rebecca M.; Jackson, Mary; McNeil, Michael R.; Lee, Richard E.

    2011-01-01

    The treatment of tuberculosis is becoming more difficult due to the ever increasing prevalence of drug resistance. Thus, it is imperative that novel anti-tuberculosis agents, with unique mechanisms of action, be discovered and developed. The direct anti-tubercular testing of a small compound library led to discovery of adamantyl urea hit compound 1. In this study, the hit was followed up through the synthesis of an optimization library. This library was generated by systematically replacing each section of the molecule with a similar moiety until a clear structure activity relationship was obtained with respect to anti-tubercular activity. The best compounds in this series contained a 1-adamantyl-3-phenyl urea core and had potent activity against Mycobacterium tuberculosis plus an acceptable therapeutic index. It was noted that the compounds identified and the pharmacophore developed is consistent with inhibitors of epoxide hydrolase family of enzymes. Consequently, the compounds were tested for inhibition of representative epoxide hydrolases: M. tuberculosis EphB and EphE; and human soluble epoxide hydrolase. Many of the optimized inhibitors showed both potent EphB and EphE inhibition suggesting the antitubercular activity is through inhibition of multiple epoxide hydrolyase enzymes. The inhibitors also showed potent inhibition of humans soluble expoxide hydrolyase, but limited cytotoxicity suggesting that future studies must be towards increasing the selectivity of epoxide hydrolyase inhibition towards the M. tuberculosis enzymes. PMID:21840723

  14. Evaluation of heat shock proteins for discriminating between latent tuberculosis infection and active tuberculosis: A preliminary report.

    PubMed

    Shekhawat, Seema D; Purohit, Hemant J; Taori, Girdhar M; Daginawala, Hatim F; Kashyap, Rajpal S

    2016-01-01

    The diagnosis of a latent tuberculosis infection (LTBI) is of the utmost concern. The available tests, the tuberculin skin test (TST) and the Quantiferon-TB Gold test (QFT-G) cannot discriminate between active TB and LTBI. Therefore, the aim of the study is to identify new biomarkers that can discriminate between active TB and LTBI and can also assess the risk of the individual developing active TB. In total, 55 blood samples were collected, of which 10 samples were from the active TB infection group, 10 were from the high-risk exposure group, 23 were from the low-risk exposure group, and 12 were from healthy controls living in a non-TB endemic area. A panel of heat shock proteins (Hsps), including host Hsp25, Hsp60, Hsp70, and Hsp90 and Mycobacterium tuberculosis (MTB) Hsp16, were evaluated in all of the collected samples using ELISA. The levels of the host Hsp(s) (Hsp25, Hsp60, Hsp70 and Hsp90) and MTB Hsp16 were significantly (p<0.05) elevated in the active TB group compared to the high-risk exposure group, the low-risk exposure group and the control group. Notably, the levels of the same panel of Hsp(s) were elevated in the high-risk exposure group compared to the low-risk exposure group. On follow-up, out of the 10 high-risk exposure participants, 3 converted into active TB, indicating that this group has the highest risk of developing TB. Thus, the evaluated panel of Hsp(s) can discriminate between LTBI and active TB. They can also identify individuals who are at the highest risk of developing active TB. Because they can be rapidly detected, Hsp(s) have an edge over the existing diagnostic tools for LTBI. The evaluation of these proteins will be useful in designing better diagnostic methods for LTBI. PMID:26300163

  15. 38 CFR 3.372 - Initial grant following inactivity of tuberculosis.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... inactivity of tuberculosis. 3.372 Section 3.372 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF... Considerations Relative to Specific Diseases § 3.372 Initial grant following inactivity of tuberculosis. When... tuberculosis and there is satisfactory evidence that the condition was active previously but is now...

  16. 38 CFR 3.372 - Initial grant following inactivity of tuberculosis.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... inactivity of tuberculosis. 3.372 Section 3.372 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF... Considerations Relative to Specific Diseases § 3.372 Initial grant following inactivity of tuberculosis. When... tuberculosis and there is satisfactory evidence that the condition was active previously but is now...

  17. 38 CFR 3.372 - Initial grant following inactivity of tuberculosis.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... inactivity of tuberculosis. 3.372 Section 3.372 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF... Considerations Relative to Specific Diseases § 3.372 Initial grant following inactivity of tuberculosis. When... tuberculosis and there is satisfactory evidence that the condition was active previously but is now...

  18. 38 CFR 3.372 - Initial grant following inactivity of tuberculosis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... inactivity of tuberculosis. 3.372 Section 3.372 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF... Considerations Relative to Specific Diseases § 3.372 Initial grant following inactivity of tuberculosis. When... tuberculosis and there is satisfactory evidence that the condition was active previously but is now...

  19. 38 CFR 3.372 - Initial grant following inactivity of tuberculosis.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... inactivity of tuberculosis. 3.372 Section 3.372 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF... Considerations Relative to Specific Diseases § 3.372 Initial grant following inactivity of tuberculosis. When... tuberculosis and there is satisfactory evidence that the condition was active previously but is now...

  20. Pancreatic Tuberculosis.

    PubMed

    Chaudhary, Poras; Bhadana, Utsav; Arora, Mohinder P

    2015-12-01

    Tuberculosis of the pancreas is extremely rare and in most of the cases mimics pancreatic carcinoma. There are a number of case reports on pancreatic tuberculosis with various different presentations, but only a few case series have been published, and most of our knowledge about this disease comes from individual case reports. Patients of pancreatic tuberculosis may remain asymptomatic initially and manifest as an abscess or a mass involving local lymph nodes and usually present with non-specific features. Pancreatic tuberculosis may present with a wide range of imaging findings. It is difficult to diagnose tuberculosis of pancreas on imaging studies as they may present with masses, cystic lesions or abscesses and mass lesions in most of the cases mimic pancreatic carcinoma. As it is a rare entity, it cannot be recommended but suggested that pancreatic tuberculosis should be considered in cases with a large space occupying lesions associated with necrotic peripancreatic lymph nodes and constitutional symptoms. Ultrasonography/computed tomography/endosonography-guided biopsy is the recommended diagnostic technique. Most patients achieve complete cure with standard antituberculous therapy. The aims of this study are to review clinical presentation, diagnostic studies, and management of pancreatic tuberculosis and to present our experience of 5 cases of pancreatic tuberculosis. PMID:26884661

  1. Tuberculosis at the human-animal interface: an emerging disease of elephants.

    PubMed

    Mikota, Susan K; Maslow, Joel N

    2011-05-01

    Over the past 15 years, cases of infection with organisms of the Mycobacterium tuberculosis complex have been diagnosed among captive elephants in the United States and worldwide. Outbreak investigations have documented that among staff employed at facilities housing infected animals, skin test conversion to purified protein derivative have been documented. Clonal spread among animals in close contact and even inter-species spread between elephant and human has been documented. Detection of actively infected animals relies on samples obtained by trunk wash. Diagnosis has been augmented by the development of a multi-antigen serologic assay with excellent specificity and sensitivity. Treatment regimens are still in development with efficacy largely unknown due to a paucity of both premortem follow-up and necropsy data of treated animals. The epidemiology, diagnosis and treatment of tuberculosis in elephants require additional careful study of clinical data. PMID:21397564

  2. Potential Role of M. tuberculosis Specific IFN-γ and IL-2 ELISPOT Assays in Discriminating Children with Active or Latent Tuberculosis

    PubMed Central

    Chiappini, Elena; Della Bella, Chiara; Bonsignori, Francesca; Sollai, Sara; Amedei, Amedeo; Galli, Luisa; Niccolai, Elena; Singh, Mahavir; D'Elios, Mario M.; de Martino, Maurizio

    2012-01-01

    Background Although currently available IGRA have been reported to be promising markers for TB infection, they cannot distinguish active tuberculosis (TB) from latent infection (LTBI). Objective Children with LTBI, active TB disease or uninfected were prospectively evaluated by an in-house ELISPOT assay in order to investigate possible immunological markers for a differential diagnosis between LTBI and active TB. Methods Children at risk for TB infection prospectively enrolled in our infectious disease unit were evaluated by in-house IFN-γ and IL-2 based ELISPOT assays using a panel of Mycobacterium tuberculosis antigens. Results Twenty-nine children were classified as uninfected, 21 as LTBI and 25 as active TB cases (including 5 definite and 20 probable cases). Significantly higher IFN-γ ELISPOT responses were observed in infected vs. uninfected children for ESAT-6 (p<0.0001), CFP-10 (p<0.0001), TB 10.3 (p = 0.003), and AlaDH (p = 0.001), while differences were not significant considering Ag85B (p = 0.063), PstS1 (p = 0.512), and HspX (16 kDa) (p = 0.139). IL-2 ELISPOT assay responses were different for ESAT-6 (p<0.0001), CFP-10 (p<0.0001), TB 10.3 (p<0.0001), HspX (16 kDa) (p<0.0001), PstS1 (p<0.0001) and AlaDH (p = 0.001); but not for Ag85B (p = 0.063). Comparing results between children with LTBI and those with TB disease differences were significant for IFN-γ ELISPOT only for AlaDH antigen (p = 0.021) and for IL-2 ELISPOT assay for AlaDH (p<0.0001) and TB 10.3 antigen (p = 0.043). ROC analyses demonstrated sensitivity of 100% and specificity of 81% of AlaDH-IL-2 ELISPOT assay in discriminating between latent and active TB using a cut off of 12.5 SCF per million PBMCs. Conclusion Our data suggest that IL-2 based ELISPOT with AlaDH antigen may be of help in discriminating children with active from those with latent TB. PMID:23029377

  3. A Rare Case of Pott’s Disease (Spinal Tuberculosis) Mimicking Metastatic Disease in the Southern Region of Denmark

    PubMed Central

    Osmanagic, Azra; Emamifar, Amir; Bang, Jacob Christian; Hansen, Inger Marie Jensen

    2016-01-01

    Patient: Female, 78 Final Diagnosis: Pott’s disease Symptoms: Back pain • nausea • vomiting • weight loss Medication: — Clinical Procedure: MRI Specialty: Infectious Diseases Objective: Rare disease Background: Pott’s disease (PD) or spinal tuberculosis is a rare condition which accounts for less than 1% of total tuberculosis (TB) cases. The incidence of PD has recently increased in Europe and the United States, mainly due to immigration; however, it is still a rare diagnosis in Scandinavian countries, and if overlooked it might lead to significant neurologic complications. Case Report: A 78-year-old woman, originally from Eastern Europe, presented to the emergency department with a complaint of nausea, vomiting, weight loss, and severe back pain. On admission she was febrile and had leukocytosis and increased C-reactive protein. Initial spinal x-ray was performed and revealed osteolytic changes in the vertebral body of T11 and T12. Magnetic resonance imaging (MRI) of the spine illustrated spondylitis of T10, T11, and T12, with multiple paravertebral and epidural abscesses, which was suggestive of PD. Polymerase chain reaction (PCR) of the patient’s gastric fluid was positive for Mycobacterium tuberculosis (MT). Based on MRI and PCR findings, standard treatment for TB was initiated. Results of the spine biopsy and culture showed colonies of MT and confirmed the diagnosis afterwards. Due to the instability of the spine and severe and continuous pain, spine-stabilizing surgery was performed. Her TB was cured after nine months of treatment. Conclusions: PD is an important differential diagnosis of malignancy that should be diagnosed instantly. History of exposure to TB and classic radiologic finding can help make the diagnosis. PMID:27272065

  4. A Rare Case of Pott's Disease (Spinal Tuberculosis) Mimicking Metastatic Disease in the Southern Region of Denmark.

    PubMed

    Osmanagic, Azra; Emamifar, Amir; Christian Bang, Jacob; Jensen Hansen, Inger Marie

    2016-01-01

    BACKGROUND Pott's disease (PD) or spinal tuberculosis is a rare condition which accounts for less than 1% of total tuberculosis (TB) cases. The incidence of PD has recently increased in Europe and the United States, mainly due to immigration; however, it is still a rare diagnosis in Scandinavian countries, and if overlooked it might lead to significant neurologic complications. CASE REPORT A 78-year-old woman, originally from Eastern Europe, presented to the emergency department with a complaint of nausea, vomiting, weight loss, and severe back pain. On admission she was febrile and had leukocytosis and increased C-reactive protein. Initial spinal x-ray was performed and revealed osteolytic changes in the vertebral body of T11 and T12. Magnetic resonance imaging (MRI) of the spine illustrated spondylitis of T10, T11, and T12, with multiple paravertebral and epidural abscesses, which was suggestive of PD. Polymerase chain reaction (PCR) of the patient's gastric fluid was positive for Mycobacterium tuberculosis (MT). Based on MRI and PCR findings, standard treatment for TB was initiated. Results of the spine biopsy and culture showed colonies of MT and confirmed the diagnosis afterwards. Due to the instability of the spine and severe and continuous pain, spine-stabilizing surgery was performed. Her TB was cured after nine months of treatment. CONCLUSIONS PD is an important differential diagnosis of malignancy that should be diagnosed instantly. History of exposure to TB and classic radiologic finding can help make the diagnosis. PMID:27272065

  5. Rapid, Semiquantitative Assay To Discriminate among Compounds with Activity against Replicating or Nonreplicating Mycobacterium tuberculosis

    PubMed Central

    Roberts, Julia; Ling, Yan; Quezada, Landys Lopez; Glasheen, Jou; Ballinger, Elaine; Somersan-Karakaya, Selin; Warrier, Thulasi; Warren, J. David; Nathan, Carl

    2015-01-01

    The search for drugs that can kill replicating and nonreplicating Mycobacterium tuberculosis faces practical bottlenecks. Measurement of CFU and discrimination of bacteriostatic from bactericidal activity are costly in compounds, supplies, labor, and time. Testing compounds against M. tuberculosis under conditions that prevent the replication of M. tuberculosis often involves a second phase of the test in which conditions are altered to permit the replication of bacteria that survived the first phase. False-positive determinations of activity against nonreplicating M. tuberculosis may arise from carryover of compounds from the nonreplicating stage of the assay that act in the replicating stage. We mitigate these problems by carrying out a 96-well microplate liquid MIC assay and then transferring an aliquot of each well to a second set of plates in which each well contains agar supplemented with activated charcoal. After 7 to 10 days—about 2 weeks sooner than required to count CFU—fluorometry reveals whether M. tuberculosis bacilli in each well have replicated extensively enough to reduce a resazurin dye added for the final hour. This charcoal agar resazurin assay (CARA) distinguishes between bacterial biomasses in any two wells that differ by 2 to 3 log10 CFU. The CARA thus serves as a pretest and semiquantitative surrogate for longer, more laborious, and expensive CFU-based assays, helps distinguish bactericidal from bacteriostatic activity, and identifies compounds that are active under replicating conditions, nonreplicating conditions, or both. Results for 14 antimycobacterial compounds, including tuberculosis (TB) drugs, revealed that PA-824 (pretomanid) and TMC207 (bedaquiline) are largely bacteriostatic. PMID:26239979

  6. Rapid, Semiquantitative Assay To Discriminate among Compounds with Activity against Replicating or Nonreplicating Mycobacterium tuberculosis.

    PubMed

    Gold, Ben; Roberts, Julia; Ling, Yan; Quezada, Landys Lopez; Glasheen, Jou; Ballinger, Elaine; Somersan-Karakaya, Selin; Warrier, Thulasi; Warren, J David; Nathan, Carl

    2015-10-01

    The search for drugs that can kill replicating and nonreplicating Mycobacterium tuberculosis faces practical bottlenecks. Measurement of CFU and discrimination of bacteriostatic from bactericidal activity are costly in compounds, supplies, labor, and time. Testing compounds against M. tuberculosis under conditions that prevent the replication of M. tuberculosis often involves a second phase of the test in which conditions are altered to permit the replication of bacteria that survived the first phase. False-positive determinations of activity against nonreplicating M. tuberculosis may arise from carryover of compounds from the nonreplicating stage of the assay that act in the replicating stage. We mitigate these problems by carrying out a 96-well microplate liquid MIC assay and then transferring an aliquot of each well to a second set of plates in which each well contains agar supplemented with activated charcoal. After 7 to 10 days-about 2 weeks sooner than required to count CFU-fluorometry reveals whether M. tuberculosis bacilli in each well have replicated extensively enough to reduce a resazurin dye added for the final hour. This charcoal agar resazurin assay (CARA) distinguishes between bacterial biomasses in any two wells that differ by 2 to 3 log10 CFU. The CARA thus serves as a pretest and semiquantitative surrogate for longer, more laborious, and expensive CFU-based assays, helps distinguish bactericidal from bacteriostatic activity, and identifies compounds that are active under replicating conditions, nonreplicating conditions, or both. Results for 14 antimycobacterial compounds, including tuberculosis (TB) drugs, revealed that PA-824 (pretomanid) and TMC207 (bedaquiline) are largely bacteriostatic. PMID:26239979

  7. Anti-Mycobacterium tuberculosis activity and cytotoxicity of Calophyllum brasiliense Cambess (Clusiaceae)

    PubMed Central

    Pires, Claudia Terencio Agostinho; Brenzan, Mislaine Adriana; Scodro, Regiane Bertin de Lima; Cortez, Diógenes Aparício Garcia; Lopes, Luciana Dias Ghiraldi; Siqueira, Vera Lucia Dias; Cardoso, Rosilene Fressatti

    2014-01-01

    We evaluated the in vitro anti-Mycobacterium tuberculosis activity and the cytotoxicity of dichloromethane extract and pure compounds from the leaves of Calophyllum brasiliense. Purification of the dichloromethane extract yielded the pure compounds (-) mammea A/BB (1), (-) mammea B/BB (2) and amentoflavone (3). The compound structures were elucidated on the basis of spectroscopic and spectrometric data. The contents of bioactive compounds in the extracts were quantified using high performance liquid chromatography coupled to an ultraviolet detector. The anti-M. tuberculosis activity of the extracts and the pure compounds was evaluated using a resazurin microtitre assay plate. The cytotoxicity assay was performed in J774G.8 macrophages using the 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide colourimetric method. The quantification of the dichloromethane extract showed (1) and (2) at concentrations of 31.86 ± 2.6 and 8.24 ± 1.1 µg/mg of extract, respectively. The dichloromethane and aqueous extracts showed anti-M. tuberculosis H37Rv activity of 62.5 and 125 µg/mL, respectively. Coumarins (1) and (2) showed minimal inhibitory concentration ranges of 31.2 and 62.5 µg/mL against M. tuberculosis H37Rv and clinical isolates. Compound (3) showed no activity against M. tuberculosis H37Rv. The selectivity index ranged from 0.59-1.06. We report the activity of the extracts and coumarins from the leaves of C. brasiliense against M. tuberculosis. PMID:24676652

  8. Developing vaccines to prevent sustained infection with Mycobacterium tuberculosis: Conference proceedings: National Institute of Allergy and Infectious Diseases, Rockville, Maryland USA, November 7, 2014.

    PubMed

    2015-06-12

    On November 7, 2014, Aeras and the National Institute of Allergy and Infectious Diseases convened a conference entitled "Vaccine Prevention of Sustained Mycobacterium tuberculosis Infection." The purpose of this meeting was to explore the biologic plausibility, potential public health and economic impact, and regulatory feasibility in attempting to develop a vaccine to prevent sustained infection with Mycobacterium tuberculosis (Mtb). Currently there are two main goals for tuberculosis (TB) vaccine development, to develop a vaccine that could serve as a booster to Bacille Calmette-Guérin (BCG) vaccination and prevent active TB in adolescents and adults, and to develop an improved vaccine to replace BCG in infants. Although prevention of sustained Mtb infection is being used as a proof of biological activity for vaccines in mid-Phase 2 development, there currently are no plans for pursuing a prevention of Mtb infection licensure indication for TB vaccines. Ultimately, pursuing a prevention of sustained Mtb infection indication for TB vaccines, in parallel with ongoing efforts to develop vaccines to prevent active TB disease, was deemed a potentially important effort, but would require further resources, particularly to improve diagnostic assays, to increase the regulatory feasibility of this endeavor. PMID:25869889

  9. Latent Tuberculosis in Health Care Workers Exposed to Active Tuberculosis in a Tertiary Care Hospital in Oman

    PubMed Central

    Khamis, Faryal; Al-Lawati, Adil; Al-Zakwani, Ibrahim; Al-Abri, Seif; Al-Naamani, Jaleelah; Al-Harthi, Harith; Al-Jardani, Amina; Al-Harthi, Aliya

    2016-01-01

    Objectives Data on the prevalence of tuberculosis (TB) in healthcare workers (HCW) in Oman and the Arabian Gulf is scarce. The aim of this study was to estimate the prevalence of latent tuberculosis (LTB) among HCW exposed to active TB in one of the tertiary care hospitals in Muscat. Methods Exposed HCW were screened for LTB from January to June 2012 using skin tuberculin and serum interferon tests. Candidates were followed-up for a total of nine months. Descriptive statistics were used to summarize the data. Results A total of 371 exposed HCW were involved in the study. The incidence of LTB in exposed HCW was 33.2% (n = 123). Almost 54% (66/123) of the HCW started treatment and only 42.4% (28/66) completed the full nine-month treatment course. Conclusions The high prevalence of LTBI in exposed HCW merits further evaluation of the screening and treatment programs in the country. Future countrywide studies are warranted to provide more precise statistics on the prevalence and management of this public health issue. PMID:27403243

  10. Microfold Cells Actively Translocate Mycobacterium tuberculosis to Initiate Infection.

    PubMed

    Nair, Vidhya R; Franco, Luis H; Zacharia, Vineetha M; Khan, Haaris S; Stamm, Chelsea E; You, Wu; Marciano, Denise K; Yagita, Hideo; Levine, Beth; Shiloh, Michael U

    2016-08-01

    The prevailing paradigm is that tuberculosis infection is initiated when patrolling alveolar macrophages and dendritic cells within the terminal alveolus ingest inhaled Mycobacterium tuberculosis (Mtb). However, definitive data for this model are lacking. Among the epithelial cells of the upper airway, a specialized epithelial cell known as a microfold cell (M cell) overlies various components of mucosa-associated lymphatic tissue. Here, using multiple mouse models, we show that Mtb invades via M cells to initiate infection. Intranasal Mtb infection in mice lacking M cells either genetically or by antibody depletion resulted in reduced invasion and dissemination to draining lymph nodes. M cell-depleted mice infected via aerosol also had delayed dissemination to lymph nodes and reduced mortality. Translocation of Mtb across two M cell transwell models was rapid and transcellular. Thus, M cell translocation is a vital entry mechanism that contributes to the pathogenesis of Mtb. PMID:27452467

  11. 'Black bronchoscopy': a case of active mycobacterial tuberculosis.

    PubMed

    Inaty, Hanine; Arora, Ayush; Diacovo, Julia M; Mehta, Atul

    2016-07-01

    A 63-year-old male presents with chronic cough and hemoptysis. Computed tomography of the chest revealed a left lower lobe (LLL) area of consolidation with prominent ipsilateral hilar lymphadenopathy. Bronchoscopic airway examination revealed black mucosal discoloration and airway narrowing at the superior segment of the LLL. Bronchoalveolar lavage from the corresponding site grew mycobacterial tuberculosis. The patient's symptoms subsided with anti-tuberculous therapy with a significant decrease in the size of the LLL mass. PMID:27471594

  12. ‘Black bronchoscopy’: a case of active mycobacterial tuberculosis

    PubMed Central

    Inaty, Hanine; Arora, Ayush; Diacovo, Julia M.; Mehta, Atul

    2016-01-01

    A 63-year-old male presents with chronic cough and hemoptysis. Computed tomography of the chest revealed a left lower lobe (LLL) area of consolidation with prominent ipsilateral hilar lymphadenopathy. Bronchoscopic airway examination revealed black mucosal discoloration and airway narrowing at the superior segment of the LLL. Bronchoalveolar lavage from the corresponding site grew mycobacterial tuberculosis. The patient's symptoms subsided with anti-tuberculous therapy with a significant decrease in the size of the LLL mass. PMID:27471594

  13. A prospective cohort study of latent tuberculosis in adult close contacts of active pulmonary tuberculosis patients in Korea

    PubMed Central

    Park, Sun Hyo; Lee, Seung Jun; Cho, Yu Ji; Jeong, Yi Yeong; Kim, Ho Cheol; Lee, Jong Deog; Kim, Hee Jin; Menzies, Dick

    2016-01-01

    Background/Aims: The objective of this prospective study was to evaluate the diagnosis and treatment of latent tuberculosis infection (LTBI) in adult close contacts of active pulmonary tuberculosis (TB) patients in Korea. Methods: Adult close contacts of active pulmonary TB patients were recruited at a regional tertiary hospital in Korea. The participants were tested for LTBI using the tuberculin skin test (TST) and/or QuantiFERON-TB Gold (QFT-G) test. LTBI patients, who consented to treatment, were randomly assigned to receive isoniazid for 9 months (9INH) or rifampin for 4 months (4RIF). Results: We examined 189 adult close contacts (> 18 years) of 107 active pulmonary TB patients. The TST and QFT-G were positive (≥ 10 mm) in 75/183 (39.7%) and 45/118 (38.1%) tested participants, respectively. Among 88 TST or QFT-G positive LTBI participants, 45 participants were randomly assigned to receive 4RIF (n = 21) or 9INH (n = 24), respectively. The average treatment duration for the 4RIF and 9INH groups was 3.3 ± 1.3 and 6.1 ± 2.7 months, respectively. Treatment was completed in 25 participants (4RIF, n = 16; 9INH, n = 9). LTBI participants who accepted treatment were more likely to be women and have more cavitary lesions on the chest radiographs of index cases and positive TST and QFT-G results compared to those who refused treatment. Conclusions: About 40% of adult close contacts of active pulmonary TB patients had LTBI; about 50% of these LTBI participants agreed to treatment. PMID:27052266

  14. Differential gene expression of activating Fcγ receptor classifies active tuberculosis regardless of human immunodeficiency virus status or ethnicity.

    PubMed

    Sutherland, J S; Loxton, A G; Haks, M C; Kassa, D; Ambrose, L; Lee, J-S; Ran, L; van Baarle, D; Maertzdorf, J; Howe, R; Mayanja-Kizza, H; Boom, W H; Thiel, B A; Crampin, A C; Hanekom, W; Ota, M O C; Dockrell, H; Walzl, G; Kaufmann, S H E; Ottenhoff, T H M

    2014-04-01

    New diagnostics and vaccines for tuberculosis (TB) are urgently needed, but require an understanding of the requirements for protection from/susceptibility to TB. Previous studies have used unbiased approaches to determine gene signatures in single-site populations. The present study utilized a targeted approach, reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA), to validate these genes in a multisite study. We analysed ex vivo whole blood RNA from a total of 523 participants across four sub-Saharan countries (Ethiopia, Malawi, South Africa, and The Gambia) with differences in TB and human immunodeficiency virus (HIV) status. We found a number of genes that were expressed at significantly lower levels in participants with active disease than in those with latent TB infection (LTBI), with restoration following successful TB treatment. The most consistent classifier of active disease was FCGR1A (high-affinity IgG Fc receptor 1 (CD64)), which was the only marker expressed at significantly higher levels in participants with active TB than in those with LTBI before treatment regardless of HIV status or genetic background. This is the first study to identify a biomarker for TB that is not affected by HIV status or geo-genetic differences. These data provide valuable clues for understanding TB pathogenesis, and also provide a proof-of-concept for the use of RT-MLPA in rapid and inexpensive validation of unbiased gene expression findings. PMID:24205913

  15. Transformation of cinnamic acid from trans- to cis-form raises a notable bactericidal and synergistic activity against multiple-drug resistant Mycobacterium tuberculosis.

    PubMed

    Chen, Yen-Ling; Huang, Shao-Tsung; Sun, Fang-Ming; Chiang, Yu-Ling; Chiang, Chia-Jung; Tsai, Chiung-Man; Weng, Chia-Jui

    2011-06-14

    Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis. The long course of treatments on TB with a combination of antibiotics leads unfavorable side effects and poor patient compliance which contributes to sustaining multiple-drug resistant tuberculosis (MDR-TB). Therefore, the development of a new effective drug or synergist to reduce the prevalence of MDR-TB is urgent to date. Cinnamic acid (CA) is a natural occurring phenolic compound with anti-microbial activity. Both trans- and cis-isoforms of CA exist in planta, and cis-cinnamic acid (c-CA) can be transformed from trans-cinnamic acid (t-CA) under sunlight. Due to the unavailability of c-CA, the literature regarding the biological functions of c-CA is still limited. We had previously developed a practicable method for the transformation of c-CA from t-CA and the isolation of c-CA. Using the techniques, sufficient c-CA was obtained to evaluate its antituberculosis activity against a MDR M. tuberculosis strain. Moreover, the synergistic effects of c-CA and t-CA with two first-line anti-TB antibiotics, isoniazid (INH) and rifampicin (RIF), were also determined. Although both of c-CA and t-CA decreased the viability of MDR-TB bacilli in a dose-dependent manner, the antituberculosis activity of c-CA was approximately 120-fold of t-CA. Furthermore, the c-CA exhibited higher synergistic effect with INH or RIF against tuberculosis than t-CA. The micrographs of scanning electron microscope (SEM) display that c-CA caused an injury on the out-layer of MDR-TB bacilli. The c-CA might be a potential anti-mycobacterial or synergistic agent that can be developed to against tuberculosis. PMID:21536127

  16. Differential expression of HLA-G and ILT-2 receptor in human tuberculosis: Localized versus disseminated disease.

    PubMed

    Saurabh, Abhinav; Thakral, Deepshi; Mourya, Manish K; Singh, Amar; Mohan, Anant; Bhatnagar, Anuj K; Mitra, Dipendra K; Kanga, Uma

    2016-09-01

    Human leukocyte antigen-G (HLA-G) is an anti-inflammatory and immunosuppressive molecule that can modulate immune cell activation. The role of HLA-G in tuberculosis, an immune-mediated and chronic bacterial disease remains to be elucidated. We investigated the expression profile of soluble and membrane bound HLA-G in pulmonary TB (PTB), TB pleural effusion (TB-PE, localized disease) and Miliary TB (disseminated form). The expression of HLA-G receptor, ILT-2 was also determined on the immune cells. We observed that the plasma sHLA-G levels were significantly increased in Miliary TB than in TB-PE patients. In contrast, immunophenotyping revealed that the percent frequency of CD3(+) T cells expressing HLA-G was significantly reduced in Miliary TB as compared to TB-PE, whereas frequency of CD14(+) monocytes expressing HLA-G was significantly higher in TB-PE patients. Strikingly in the TB-PE cases, comparison of disease site, i.e. pleural effusion with peripheral blood showed increased expression of both soluble and surface HLA-G, whereas ILT-2 expressing cells were reduced at the local disease site. Furthermore, we demonstrated that in TB-PE cases, HLA-G expression on CD3(+) T cells was influenced by broad spectrum MMP inhibitor. Thus, differential expression of HLA-G could potentially be a useful biomarker to distinguish different states of TB disease. PMID:26776460

  17. Radioiodinated DPA-713 Imaging Correlates with Bactericidal Activity of Tuberculosis Treatments in Mice

    PubMed Central

    Ordonez, Alvaro A.; Pokkali, Supriya; DeMarco, Vincent P.; Klunk, Mariah; Mease, Ronnie C.; Foss, Catherine A.; Pomper, Martin G.

    2014-01-01

    Current tools for monitoring response to tuberculosis treatments have several limitations. Noninvasive biomarkers could accelerate tuberculosis drug development and clinical studies, but to date little progress has been made in developing new imaging technologies for this application. In this study, we developed pulmonary single-photon emission computed tomography (SPECT) using radioiodinated DPA-713 to serially monitor the activity of tuberculosis treatments in live mice, which develop necrotic granulomas and cavitary lesions. C3HeB/FeJ mice were aerosol infected with Mycobacterium tuberculosis and administered either a standard or a highly active bedaquiline-containing drug regimen. Serial 125I-DPA-713 SPECT imaging was compared with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and standard microbiology. Ex vivo studies were performed to characterize and correlate DPA-713 imaging with cellular and cytokine responses. Pulmonary 125I-DPA-713 SPECT, but not 18F-FDG PET, was able to correctly identify the bactericidal activities of the two tuberculosis treatments as early as 4 weeks after the start of treatment (P < 0.03). DPA-713 readily penetrated the fibrotic rims of necrotic and cavitary lesions. A time-dependent decrease in both tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels was observed with treatments, with 125I-DPA-713 SPECT correlating best with tissue TNF-α levels (ρ = 0.94; P < 0.01). 124I-DPA-713 was also evaluated as a PET probe and demonstrated a 4.0-fold-higher signal intensity in the infected tuberculous lesions than uninfected controls (P = 0.03). These studies provide proof of concept for application of a novel noninvasive imaging biomarker to monitor tuberculosis treatments, with the potential for application for humans. PMID:25403669

  18. Radioiodinated DPA-713 imaging correlates with bactericidal activity of tuberculosis treatments in mice.

    PubMed

    Ordonez, Alvaro A; Pokkali, Supriya; DeMarco, Vincent P; Klunk, Mariah; Mease, Ronnie C; Foss, Catherine A; Pomper, Martin G; Jain, Sanjay K

    2015-01-01

    Current tools for monitoring response to tuberculosis treatments have several limitations. Noninvasive biomarkers could accelerate tuberculosis drug development and clinical studies, but to date little progress has been made in developing new imaging technologies for this application. In this study, we developed pulmonary single-photon emission computed tomography (SPECT) using radioiodinated DPA-713 to serially monitor the activity of tuberculosis treatments in live mice, which develop necrotic granulomas and cavitary lesions. C3HeB/FeJ mice were aerosol infected with Mycobacterium tuberculosis and administered either a standard or a highly active bedaquiline-containing drug regimen. Serial (125)I-DPA-713 SPECT imaging was compared with (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) and standard microbiology. Ex vivo studies were performed to characterize and correlate DPA-713 imaging with cellular and cytokine responses. Pulmonary (125)I-DPA-713 SPECT, but not (18)F-FDG PET, was able to correctly identify the bactericidal activities of the two tuberculosis treatments as early as 4 weeks after the start of treatment (P < 0.03). DPA-713 readily penetrated the fibrotic rims of necrotic and cavitary lesions. A time-dependent decrease in both tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels was observed with treatments, with (125)I-DPA-713 SPECT correlating best with tissue TNF-α levels (ρ = 0.94; P < 0.01). (124)I-DPA-713 was also evaluated as a PET probe and demonstrated a 4.0-fold-higher signal intensity in the infected tuberculous lesions than uninfected controls (P = 0.03). These studies provide proof of concept for application of a novel noninvasive imaging biomarker to monitor tuberculosis treatments, with the potential for application for humans. PMID:25403669

  19. Untreated Active Tuberculosis in Pregnancy with Intraocular Dissemination: A Case Report and Review of the Literature

    PubMed Central

    LoBue, Stephen; Adams, Daniel; Oladipo, Yewande; Posso, Ramses; Mapp, Tiffany; Santiago, Crystal; Jain, Manisha; Marino, William D.; Henderson, Cassandra E.

    2015-01-01

    Background. Tuberculosis (TB) is a disease that affects hundreds of millions of people across the world. However, the incidence in developed countries has decreased over the past decades causing physicians to become unfamiliar with its unspecific symptoms. Pregnant individuals are especially difficult because many symptoms of active TB can mimic normal physiological changes of pregnancy. We present a case report of a 26-year-old multiparous woman, G4P3003, at 38-week gestation with a history of positive PPD who emigrated from Ghana 6 years ago. She came to the hospital with an initial complaint of suprapubic pain, pressure, and possible leakage of amniotic fluid for the past week. Patient also complained of a productive cough for the past 3 to 4 months with a decrease in vision occurring with the start of pregnancy. Visual acuity was worse than 20/200 in both eyes. Definitive diagnosis of active TB was delayed due to patient refusal of chest X-ray. Fortunately, delay in diagnosis was minimized since patient delivered within 24 hours of admission. Active TB was confirmed with intraocular dissemination. Patient had optic atrophy OS (left eye) and papillitis, choroiditis, and uveitis OD (right eye) due to TB infiltration. Fetus was asymptomatic and anti-TB therapy was started for both patients. PMID:26693374

  20. An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis

    DOE PAGESBeta

    Jastrab, Jordan B.; Wang, Tong; Murphy, J. Patrick; Bai, Lin; Hu, Kuan; Merkx, Remco; Huang, Jessica; Chatterjee, Champak; Ovaa, Huib; Gygi, Steven P.; et al

    2015-03-23

    Mycobacterium tuberculosis encodes a proteasome that is highly similar to eukaryotic proteasomes and is required to cause lethal infections in animals. The only pathway known to target proteins for proteasomal degradation in bacteria is pupylation, which is functionally analogous to eukaryotic ubiquitylation. However, evidence suggests that the M. tuberculosis proteasome contributes to pupylation-independent pathways as well. To identify new proteasome cofactors that might contribute to such pathways, we isolated proteins that bound to proteasomes overproduced in M. tuberculosis and found a previously uncharacterized protein, Rv3780, which formed rings and capped M. tuberculosis proteasome core particles. Rv3780 enhanced peptide and proteinmore » degradation by proteasomes in an adenosine triphosphate (ATP)-independent manner. We identified putative Rv3780-dependent proteasome substrates and found that Rv3780 promoted robust degradation of the heat shock protein repressor, HspR. Importantly, an M. tuberculosis Rv3780 mutant had a general growth defect, was sensitive to heat stress, and was attenuated for growth in mice. Collectively, these data demonstrate that ATP-independent proteasome activators are not confined to eukaryotes and can contribute to the virulence of one the world’s most devastating pathogens.« less

  1. An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis

    SciTech Connect

    Jastrab, Jordan B.; Wang, Tong; Murphy, J. Patrick; Bai, Lin; Hu, Kuan; Merkx, Remco; Huang, Jessica; Chatterjee, Champak; Ovaa, Huib; Gygi, Steven P.; Li, Huilin; Darwin, K. Heran

    2015-03-23

    Mycobacterium tuberculosis encodes a proteasome that is highly similar to eukaryotic proteasomes and is required to cause lethal infections in animals. The only pathway known to target proteins for proteasomal degradation in bacteria is pupylation, which is functionally analogous to eukaryotic ubiquitylation. However, evidence suggests that the M. tuberculosis proteasome contributes to pupylation-independent pathways as well. To identify new proteasome cofactors that might contribute to such pathways, we isolated proteins that bound to proteasomes overproduced in M. tuberculosis and found a previously uncharacterized protein, Rv3780, which formed rings and capped M. tuberculosis proteasome core particles. Rv3780 enhanced peptide and protein degradation by proteasomes in an adenosine triphosphate (ATP)-independent manner. We identified putative Rv3780-dependent proteasome substrates and found that Rv3780 promoted robust degradation of the heat shock protein repressor, HspR. Importantly, an M. tuberculosis Rv3780 mutant had a general growth defect, was sensitive to heat stress, and was attenuated for growth in mice. Collectively, these data demonstrate that ATP-independent proteasome activators are not confined to eukaryotes and can contribute to the virulence of one the world’s most devastating pathogens.

  2. The in vitro activity of beta-lactamase inhibitors in combination with cephalosporins against M. tuberculosis.

    PubMed

    Chen, C H; Yang, M H; Lin, J S; Lee, Y C; Perng, R P

    1995-04-01

    Although there are reports that the addition of a beta-lactamase inhibitor to ampicillin or amoxicillin greatly improves their in vitro activity against M. tuberculosis, there are no written reports about the antituberculosis effects of beta-lactamase inhibitors in combination with cephalosporins against M. tuberculosis. In this report, we have determined the minimal inhibitory concentrations (MIC) of 5 cephalosporins with or without combination with beta-lactamase inhibitor against M. tuberculosis strains isolated from patients before antituberculosis treatment and checked the production of beta-lactamase by bacteria before this procedure. Four strains of M. tuberculosis were contaminated during the experiment, and all the other 16 strains hydrolyzed the nitrocefin disc, thus indicating a beta-lactamase producer. The MICs of cephalosporins alone against M. tuberculosis were 200-400 micrograms/ml for ceforanide, 100-400 micrograms/ml for cephapirin, 400-1600 micrograms/ml for cefamandole, 200-1600 micrograms/ml for cefotaxime, and 800-1600 micrograms/ml for ceftriaxone. After adding the equimolar concentrations of sulbactam, the MICs were reduced to 100-200 micrograms/ml for ceforanide, 12.5-100 micrograms/ml for cephapirin, 100-400 micrograms/ml for cefamandole, 25-200 micrograms/ml for cefotaxime, and 100-800 micrograms/ml for ceftriaxone. We concluded that sulbactam enhanced the antituberculosis effect of cephalosporins. PMID:7624446

  3. Tuberculosis and HIV Coinfection.

    PubMed

    Bruchfeld, Judith; Correia-Neves, Margarida; Källenius, Gunilla

    2015-07-01

    Tuberculosis (TB) and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) constitute the main burden of infectious disease in resource-limited countries. In the individual host, the two pathogens, Mycobacterium tuberculosis and HIV, potentiate one another, accelerating the deterioration of immunological functions. In high-burden settings, HIV coinfection is the most important risk factor for developing active TB, which increases the susceptibility to primary infection or reinfection and also the risk of TB reactivation for patients with latent TB. M. tuberculosis infection also has a negative impact on the immune response to HIV, accelerating the progression from HIV infection to AIDS. The clinical management of HIV-associated TB includes the integration of effective anti-TB treatment, use of concurrent antiretroviral therapy (ART), prevention of HIV-related comorbidities, management of drug cytotoxicity, and prevention/treatment of immune reconstitution inflammatory syndrome (IRIS). PMID:25722472

  4. Combinatorial active-site variants confer sustained clavulanate resistance in BlaC β-lactamase from Mycobacterium tuberculosis

    PubMed Central

    Egesborg, Philippe; Carlettini, Hélène; Volpato, Jordan P; Doucet, Nicolas

    2015-01-01

    Bacterial resistance to β-lactam antibiotics is a global issue threatening the success of infectious disease treatments worldwide. Mycobacterium tuberculosis has been particularly resilient to β-lactam treatment, primarily due to the chromosomally encoded BlaC β-lactamase, a broad-spectrum hydrolase that renders ineffective the vast majority of relevant β-lactam compounds currently in use. Recent laboratory and clinical studies have nevertheless shown that specific β-lactam–BlaC inhibitor combinations can be used to inhibit the growth of extensively drug-resistant strains of M. tuberculosis, effectively offering new tools for combined treatment regimens against resistant strains. In the present work, we performed combinatorial active-site replacements in BlaC to demonstrate that specific inhibitor-resistant (IRT) substitutions at positions 69, 130, 220, and/or 234 can act synergistically to yield active-site variants with several thousand fold greater in vitro resistance to clavulanate, the most common clinical β-lactamase inhibitor. While most single and double variants remain sensitive to clavulanate, double mutants R220S-K234R and S130G-K234R are substantially less affected by time-dependent clavulanate inactivation, showing residual β-lactam hydrolytic activities of 46% and 83% after 24 h incubation with a clinically relevant inhibitor concentration (5 μg/ml, 25 µM). These results demonstrate that active-site alterations in BlaC yield resistant variants that remain active and stable over prolonged bacterial generation times compatible with mycobacterial proliferation. These results also emphasize the formidable adaptive potential of inhibitor-resistant substitutions in β-lactamases, potentially casting a shadow on specific β-lactam–BlaC inhibitor combination treatments against M. tuberculosis. PMID:25492589

  5. Angiotensin-Converting Enzyme Inhibitors and Active Tuberculosis: A Population-Based Study.

    PubMed

    Wu, Jiunn-Yih; Lee, Meng-Tse Gabriel; Lee, Si-Huei; Lee, Shih-Hao; Tsai, Yi-Wen; Hsu, Shou-Chien; Chang, Shy-Shin; Lee, Chien-Chang

    2016-05-01

    Numerous epidemiological data suggest that the use of angiotensin-converting enzyme inhibitors (ACEis) can improve the clinical outcomes of pneumonia. Tuberculosis (TB) is an airborne bacteria like pneumonia, and we aimed to find out whether the use of ACEis can decrease the risk of active TB.We conducted a nested case-control analysis by using a 1 million longitudinally followed cohort, from Taiwan national health insurance research database. The rate ratios (RRs) for TB were estimated by conditional logistic regression, and adjusted using a TB-specific disease risk score (DRS) with 71 TB-related covariates.From January, 1997 to December, 2011, a total of 75,536 users of ACEis, and 7720 cases of new active TB were identified. Current use (DRS adjusted RR, 0.87 [95% CI, 0.78-0.97]), but not recent and past use of ACEis, was associated with a decrease in risk of active TB. Interestingly, it was found that chronic use (>90 days) of ACEis was associated with a further decrease in the risk of TB (aRR, 0.74, [95% CI, 0.66-0.83]). There was also a duration response effect, correlating decrease in TB risk with longer duration of ACEis use. The decrease in TB risk was also consistent across all patient subgroups (age, sex, heart failure, cerebrovascular diseases, myocardial infraction, renal diseases, and diabetes) and patients receiving other cardiovascular medicine.In this large population-based study, we found that subjects with recent and chronic use of ACEis were associated with decrease in TB risk. PMID:27175655

  6. Esophageal tuberculosis: mimicry of gastrointestinal malignancy.

    PubMed

    Damtew, B; Frengley, D; Wolinsky, E; Spagnuolo, P J

    1987-01-01

    A case of tuberculous involvement of the esophagus was studied in an adult with mediastinal lymphadenopathy unrecognized by roentgenography of the chest. The roentgenographic and endoscopic features in this case were more consistent with malignancy than with tuberculosis. Nineteen additional cases from the English-language literature were reviewed. Although esophageal tuberculosis is a rare disease, it should be strongly suspected in a patient with dysphagia who has a positive tuberculin skin test, active pulmonary disease, or mediastinal adenopathy. PMID:3823717

  7. [Update on the radiological study of pulmonary tuberculosis].

    PubMed

    Navarro Ballester, A; Marco Domenech, S F

    2015-01-01

    Tuberculosis has made a comeback in recent years. This upsurge has been attributed to factors such as increased immigration and the human immunodeficiency virus epidemic. Primary pulmonary tuberculosis manifests radiologically with parenchymal involvement, lymph node involvement, pleural effusion, and/or miliary disease. In post-primary tuberculosis, the earliest radiological sign is small nodules and branching centrilobular lesions that increase in size and coalesce to form ill-defined patchy consolidations; cavitations are very characteristic of active disease. The aim of this article is to describe the radiologic findings for pulmonary tuberculosis and its complications. PMID:26074301

  8. Dynamics of a Mathematical Model for Tuberculosis with Variability in Susceptibility and Disease Progressions Due to Difference in Awareness Level

    PubMed Central

    Okuonghae, Daniel; Ikhimwin, Bernard O.

    2016-01-01

    This work extends a mathematical model for the transmission dynamics of tuberculosis that examined the impact of certain factors on tuberculosis case detection (Okuonghae and Omosigho, 2011). The extended model now classifies the latently infected individuals by their level of tuberculosis awareness (as was done for the susceptible sub-population) and further expands the number of key factors that can positively affect the tuberculosis case detection rate. The effect of these identified factors on the associated reproduction number of the model is considered. It is shown that the system can undergo the phenomenon of backward bifurcation when the associated reproduction number of the model is less than unity; in a special case, the effect of exogenous re-infection on the backward bifurcation phenomenon is significantly dictated by the level of awareness of the latently infected individuals. Qualitative and quantitative analysis of the model showed the effect of key identified factors on the dynamics of tuberculosis while suggesting a serious concentration on tuberculosis awareness programmes, active case finding strategies and use of active cough identification for identifying likely TB cases and sustaining awareness campaigns over a long period of time. PMID:26858691

  9. Characterization of the helicase activity and substrate specificity of Mycobacterium tuberculosis UvrD.

    PubMed

    Curti, Elena; Smerdon, Stephen J; Davis, Elaine O

    2007-03-01

    UvrD is a helicase that is widely conserved in gram-negative bacteria. A uvrD homologue was identified in Mycobacterium tuberculosis on the basis of the homology of its encoded protein with Escherichia coli UvrD, with which it shares 39% amino acid identity, distributed throughout the protein. The gene was cloned, and a histidine-tagged form of the protein was expressed and purified to homogeneity. The purified protein had in vitro ATPase activity that was dependent upon the presence of DNA. Oligonucleotides as short as four nucleotides were sufficient to promote the ATPase activity. The DNA helicase activity of the enzyme was only fueled by ATP and dATP. UvrD preferentially unwound 3'-single-stranded tailed duplex substrates over 5'-single-stranded ones, indicating that the protein had a duplex-unwinding activity with 3'-to-5' polarity. A 3' single-stranded DNA tail of 18 nucleotides was required for effective unwinding. By using a series of synthetic oligonucleotide substrates, we demonstrated that M. tuberculosis UvrD has an unwinding preference towards nicked DNA duplexes and stalled replication forks, representing the likely sites of action in vivo. The potential role of M. tuberculosis UvrD in maintenance of bacterial genomic integrity makes it a promising target for drug design against M. tuberculosis. PMID:17158674

  10. Inhibition of Nuclear Factor-Kappa B Activation Decreases Survival of Mycobacterium tuberculosis in Human Macrophages

    PubMed Central

    Chmura, Kathryn; Ovrutsky, Alida R.; Su, Wen-Lin; Griffin, Laura; Pyeon, Dohun; McGibney, Mischa T.; Strand, Matthew J.; Numata, Mari; Murakami, Seiji; Gaido, Loretta; Honda, Jennifer R.; Kinney, William H.; Oberley-Deegan, Rebecca E.; Voelker, Dennis R.; Ordway, Diane J.; Chan, Edward D.

    2013-01-01

    Nuclear factor-kappa B (NFκB) is a ubiquitous transcription factor that mediates pro-inflammatory responses required for host control of many microbial pathogens; on the other hand, NFκB has been implicated in the pathogenesis of other inflammatory and infectious diseases. Mice with genetic disruption of the p50 subunit of NFκB are more likely to succumb to Mycobacterium tuberculosis (MTB). However, the role of NFκB in host defense in humans is not fully understood. We sought to examine the role of NFκB activation in the immune response of human macrophages to MTB. Targeted pharmacologic inhibition of NFκB activation using BAY 11-7082 (BAY, an inhibitor of IκBα kinase) or an adenovirus construct with a dominant-negative IκBα significantly decreased the number of viable intracellular mycobacteria recovered from THP-1 macrophages four and eight days after infection. The results with BAY were confirmed in primary human monocyte-derived macrophages and alveolar macrophages. NFκB inhibition was associated with increased macrophage apoptosis and autophagy, which are well-established killing mechanisms of intracellular MTB. Inhibition of the executioner protease caspase-3 or of the autophagic pathway significantly abrogated the effects of BAY. We conclude that NFκB inhibition decreases viability of intracellular MTB in human macrophages via induction of apoptosis and autophagy. PMID:23634218

  11. Inhibition of nuclear factor-kappa B activation decreases survival of Mycobacterium tuberculosis in human macrophages.

    PubMed

    Bai, Xiyuan; Feldman, Nicole E; Chmura, Kathryn; Ovrutsky, Alida R; Su, Wen-Lin; Griffin, Laura; Pyeon, Dohun; McGibney, Mischa T; Strand, Matthew J; Numata, Mari; Murakami, Seiji; Gaido, Loretta; Honda, Jennifer R; Kinney, William H; Oberley-Deegan, Rebecca E; Voelker, Dennis R; Ordway, Diane J; Chan, Edward D

    2013-01-01

    Nuclear factor-kappa B (NFκB) is a ubiquitous transcription factor that mediates pro-inflammatory responses required for host control of many microbial pathogens; on the other hand, NFκB has been implicated in the pathogenesis of other inflammatory and infectious diseases. Mice with genetic disruption of the p50 subunit of NFκB are more likely to succumb to Mycobacterium tuberculosis (MTB). However, the role of NFκB in host defense in humans is not fully understood. We sought to examine the role of NFκB activation in the immune response of human macrophages to MTB. Targeted pharmacologic inhibition of NFκB activation using BAY 11-7082 (BAY, an inhibitor of IκBα kinase) or an adenovirus construct with a dominant-negative IκBα significantly decreased the number of viable intracellular mycobacteria recovered from THP-1 macrophages four and eight days after infection. The results with BAY were confirmed in primary human monocyte-derived macrophages and alveolar macrophages. NFκB inhibition was associated with increased macrophage apoptosis and autophagy, which are well-established killing mechanisms of intracellular MTB. Inhibition of the executioner protease caspase-3 or of the autophagic pathway significantly abrogated the effects of BAY. We conclude that NFκB inhibition decreases viability of intracellular MTB in human macrophages via induction of apoptosis and autophagy. PMID:23634218

  12. Tuberculosis treatment and drug regimens.

    PubMed

    Sotgiu, Giovanni; Centis, Rosella; D'ambrosio, Lia; Migliori, Giovanni Battista

    2015-05-01

    Tuberculosis is an airborne infectious disease treated with combination therapeutic regimens. Adherence to long-term antituberculosis therapy is crucial for maintaining adequate blood drug level. The emergence and spread of drug-resistant Mycobacterium tuberculosis strains are mainly favored by the inadequate medical management of the patients. The therapeutic approach for drug-resistant tuberculosis is cumbersome, because of the poor, expensive, less-effective, and toxic alternatives to the first-line drugs. New antituberculosis drugs (bedaquiline and delamanid) have been recently approved by the health authorities, but they cannot represent the definitive solution to the clinical management of drug-resistant tuberculosis forms, particularly in intermediate economy settings where the prevalence of drug resistance is high (China, India, and former Soviet Union countries). New research and development activities are urgently needed. Public health policies are required to preserve the new and old therapeutic options. PMID:25573773

  13. Enhancement of antibiotic activity by efflux inhibitors against multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil

    PubMed Central

    Coelho, Tatiane; Machado, Diana; Couto, Isabel; Maschmann, Raquel; Ramos, Daniela; von Groll, Andrea; Rossetti, Maria L.; Silva, Pedro A.; Viveiros, Miguel

    2015-01-01

    Drug resistant tuberculosis continues to increase and new approaches for its treatment are necessary. The identification of M. tuberculosis clinical isolates presenting efflux as part of their resistant phenotype has a major impact in tuberculosis treatment. In this work, we used a checkerboard procedure combined with the tetrazolium microplate-based assay (TEMA) to study single combinations between antituberculosis drugs and efflux inhibitors (EIs) against multidrug resistant M. tuberculosis clinical isolates using the fully susceptible strain H37Rv as reference. Efflux activity was studied on a real-time basis by a fluorometric method that uses ethidium bromide as efflux substrate. Quantification of efflux pump genes mRNA transcriptional levels were performed by RT-qPCR. The fractional inhibitory concentrations (FIC) indicated synergistic activity for the interactions between isoniazid, rifampicin, amikacin, ofloxacin, and ethidium bromide plus the EIs verapamil, thioridazine and chlorpromazine. The FICs ranged from 0.25, indicating a four-fold reduction on the MICs, to 0.015, 64-fold reduction. The detection of active efflux by real-time fluorometry showed that all strains presented intrinsic efflux activity that contributes to the overall resistance which can be inhibited in the presence of the EIs. The quantification of the mRNA levels of the most important efflux pump genes on these strains shows that they are intrinsically predisposed to expel toxic compounds as the exposure to subinhibitory concentrations of antibiotics were not necessary to increase the pump mRNA levels when compared with the non-exposed counterpart. The results obtained in this study confirm that the intrinsic efflux activity contributes to the overall resistance in multidrug resistant clinical isolates of M. tuberculosis and that the inhibition of efflux pumps by the EIs can enhance the clinical effect of antibiotics that are their substrates. PMID:25972842

  14. Tuberculosis in elephants-a reemergent disease: diagnostic dilemmas, the natural history of infection, and new immunological tools.

    PubMed

    Maslow, J N; Mikota, S K

    2015-05-01

    Tuberculosis (TB) in elephants has been described since ancient times. However, it was not until 1996 when infection with Mycobacterium tuberculosis was identified in a herd of circus elephants that significant research into this disease began. The epidemiology and natural history of TB were unknown in elephants since there had been no comprehensive screening programs, and diagnostic techniques developed for cervidae and bovidae were of unknown value. And, while precepts of test and slaughter were the norm for cattle and deer, this was considered untenable for an endangered species. With no precedent for the treatment of TB in animals, treatment regimens for elephants were extrapolated from human protocols, which guided changes to the Guidelines for the Control of Tuberculosis in Elephants. In the absence of diagnostic testing to confirm cure in elephants, the efficacy of these treatment regimens is only beginning to be understood as treated elephants die and are examined postmortem. However, because of pressures arising from public relations related to elephant husbandry and the added considerations of TB infection in animals (whether real or imagined), sharing of information to aid in research and treatment has been problematic. Here we review the challenges and successes of the diagnosis of tuberculosis in elephants and discuss the natural history of the disease to put the work of Landolfi et al on the immunological response to tuberculosis in elephants in perspective. PMID:25633896

  15. [Tuberculosis in compromised hosts].

    PubMed

    2003-11-01

    Recent development of tuberculosis in Japan tends to converge on a specific high risk group. The proportion of tuberculosis developing particularly from the compromised hosts in the high risk group is especially high. At this symposium, therefore, we took up diabetes mellitus, gastrectomy, dialysis, AIDS and the elderly for discussion. Many new findings and useful reports for practical medical treatment are submitted; why these compromised hosts are predisposed to tuberculosis, tuberculosis diagnostic and remedial notes of those compromised hosts etc. It is an important question for the future to study how to prevent tuberculosis from these compromised hosts. 1. Tuberculosis in diabetes mellitus: aggravation and its immunological mechanism: Kazuyoshi KAWAKAMI (Department of Internal Medicine, Division of Infectious Diseases, Graduate School and Faculty of Medicine, University of the Ryukyus). It has been well documented that diabetes mellitus (DM) is a major aggravating factor in tuberculosis. The onset of this disease is more frequent in DM patients than in individuals with any underlying diseases. However, the precise mechanism of this finding remains to be fully understood. Earlier studies reported that the migration, phagocytosis and bactericidal activity of neutrophils are all impaired in DM patients, which is related to their reduced host defense to infection with extracellular bacteria, such as S. aureus and E. colli. Host defense to mycobacterial infection is largely mediated by cellular immunity, and Th1-related cytokines, such as IFN-gamma and IL-12, play a central role in this response. It is reported that serum level of these cytokines and their production by peripheral blood mononuclear cells (PBMC) are reduced in tuberculosis patients with DM, and this is supposed to be involved in the high incidence of tuberculosis in DM. Our study observed similar findings and furthermore indicated that IFN-gamma and IL-12 production by BCG-stimulated PBMC was lower

  16. [Tuberculosis--a neverending story].

    PubMed

    Dzieciołowska-Baran, Edyta; Gawlikowska-Sroka, Aleksandra

    2013-01-01

    It is estimated that over one third of the human population is now exposed or has been exposed in the past to Mycobacterium tuberculosis, and new infections occur in the world at a rate of one per second. The history of tuberculosis is long and very interesting, because before the isolation of mycobacteria and the finding of a cure, the disease mercilessly killed thousands of people and deprived doctors of hope. Robert Koch's momentous discovery was a major breakthrough in the fight against tuberculosis. Unfortunately, the disease has never been fully controlled. Tuberculosis is a chronic infectious disease localized in 90-95% of cases in the lungs, and therefore it is extremely difficult to diagnose unequivocally in paleopathological material. Only the form of osteo-arthritis leaves traces in archaeological material. The earliest evidence of tuberculosis (the location of the spine, Pott's disease) in the form of fossils is dated to before 8000 BC. Another very old trace is considered to be human remains from the Neolithic period (ca 5000 BC), found near Heidelberg, where changes in the thoracic spine are typical for spondylitis in tuberculosa. Constant growth in the incidence of new cases in the world can be observed today. Not everyone infected will develop the full-blown disease. The infection may remain dormant. However, one in ten latent infections will subsequently be activated, leading, if not treated, to the death of almost half of the patients. PMID:25026769

  17. The Case for Live Attenuated Vaccines against the Neglected Zoonotic Diseases Brucellosis and Bovine Tuberculosis

    PubMed Central

    Pandey, Aseem; Cabello, Ana; Akoolo, Lavoisier; Rice-Ficht, Allison; Arenas-Gamboa, Angela; McMurray, David; Ficht, Thomas A.; de Figueiredo, Paul

    2016-01-01

    Vaccination of humans and animals with live attenuated organisms has proven to be an effective means of combatting some important infectious diseases. In fact, the 20th century witnessed tremendous improvements in human and animal health worldwide as a consequence of large-scale vaccination programs with live attenuated vaccines (LAVs). Here, we use the neglected zoonotic diseases brucellosis and bovine tuberculosis (BTb) caused by Brucella spp. and Mycobacterium bovis (M. bovis), respectively, as comparative models to outline the merits of LAV platforms with emphasis on molecular strategies that have been pursued to generate LAVs with enhanced vaccine safety and efficacy profiles. Finally, we discuss the prospects of LAV platforms in the fight against brucellosis and BTb and outline new avenues for future research towards developing effective vaccines using LAV platforms. PMID:27537413

  18. Computer-Aided Drug Discovery Approaches against the Tropical Infectious Diseases Malaria, Tuberculosis, Trypanosomiasis, and Leishmaniasis.

    PubMed

    Njogu, Peter M; Guantai, Eric M; Pavadai, Elumalai; Chibale, Kelly

    2016-01-01

    Despite the tremendous improvement in overall global health heralded by the adoption of the Millennium Declaration in the year 2000, tropical infections remain a major health problem in the developing world. Recent estimates indicate that the major tropical infectious diseases, namely, malaria, tuberculosis, trypanosomiasis, and leishmaniasis, account for more than 2.2 million deaths and a loss of approximately 85 million disability-adjusted life years annually. The crucial role of chemotherapy in curtailing the deleterious health and economic impacts of these infections has invigorated the search for new drugs against tropical infectious diseases. The research efforts have involved increased application of computational technologies in mainstream drug discovery programs at the hit identification, hit-to-lead, and lead optimization stages. This review highlights various computer-aided drug discovery approaches that have been utilized in efforts to identify novel antimalarial, antitubercular, antitrypanosomal, and antileishmanial agents. The focus is largely on developments over the past 5 years (2010-2014). PMID:27622945

  19. Role of the Infectious Disease Consultant in Management of Patients With Tuberculosis-Associated Ocular Inflammation

    PubMed Central

    Conant, Marjorie M.; Vrasich, Chuck R.; Wongskhaluang, Jeff V.; Ferenchak, Kevin; Asano, Matthew K.; Becker, Norbert; DeMarais, Patricia

    2016-01-01

    Background. Tuberculosis is a disease with continued worldwide prevalence, morbidity, and mortality. Tuberculosis-associated ocular inflammation (TB-AOI) is a manifestation that can occur with pulmonary or extrapulmonary TB. Evaluation of these ocular presentations and treatment in the United States are limited. Our objective was to describe cases in an urban area and assess the role of the infectious diseases specialist in managing these complex patients. Methods. We performed a retrospective case series of all patients referred to our infectious disease clinic for presumed TB-AOI from 2005 through 2013. Patients with ocular inflammation were determined to have presumed TB-AOI based on clinical presentation with correlative positive tuberculin skin test and/or QuantiFERON-TB Gold. Attempts were made to exclude other diagnoses. Data were collected and analyzed with respect to demographics, ocular manifestations, and treatment. Results. Sixty eyes of 42 patients were included in the study; anterior uveitis was the most common site of involvement. The median age was 46 years, and 33 patients (79%) were foreign born. Forty patients (95%) received a course of antituberculous therapy with 38% experiencing treatment-related side effects. A 6-month duration was recommended in 78% cases. There was improvement or stability of the vision in 42 eyes (74%) of those treated. Conclusions. Ocular involvement is an uncommon but important manifestation of TB. Our data further characterize TB-AOI cases in the United States. Treatment provides significant benefit to properly selected patients. A multidisciplinary approach, with care provided by ophthalmology and infectious disease providers, should be used to allow for the most efficacious treatment. PMID:26811844

  20. [Health examination in future at the era of low tuberculosis incidence--from contacts examination toward active epidemiological studies].

    PubMed

    Maeda, Hideo; Shirai, Chika

    2013-03-01

    Japan is still "intermediate burden" country as medium-incidence of tuberculosis (TB). But the incidence of TB varies by public health units. The priority for TB control would be lowering in the areas where the incidence of TB is relatively low. In addition, younger age groups get low prevalence of TB infection than elderly persons. As a result, fewer experiences for TB diagnosis and treatment in the hospital and the medical facility would cause the delay in the detection of TB patients which eventually cause outbreaks. Although there are differences in population density and population mobility between urban and rural areas, the socially economic vulnerable patients and foreign patients are the common risks. Any public health units' policies of TB should correspond to the individual situation. At the era of low tuberculosis incidence, the infection risk is to be "From ubiquitous to the uneven distribution". This makes TB detection much more difficult. At this symposium, each speaker presented the case for actually experienced with QFT test and/or VNTR analysis. They mainly focused on the paradigm shift in TB control which is indispensable for resolving the gaps in regional differences and the differences in diagnostic capability. Although the cases in this symposium were not for the low incidence situation, the pioneering approaches presented here would boost the future application of QFT and VNTR analysis nationwide. The discussions also partially covered the technical infrastructure for molecular epidemiology which covers the whole country. By making full use of QFT test and VNTR analysis as a contact screening tool, we can appropriately understand the risk of TB infection in the region from a buildup of bacteria and patient information. Now is the time to prepare for. Active surveillance of TB by this way would clarify the risk of the disease and lead to the advocacy essential for the resolution. 1. Current situation and challenge of contact survey by using QFT

  1. Tuberculosis and Diabetes

    MedlinePlus

    TUBERCULOSIS www.who.int/tb & DIABETES THE DUAL EPIDEMIC OF TB AND DIABETES DEADLY LINKAGES  People with ... higher risk of progressing from latent to active tuberculosis.  Diabetes triples a person’s risk of developing TB. ...

  2. Relevance of bovine tuberculosis research to the understanding of human disease: Historical perspectives, approaches, and immunologic mechanisms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pioneer studies on infectious disease and immunology by Jenner, Pasteur, Koch, Von Behring, Nocard, Roux, and Ehrlich forged a path for the dual-purpose with dual benefit approach, demonstrating a profound relevance of veterinary studies for biomedical applications. Tuberculosis (TB), primarily due ...

  3. Transcriptional suppression of IL-27 production by Mycobacterium tuberculosis-activated p38 MAPK via inhibition of AP-1 binding.

    PubMed

    Zhang, Jidong; Qian, Xuesong; Ning, Huan; Eickhoff, Christopher S; Hoft, Daniel F; Liu, Jianguo

    2011-05-15

    Mycobacterium tuberculosis remains a major global challenge to human health care, and the mechanisms of how M. tuberculosis evades host immune surveillance to favor its survival are still largely unknown. In this study, we found that bacillus Calmette-Guérin (BCG) and viable M. tuberculosis as well as M. tuberculosis lysates could activate IL-27 expression in human and mouse macrophages by induction of p28 subunit transcription. However, in parallel with these effects, BCG and M. tuberculosis lysate stimulation of macrophages induced activation of p38 MAPK signaling molecules MLK3/MKK3/MK2 to prevent maximal IL-27 production. M. tuberculosis lysate-induced p28 transcription was dependent on MyD88 signaling pathway. AP-1/c-Fos was shown to bind directly to the p28 promoter and induce p28 expression after M. tuberculosis lysate stimulation. Overexpression of p38α inhibited the binding of c-Fos to the p28 promoter but had no effect on c-Fos protein expression or phosphorylation in response to M. tuberculosis lysate stimulation. Furthermore, blockade of p38 by SB203580 enhanced M. tuberculosis-induced AP-1 binding to the p28 promoter. Importantly, we show that adding exogenous IL-27 to increase the levels produced by PBMCs stimulated with live mycobacteria enhanced the ability of BCG-expanded T cells to inhibit intracellular mycobacterial growth in human macrophages. Taken together, our data demonstrate that mycobacterial stimulation induces both IL-27 production and p38 MAPK activation. Strategies designed to tip the balance toward positive regulation of p28 induction by mycobacteria could lead to enhanced protective tuberculosis immunity. PMID:21482740

  4. Reporter Phage and Breath Tests: Emerging Phenotypic Assays for Diagnosing Active Tuberculosis, Antibiotic Resistance, and Treatment Efficacy

    PubMed Central

    Jain, Paras; Thaler, David S.; Maiga, Mamoudou; Timmins, Graham S.; Bishai, William R.; Hatfull, Graham F.; Larsen, Michelle H.; Jacobs, William R.

    2011-01-01

    The rapid and accurate diagnosis of active tuberculosis (TB) and its drug susceptibility remain a challenge. Phenotypic assays allow determination of antibiotic susceptibilities even if sequence data are not available or informative. We review 2 emerging diagnostic approaches, reporter phage and breath tests, both of which assay mycobacterial metabolism. The reporter phage signal, Green fluorescent protein (GFP) or β-galactosidase, indicates transcription and translation inside the recipient bacilli and its attenuation by antibiotics. Different breath tests assay, (1) exhaled antigen 85, (2) mycobacterial urease activity, and (3) detection by trained rats of disease-specific odor in sputum, have also been developed. When compared with culture, reporter phage assays shorten the time for initial diagnosis of drug susceptibility by several days. Both reporter phage and breath tests have promise as early markers to determine the efficacy of treatment. While sputum often remains smear and Mycobacterium tuberculosis DNA positive early in the course of efficacious antituberculous treatment, we predict that both breath and phage tests will rapidly become negative. If this hypothesis proves correct, phage assays and breath tests could become important surrogate markers in early bactericidal activity (EBA) studies of new antibiotics. PMID:21996696

  5. Antitubercular activity of disulfiram, an antialcoholism drug, against multidrug- and extensively drug-resistant Mycobacterium tuberculosis isolates.

    PubMed

    Horita, Yasuhiro; Takii, Takemasa; Yagi, Tetsuya; Ogawa, Kenji; Fujiwara, Nagatoshi; Inagaki, Emi; Kremer, Laurent; Sato, Yasuo; Kuroishi, Ryuji; Lee, Yoosa; Makino, Toshiaki; Mizukami, Hajime; Hasegawa, Tomohiro; Yamamoto, Ryuji; Onozaki, Kikuo

    2012-08-01

    The antimycobacterial activities of disulfiram (DSF) and diethyldithiocarbamate (DDC) against multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB) clinical isolates were evaluated in vitro. Both DSF and DDC exhibited potent antitubercular activities against 42 clinical isolates of M. tuberculosis, including MDR/XDR-TB strains. Moreover, DSF showed remarkable bactericidal activity ex vivo and in vivo. Therefore, DSF might be a drug repurposed for the treatment of MDR/XDR-TB. PMID:22615274

  6. Antitubercular Activity of Disulfiram, an Antialcoholism Drug, against Multidrug- and Extensively Drug-Resistant Mycobacterium tuberculosis Isolates

    PubMed Central

    Horita, Yasuhiro; Yagi, Tetsuya; Ogawa, Kenji; Fujiwara, Nagatoshi; Inagaki, Emi; Kremer, Laurent; Sato, Yasuo; Kuroishi, Ryuji; Lee, YooSa; Makino, Toshiaki; Mizukami, Hajime; Hasegawa, Tomohiro; Yamamoto, Ryuji; Onozaki, Kikuo

    2012-01-01

    The antimycobacterial activities of disulfiram (DSF) and diethyldithiocarbamate (DDC) against multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB) clinical isolates were evaluated in vitro. Both DSF and DDC exhibited potent antitubercular activities against 42 clinical isolates of M. tuberculosis, including MDR/XDR-TB strains. Moreover, DSF showed remarkable bactericidal activity ex vivo and in vivo. Therefore, DSF might be a drug repurposed for the treatment of MDR/XDR-TB. PMID:22615274

  7. Acute and chronic Legionnaires' disease and co-existent tuberculosis: a trial of erythromycin.

    PubMed

    Hamedani, P; Hafeez, S; Ali, J; Memon, R; Ali, S; Ali, M; Ansari, M; Raza, R

    1989-01-01

    To assess the prevalence of Legionnaires' disease, 115 patients with 'difficult-to-treat' chest infections were screened for Legionnella pneumophila. The results were positive in 10 (37%) of 27 patients with pulmonary tuberculosis, 15 (22%) of 68 with a recent onset acute respiratory infection, and 7 (35%) of 20 patients with history of a chronic respiratory infection. These 32 patients were enrolled in an open therapeutic trial of erythromycin. Less severe cases (17 of 32) received erythromycin stearate orally (500 mg 4-times daily) for up to 28 days, while severe cases were treated for the first few days with intravenous erythromycin lactobionate (4 g/day). Weekly chest X-ray examinations revealed prompt resolution. Most patients had no signs and symptoms detectable after 7 days, and none persisted up to 28 days. There were no therapeutic failures and microbiological tests on Day 28 were negative for Legionella pneumophila. It is suggested that the possibility of co-existing legionellosis should be considered in all patients with difficult to treat acute and chronic chest infections, particularly in developing countries where tuberculosis is very common, and treatment instituted or supplemented with erythromycin as the drug of choice. PMID:2680287

  8. Cerebral aspergillosis and pulmonary tuberculosis in a child with chronic granulomatous disease

    PubMed Central

    Waqas, Muhammed; Zafar, Sidra; Rehman, Tooba; Riyaz, Muhammed; Bari, Muhammed E.; Idrees, Romana

    2016-01-01

    Background: Chronic granulomatous disease (CGD) is an immune disorder that affects phagocytes. It is characterized by recurrent or persistent bacterial and fungal infections. Reports of tuberculosis (TB) in patients with CGD are rare. In developing countries, where TB is endemic, possibility of other chronic infections is often overlooked by physicians. Case Description: We report the case of a 4-year-old boy who had recurrent respiratory infections and episodes of headache. He was put on antituberculosis (ATT) drugs without microbiological or pathological evidence 2 months prior to presentation. The child did not improve and was brought to our hospital where a computed tomography scan revealed multiple cerebral abscesses. These abscesses were excised. The microbiological specimen was determined to be positive for Aspergillus fumigatus. His tracheal aspirate was positive for Mycobacterium tuberculosis polymerase chain reaction assay. Further work-up confirmed the diagnosis of CGD in the child. Conclusion: This report describes the course of the patient's illness in order to highlight the challenges associated with the management of these infections. We also aim to stress on the importance of pathological diagnosis before starting a therapy. PMID:27308089

  9. Developing aerosol vaccines for Mycobacterium tuberculosis: Workshop proceedings: National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA, April 9, 2014.

    PubMed

    2015-06-12

    On April 9, 2014, Aeras and the National Institute of Allergy and Infectious Diseases convened a workshop entitled "Developing Aerosol Vaccines for Mycobacterium tuberculosis" in Bethesda, MD. The purpose of the meeting was to explore the potential for developing aerosol vaccines capable of preventing infection with M. tuberculosis (Mtb), preventing the development of active tuberculosis (TB) among those latently infected with Mtb, or as immunotherapy for persons with active TB. The workshop was organized around four key questions relevant to developing and assessing aerosol TB vaccines: (1) What is the current knowledge about lung immune responses and early pathogenesis resulting after Mtb infection and what are the implications for aerosol TB vaccine strategies? (2) What are the technical issues surrounding aerosol vaccine delivery? (3) What is the current experience in aerosol TB vaccine development? and (4) What are the regulatory implications of developing aerosol vaccines, including those for TB? Lessons learned from the WHO effort to develop an aerosol measles vaccine served as a case example for overall discussions at the meeting. Workshop participants agreed that aerosol delivery represents a potentially important strategy in advancing TB vaccine development efforts. As no major regulatory, manufacturing or clinical impediments were identified, members of the workshop emphasized the need for greater support to further explore the potential for this delivery methodology, either alone or as an adjunct to traditional parenteral methods of vaccine administration. PMID:25869894

  10. CD4 T Cell-Derived IFN-γ Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal Disease

    PubMed Central

    Sakai, Shunsuke; Kauffman, Keith D.; Sallin, Michelle A.; Sharpe, Arlene H.; Young, Howard A.; Ganusov, Vitaly V.; Barber, Daniel L.

    2016-01-01

    IFN-γ–producing CD4 T cells are required for protection against Mycobacterium tuberculosis (Mtb) infection, but the extent to which IFN-γ contributes to overall CD4 T cell-mediated protection remains unclear. Furthermore, it is not known if increasing IFN-γ production by CD4 T cells is desirable in Mtb infection. Here we show that IFN-γ accounts for only ~30% of CD4 T cell-dependent cumulative bacterial control in the lungs over the first six weeks of infection, but >80% of control in the spleen. Moreover, increasing the IFN-γ–producing capacity of CD4 T cells by ~2 fold exacerbates lung infection and leads to the early death of the host, despite enhancing control in the spleen. In addition, we show that the inhibitory receptor PD-1 facilitates host resistance to Mtb by preventing the detrimental over-production of IFN-γ by CD4 T cells. Specifically, PD-1 suppressed the parenchymal accumulation of and pathogenic IFN-γ production by the CXCR3+KLRG1-CX3CR1- subset of lung-homing CD4 T cells that otherwise mediates control of Mtb infection. Therefore, the primary role for T cell-derived IFN-γ in Mtb infection is at extra-pulmonary sites, and the host-protective subset of CD4 T cells requires negative regulation of IFN-γ production by PD-1 to prevent lethal immune-mediated pathology. PMID:27244558

  11. CD4 T Cell-Derived IFN-γ Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal Disease.

    PubMed

    Sakai, Shunsuke; Kauffman, Keith D; Sallin, Michelle A; Sharpe, Arlene H; Young, Howard A; Ganusov, Vitaly V; Barber, Daniel L

    2016-05-01

    IFN-γ-producing CD4 T cells are required for protection against Mycobacterium tuberculosis (Mtb) infection, but the extent to which IFN-γ contributes to overall CD4 T cell-mediated protection remains unclear. Furthermore, it is not known if increasing IFN-γ production by CD4 T cells is desirable in Mtb infection. Here we show that IFN-γ accounts for only ~30% of CD4 T cell-dependent cumulative bacterial control in the lungs over the first six weeks of infection, but >80% of control in the spleen. Moreover, increasing the IFN-γ-producing capacity of CD4 T cells by ~2 fold exacerbates lung infection and leads to the early death of the host, despite enhancing control in the spleen. In addition, we show that the inhibitory receptor PD-1 facilitates host resistance to Mtb by preventing the detrimental over-production of IFN-γ by CD4 T cells. Specifically, PD-1 suppressed the parenchymal accumulation of and pathogenic IFN-γ production by the CXCR3+KLRG1-CX3CR1- subset of lung-homing CD4 T cells that otherwise mediates control of Mtb infection. Therefore, the primary role for T cell-derived IFN-γ in Mtb infection is at extra-pulmonary sites, and the host-protective subset of CD4 T cells requires negative regulation of IFN-γ production by PD-1 to prevent lethal immune-mediated pathology. PMID:27244558

  12. Transmission and Progression to Disease of Mycobacterium tuberculosis Phylogenetic Lineages in The Netherlands

    PubMed Central

    Verhagen, Lilly M.; Borgdorff, Martien W.; van Soolingen, Dick

    2015-01-01

    The aim of this study was to determine if mycobacterial lineages affect infection risk, clustering, and disease progression among Mycobacterium tuberculosis cases in The Netherlands. Multivariate negative binomial regression models adjusted for patient-related factors and stratified by patient ethnicity were used to determine the association between phylogenetic lineages and infectivity (mean number of positive contacts around each patient) and clustering (as defined by number of secondary cases within 2 years after diagnosis of an index case sharing the same fingerprint) indices. An estimate of progression to disease by each risk factor was calculated as a bootstrapped risk ratio of the clustering index by the infectivity index. Compared to the Euro-American reference, Mycobacterium africanum showed significantly lower infectivity and clustering indices in the foreign-born population, while Mycobacterium bovis showed significantly lower infectivity and clustering indices in the native population. Significantly lower infectivity was also observed for the East African Indian lineage in the foreign-born population. Smear positivity was a significant risk factor for increased infectivity and increased clustering. Estimates of progression to disease were significantly associated with age, sputum-smear status, and behavioral risk factors, such as alcohol and intravenous drug abuse, but not with phylogenetic lineages. In conclusion, we found evidence of a bacteriological factor influencing indicators of a strain's transmissibility, namely, a decreased ability to infect and a lower clustering index in ancient phylogenetic lineages compared to their modern counterparts. Confirmation of these findings via follow-up studies using tuberculin skin test conversion data should have important implications on M. tuberculosis control efforts. PMID:26224845

  13. Spinal Tuberculosis (Pott's disease) Mimicking Paravertebral Malignant Tumor in a Child Presenting with Spinal Cord Compression

    PubMed Central

    Emir, Suna; Erdem, Arzu Y; Demir, Haci A; Kaçar, Ayper; Tunç, Bahattin

    2012-01-01

    Paravertebral tumors may interfere with the radiological and clinical features of spinal tuberculosis. We report a case of a 3-year-old boy with spinal tuberculosis who was initially misdiagnosed as having a paraspinal tumor. The diagnosis of tuberculosis was made on the basis of intraoperative findings and confirmed by histopathology. This case highlights the importance of awareness of the different radiographic features of spinal tuberculosis, which can mimic a spinal malignancy. In order to avoid delayed diagnosis, pediatricians and radiologists must be aware of spinal tuberculosis, which may interfere with other clinical conditions. PMID:23439455

  14. Assessment of treatment response in tuberculosis.

    PubMed

    Rockwood, Neesha; du Bruyn, Elsa; Morris, Thomas; Wilkinson, Robert J

    2016-06-01

    Antibiotic treatment of tuberculosis has a duration of several months. There is significant variability of the host immune response and the pharmacokinetic-pharmacodynamic properties of Mycobacterium tuberculosis sub-populations at the site of disease. A limitation of sputum-based measures of treatment response may be sub-optimal detection and monitoring of Mycobacterium tuberculosis sub-populations. Potential biomarkers and surrogate endpoints should be benchmarked against hard clinical outcomes (failure/relapse/death) and may need tailoring to specific patient populations. Here, we assess the evidence supporting currently utilized and future potential host and pathogen-based models and biomarkers for monitoring treatment response in active and latent tuberculosis. Biomarkers for monitoring treatment response in extrapulmonary, pediatric and drug resistant tuberculosis are research priorities. PMID:27030924

  15. Pleural tuberculosis.

    PubMed

    Chakrabarti, B; Davies, P D O

    2006-03-01

    Pleural effusions in tuberculosis are commonly seen in young adults as an immunological phenomenon occurring soon after primary infection. However, the epidemiology and demographics of tuberculous pleurisy are changing due to the impact of HIV co-infection and the increasing number of pleural effusions seen as part of re-activation disease. Pleural biopsy for histology and culture is the mainstay of diagnosis with closed needle biopsy adequate in the majority of cases. Techniques such as PCR of biopsy specimens and the role of pleural fluid ADA are still being evaluated as a diagnostic aid. Tuberculous empyema is less commonly seen in the western world and the diagnostic yield from pleural fluid here is greater than in "primary" effusions. Treatment with appropriate antituberculous chemotherapy is generally successful though there is currently insufficient evidence to recommend the routine use of corticosteroids in this condition. PMID:16700190

  16. Cathepsin L maturation and activity is impaired in macrophages harboring M. avium and M. tuberculosis.

    PubMed

    Nepal, Rajeev M; Mampe, Stephanie; Shaffer, Brian; Erickson, Ann H; Bryant, Paula

    2006-06-01

    Mycobacterium tuberculosis-infected macrophages demonstrate diminished capacity to present antigens via class II MHC molecules. Since successful class II MHC-restricted antigen presentation relies on the actions of endocytic proteases, we asked whether the activities of cathepsins (Cat) B, S and L-three major lysosomal cysteine proteases-are modulated in macrophages infected with pathogenic Mycobacterium spp. Infection of murine bone marrow-derived macrophages with either Mycobacterium avium or M. tuberculosis had no obvious effect on Cat B or Cat S activity. In contrast, the activity of Cat L was altered in infected cells. Specifically, whereas the 24-kDa two-chain mature form of active Cat L predominated in uninfected cells, we observed an increase in the steady-state activity of the precursor single-chain (30 kDa) and 25-kDa two-chain forms of the enzyme in cells infected with either M. avium or M. tuberculosis. Pulse-chase analyses revealed that maturation of nascent, single-chain Cat L into the 25-kDa two-chain form was impaired in infected macrophages, and that maturation into the 24-kDa two-chain form did not occur. Consistent with these data, M. avium infection inhibited the IFNgamma-induced secretion of active two-chain Cat L by macrophages. Viable bacilli were not required to disrupt Cat L maturation, suggesting that a constitutively expressed mycobacterial component was responsible. The absence of the major active form of lysosomal Cat L in M. avium- and M. tuberculosis-infected macrophages may influence the types of T cell epitopes generated in these antigen-presenting cells, and/or the rate of class II MHC peptide loading. PMID:16636015

  17. Tuberculosis Facts - TB and HIV/AIDS

    MedlinePlus

    Tuberculosis (TB) Facts TB and HIV/AIDS What is TB? “TB” is short for a disease called tuberculosis. TB is spread through the air from one ... Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination

  18. Childhood tuberculosis.

    PubMed

    Jacobs, R F; Eisenach, K D

    1993-01-01

    The dramatic resurgence and increase in the total number of cases of tuberculous infection and disease in children is alarming in the United States. With poverty, poor access to health care, overcrowding (predominantly in inner-city areas), and an increase in immigration from areas with high endemic rates of tuberculosis, the problem in children will continue to increase. If the impact of coinfection with HIV and M. tuberculosis becomes significant, as it has in adults in the United States, this increase in the total number of cases of tuberculous disease could be staggering. The impact of multiple drug-resistant strains of M. tuberculosis and the current crises in availability of effective antituberculous drugs will need to undergo basic and clinical research. Although the possibility for eradication of M. tuberculosis as a human pathogen in the United States still exists, clinicians must reeducate themselves regarding the epidemiology, pathophysiology, diagnostic work-up, and effective treatment of children with tuberculosis in the current situation of increasing tuberculous disease and resistant organisms in children. PMID:8217004

  19. Detection of Tuberculosis Infection Hotspots Using Activity Spaces Based Spatial Approach in an Urban Tokyo, from 2003 to 2011

    PubMed Central

    Izumi, Kiyohiko; Ohkado, Akihiro; Uchimura, Kazuhiro; Murase, Yoshiro; Tatsumi, Yuriko; Kayebeta, Aya; Watanabe, Yu; Ishikawa, Nobukatsu

    2015-01-01

    Background Identifying ongoing tuberculosis infection sites is crucial for breaking chains of transmission in tuberculosis-prevalent urban areas. Previous studies have pointed out that detection of local accumulation of tuberculosis patients based on their residential addresses may be limited by a lack of matching between residences and tuberculosis infection sites. This study aimed to identify possible tuberculosis hotspots using TB genotype clustering statuses and a concept of “activity space”, a place where patients spend most of their waking hours. We further compared the spatial distribution by different residential statuses and describe urban environmental features of the detected hotspots. Methods Culture-positive tuberculosis patients notified to Shinjuku city from 2003 to 2011 were enrolled in this case-based cross-sectional study, and their demographic and clinical information, TB genotype clustering statuses, and activity space were collected. Spatial statistics (Global Moran’s I and Getis-Ord Gi* statistics) identified significant hotspots in 152 census tracts, and urban environmental features and tuberculosis patients’ characteristics in these hotspots were assessed. Results Of the enrolled 643 culture-positive tuberculosis patients, 416 (64.2%) were general inhabitants, 42 (6.5%) were foreign-born people, and 184 were homeless people (28.6%). The percentage of overall genotype clustering was 43.7%. Genotype-clustered general inhabitants and homeless people formed significant hotspots around a major railway station, whereas the non-clustered general inhabitants formed no hotspots. This suggested the detected hotspots of activity spaces may reflect ongoing tuberculosis transmission sites and were characterized by smaller residential floor size and a higher proportion of non-working households. Conclusions Activity space-based spatial analysis suggested possible TB transmission sites around the major railway station and it can assist in further

  20. Local Inflammation, Dissemination and Coalescence of Lesions Are Key for the Progression toward Active Tuberculosis: The Bubble Model.

    PubMed

    Prats, Clara; Vilaplana, Cristina; Valls, Joaquim; Marzo, Elena; Cardona, Pere-Joan; López, Daniel

    2016-01-01

    The evolution of a tuberculosis (TB) infection toward active disease is driven by a combination of factors mostly related to the host response. The equilibrium between control of the bacillary load and the pathology generated is crucial as regards preventing the growth and proliferation of TB lesions. In addition, some experimental evidence suggests an important role of both local endogenous reinfection and the coalescence of neighboring lesions. Herein we propose a mathematical model that captures the essence of these factors by defining three hypotheses: (i) lesions grow logistically due to the inflammatory reaction; (ii) new lesions can appear as a result of extracellular bacilli or infected macrophages that escape from older lesions; and (iii) lesions can merge when they are close enough. This model was implemented in Matlab to simulate the dynamics of several lesions in a 3D space. It was also fitted to available microscopy data from infected C3HeB/FeJ mice, an animal model of active TB that reacts against Mycobacterium tuberculosis with an exaggerated inflammatory response. The results of the simulations show the dynamics observed experimentally, namely an initial increase in the number of lesions followed by fluctuations, and an exponential increase in the mean area of the lesions. In addition, further analysis of experimental and simulation results show a strong coincidence of the area distributions of lesions at day 21, thereby highlighting the consistency of the model. Three simulation series removing each one of the hypothesis corroborate their essential role in the dynamics observed. These results demonstrate that three local factors, namely an exaggerated inflammatory response, an endogenous reinfection, and a coalescence of lesions, are needed in order to progress toward active TB. The failure of one of these factors stops induction of the disease. This mathematical model may be used as a basis for developing strategies to stop the progression of

  1. Local Inflammation, Dissemination and Coalescence of Lesions Are Key for the Progression toward Active Tuberculosis: The Bubble Model

    PubMed Central

    Prats, Clara; Vilaplana, Cristina; Valls, Joaquim; Marzo, Elena; Cardona, Pere-Joan; López, Daniel

    2016-01-01

    The evolution of a tuberculosis (TB) infection toward active disease is driven by a combination of factors mostly related to the host response. The equilibrium between control of the bacillary load and the pathology generated is crucial as regards preventing the growth and proliferation of TB lesions. In addition, some experimental evidence suggests an important role of both local endogenous reinfection and the coalescence of neighboring lesions. Herein we propose a mathematical model that captures the essence of these factors by defining three hypotheses: (i) lesions grow logistically due to the inflammatory reaction; (ii) new lesions can appear as a result of extracellular bacilli or infected macrophages that escape from older lesions; and (iii) lesions can merge when they are close enough. This model was implemented in Matlab to simulate the dynamics of several lesions in a 3D space. It was also fitted to available microscopy data from infected C3HeB/FeJ mice, an animal model of active TB that reacts against Mycobacterium tuberculosis with an exaggerated inflammatory response. The results of the simulations show the dynamics observed experimentally, namely an initial increase in the number of lesions followed by fluctuations, and an exponential increase in the mean area of the lesions. In addition, further analysis of experimental and simulation results show a strong coincidence of the area distributions of lesions at day 21, thereby highlighting the consistency of the model. Three simulation series removing each one of the hypothesis corroborate their essential role in the dynamics observed. These results demonstrate that three local factors, namely an exaggerated inflammatory response, an endogenous reinfection, and a coalescence of lesions, are needed in order to progress toward active TB. The failure of one of these factors stops induction of the disease. This mathematical model may be used as a basis for developing strategies to stop the progression of

  2. [Smoking and tuberculosis].

    PubMed

    Underner, Michel; Perriot, Jean

    2012-12-01

    Smoking and tuberculosis represent two major world health issues particularly in developing countries. Tobacco smoke increases risk of Mycobaterium tuberculosis infection by several means: alteration of muco-ciliary clearance, reduced alveolar macrophage activity; immune-depression of pulmonary lymphocytes, reduction of cytotoxic activity of natural killer cells, alteration of the activity of the pulmonary dendritic cells. Both active and passive smoking increases the risk of latent tubercular infection and of pulmonary and extra-pulmonary tuberculosis. Active smoking increases the severity of pulmonary tuberculosis (gravity of radiological lesions). The diagnostic delay and recovery details are more important for smokers. Active smoking increases relapses of both pulmonary and extra-pulmonary tuberculosis after treatment with or without the Directly Observed Treatment Short course (DOTS) with poor observance of treatment. The mortality risk from tuberculosis is heightened among smokers. Smoking cessation represents an essential means of controlling tuberculosis epidemics in developing countries. PMID:22465718

  3. In vitro-in vivo activity relationship of substituted benzimidazole cell division inhibitors with activity against Mycobacteria tuberculosis

    PubMed Central

    Knudson, Susan E.; Kumar, Kunal; Awasthi, Divya; Ojima, Iwao; Slayden, Richard A.

    2014-01-01

    Structure based drug design was used to develop a compound library of novel 2,5,6- and 2,5,7-trisubstituted benzimidazoles. Three structural analogs, SB-P1G10, SB-P8B2 and SB-P3G2 were selected from this library based on previous studies for advanced study. In vitro studies revealed that SB-P8B2 and SB-P3G2 had sigmoidal kill-curves while in contrast SB-P1G10 showed a narrow zonal susceptibility. The in vitro studies also demonstrated that exposure to SB-P8B2 or SB-P3G2 was bactericidal, while SB-P1G10 treatment never resulted in complete killing. The dose curves for the three compounds against clinical isolates were comparable to their respective dose curves in the laboratory strain of M. tuberculosis. SB-P8B2 and SB-P3G2 exhibited antibacterial activity against non-replicating bacilli under low oxygen conditions. SB-P3G2 and SB-P1G10 were assessed in acute short-term animal models of tuberculosis, which showed that SB-P3G2 treatment demonstrated activity against M. tuberculosis. Together, these studies reveal an in vitro- in vivo relationship of the 2,5,6-trisubstituted benzimidazoles that serves as a criterion for advancing this class of cell division inhibitors into more resource intensive in vivo efficacy models such as the long-term murine model of tuberculosis and Pre-IND PK/PD studies. Specifically, these studies are the first demonstration of efficacy and an in vitro–in vivo activity relationship for 2,5,6-trisubstituted benzimidazoles. The in vivo activity presented in this manuscript substantiates this class of cell division inhibitors as having potency and efficacy against M. tuberculosis. PMID:24746463

  4. Transglutaminase activation in neurodegenerative diseases

    PubMed Central

    Jeitner, Thomas M; Muma, Nancy A; Battaile, Kevin P; Cooper, Arthur JL

    2009-01-01

    The following review examines the role of calcium in promoting the in vitro and in vivo activation of transglutaminases in neurodegenerative disorders. Diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease exhibit increased transglutaminase activity and rises in intracellular calcium concentrations, which may be related. The aberrant activation of transglutaminase by calcium is thought to give rise to a variety of pathological moieties in these diseases, and the inhibition has been shown to have therapeutic benefit in animal and cellular models of neurodegeneration. Given the potential clinical relevance of transglutaminase inhibitors, we have also reviewed the recent development of such compounds. PMID:20161049

  5. The role of Ca²⁺ in the activity of Mycobacterium tuberculosis DNA gyrase.

    PubMed

    Karkare, Shantanu; Yousafzai, Faridoon; Mitchenall, Lesley A; Maxwell, Anthony

    2012-10-01

    DNA gyrase is the only type II topoisomerase in Mycobacterium tuberculosis and needs to catalyse DNA supercoiling, relaxation and decatenation reactions in order to fulfil the functions normally carried out by gyrase and DNA topoisomerase IV in other bacteria. We have obtained evidence for the existence of a Ca(2+)-binding site in the GyrA subunit of M. tuberculosis gyrase. Ca(2+) cannot support topoisomerase reactions in the absence of Mg(2+), but partial removal of Ca(2+) from GyrA by dialysis against EGTA leads to a modest loss in relaxation activity that can be restored by adding back Ca(2+). More extensive removal of Ca(2+) by denaturation of GyrA and dialysis against EGTA results in an enzyme with greatly reduced enzyme activities. Mutation of the proposed Ca(2+)-binding residues also leads to loss of activity. We propose that Ca(2+) has a regulatory role in M. tuberculosis gyrase and suggest a model for the modulation of gyrase activity by Ca(2+) binding. PMID:22844097

  6. Novel aryloxy azolyl chalcones with potent activity against Mycobacterium tuberculosis H37Rv.

    PubMed

    Marrapu, Vijay K; Chaturvedi, Vinita; Singh, Shubhra; Singh, Shyam; Sinha, Sudhir; Bhandari, Kalpana

    2011-09-01

    A series of twenty seven novel aryloxy azolyl chalcones were synthesized and evaluated in vitro for the growth inhibition of Mycobacterium tuberculosis H37Rv. Ten compounds from this series exhibited good activity with MIC in the range of 3.12-0.78 μg/mL and six of them were found non-toxic against VERO cells and MBMDMøs (mouse bone-marrow derived macrophages), were further evaluated ex-vivo for their potential to kill intracellular bacilli. Two compounds 4 and 19 showed 99% and 71% killing respectively, of intracellular bacilli in MBMDMøs infection model. Further, compound 19, an imidazolyl chalcone with a 2,4-difluorobenzyloxy moiety also exhibited moderate in vivo activity in mice against virulent M. tuberculosis, thus providing a new structural lead towards TB drug development. PMID:21764184

  7. Comparative cytotoxic and anti-tuberculosis activity of Aplysina caissara marine sponge crude extracts.

    PubMed

    Azevedo, Luciana G; Muccillo-Baisch, Ana L; Filgueira, Daza de M V B; Boyle, Robert T; Ramos, Daniela F; Soares, Andrea D; Lerner, Clea; Silva, Pedro A; Trindade, Gilma S

    2008-01-01

    Three crude extracts of Aplysina caissara, a marine sponge endemic to Brazil, were tested against a hepatoma cell line and Mycobacterium tuberculosis. The results demonstrate that all extracts are toxic and capable of inhibiting cellular growth. Additionally, the extracts produced morphological aberrations and inhibited cell attachment to culture substrates. These effects were dose/time dependent. Our results also suggest that reactive oxygen species (ROS) production is not involved in the cytotoxic processes levied by the extracts employed in this study and that active metabolites are likely to be present in the polar fractions of the crude extracts. Finally, our results indicate that all three extracts exhibit a moderate anti-tuberculosis capacity, and that the removal of an extract's lipid fraction appears to diminish this activity. PMID:17826358

  8. Control measures to trace ≤ 15-year-old contacts of index cases of active pulmonary tuberculosis

    PubMed Central

    Oliveira, Cláudia Di Lorenzo; de Melo, Angelita Cristine; de Oliveira, Lílian Ruth Silva; Froede, Emerson Lopes; Camargos, Paulo

    2015-01-01

    This was descriptive study carried out in a medium-sized Brazilian city. In ≤ 15-year-old contacts of index cases of active pulmonary tuberculosis, we assessed compliance with the Brazilian national guidelines for tuberculosis control. We interviewed 43 contacts and their legal guardians. Approximately 80% of the contacts were not assessed by the municipal public health care system, and only 21% underwent tuberculin skin testing. The results obtained with the Chi-square Automatic Interaction Detector method suggest that health care teams have a biased attitude toward assessing such contacts and underscore the need for training health professionals regarding tuberculosis control programs. PMID:26578137

  9. FOXO3 rs12212067: T > G Association with Active Tuberculosis in Han Chinese Population.

    PubMed

    Lu, Yanjun; Zhu, Yaowu; Wang, Xiong; Wang, Feng; Peng, Jing; Hou, Hongyan; Sun, Ziyong

    2016-02-01

    It is well known that the human innate immune and adaptive immune response play important role in tuberculosis (TB) infection and progress. Emerging evidence shows that FOXO3 plays an important role in the human immune system. Recent research has shown that the FOXO3 genetic variants are associated malaria infection. In this study, 268 confirmed TB patients, 321 patients with latent tuberculosis infection (LTBI), and 475 TB-free controls were recruited; the single-nucleotide polymorphism (SNP) rs12212067: T > G in FOXO3 was genotyped using predesigned TaqMan® allelic discrimination assays. The results showed that the G allele of rs12212067 in FOXO3 was more common in health control and the latent TB group compared with the active TB group (p = 0.048, odds ratio (OR) 95 % confidence intervals (CI) = 1.37 (1.00-1.89); p = 0.042, OR 95 % CI = 1.42 (1.01-1.99), respectively); furthermore, within active TB patients, the G allele of rs12212067 in FOXO3 was more frequent in extra-pulmonary tuberculosis (EPTB) group compared to pulmonary tuberculosis (PTB) group (p = 0.035, OR 95 % CI = 0.57 (0.33-0.97). In conclusion, this study found that rs12212067 in FOXO3 was associated with increased risk of active TB. The minor G allele might be a protection factor which was found more common in latent TB patients and healthy controls than active TB patients. PMID:26223437

  10. Clinical management of concurrent diabetes and tuberculosis and the implications for patient services

    PubMed Central

    Riza, Anca Lelia; Pearson, Fiona; Ugarte-Gil, Cesar; Alisjahbana, Bachti; van de Vijver, Steven; Panduru, Nicolae M; Hill, Philip C; Ruslami, Rovina; Moore, David; Aarnoutse, Rob; Critchley, Julia A; van Crevel, Reinout

    2016-01-01

    Diabetes triples the risk for active tuberculosis, thus the increasing burden of type 2 diabetes will help to sustain the present tuberculosis epidemic. Recommendations have been made for bidirectional screening, but evidence is scarce about the performance of specific tuberculosis tests in individuals with diabetes, specific diabetes tests in patients with tuberculosis, and screening and preventive therapy for latent tuberculosis infections in individuals with diabetes. Clinical management of patients with both diseases can be difficult. Tuberculosis patients with diabetes have a lower concentration of tuberculosis drugs and a higher risk of drug toxicity than tuberculosis patients without diabetes. Good glycaemic control, which reduces long-term diabetes complications and could also improve tuberculosis treatment outcomes, is hampered by chronic inflammation, drug-drug interactions, suboptimum adherence to drug treatments, and other factors. Besides drug treatments for tuberculosis and diabetes, other interventions, such as education, intensive monitoring, and lifestyle interventions, might be needed, especially for patients with newly diagnosed diabetes or those who need insulin. From a health systems point of view, delivery of optimum care and integration of services for tuberculosis and diabetes is a huge challenge in many countries. Experience from the combined tuberculosis and HIV/AIDS epidemic could serve as an example, but more studies are needed that include economic assessments of recommended screening and systems to manage concurrent tuberculosis and diabetes. PMID:25194887

  11. Nitric oxide generated from isoniazid activation by KatG: source of nitric oxide and activity against Mycobacterium tuberculosis.

    PubMed

    Timmins, Graham S; Master, Sharon; Rusnak, Frank; Deretic, Vojo

    2004-08-01

    Isonicotinic acid hydrazide (INH) is a frontline antituberculosis agent. Once taken up by Mycobacterium tuberculosis, INH requires activation by the catalase-peroxidase KatG, converting INH from its prodrug form into a range of bactericidal reactive species. Here we used 15N-labeled INH together with electron paramagnetic resonance spin trapping techniques to demonstrate that nitric oxide (NO*) is generated from oxidation at the hydrazide nitrogens during the activation of INH by M. tuberculosis KatG. We also observed that a specific scavenger of NO* provided protection against the antimycobacterial activity of INH in bacterial culture. No significant increases in mycobacterial protein nitration were detected, suggesting that NOdot; and not peroxynitrite, a nitrating metabolite of NO*, is involved in antimycobacterial action. In conclusion, INH-derived NO* has biological activity, which directly contributes to the antimycobacterial action of INH. PMID:15273113

  12. Tuberculosis outbreak in a Texas prison, 1994.

    PubMed

    Bergmire-Sweat, D; Barnett, B J; Harris, S L; Taylor, J P; Mazurek, G H; Reddy, V

    1996-12-01

    In 1994 a Texas prison containing a population of mentally retarded inmates experienced a large tuberculosis outbreak. Fifteen cases of tuberculosis were identified (8 confirmed by positive cultures for Mycobacterium tuberculosis) and more than 100 inmates became infected. The culture-confirmed patients were infected with an identical strain of tuberculosis as demonstrated by polymerase chain reaction (PCR) based DNA fingerprinting technique. The prison followed standard tuberculosis infection control policies, but these controls were inadequate to prevent tuberculosis transmission in this special population. Two hundred and thirty inmates (119 inmates showing evidence of new tuberculosis infection or active disease and 111 healthy controls) were enrolled in the investigation. Inmate cell assignments, job duties, and educational classes were identified and medical chart reviews were conducted on all inmates. Tuberculosis transmission was associated with residing on the D Wing of the prison (OR = 25.84, P < 0.01), attending school in Classroom A (OR = 8.34, P = 0.01) and working on the prison utility work crew (OR = 2.52, P < 0.01). The index case in the outbreak had been prescribed 6 months of isoniazid (INH) chemoprophylaxis in 1988. PMID:8972673

  13. Interferon-gamma release assay performance for diagnosing tuberculosis disease in 0- to 5-year-old children.

    PubMed

    Debord, Camille; De Lauzanne, Agathe; Gourgouillon, Nadège; Guérin-El Khourouj, Valérie; Pédron, Béatrice; Gaudelus, Joel; Faye, Albert; Sterkers, Ghislaine

    2011-11-01

    QuantiFERON-TB Gold In-Tube performance was evaluated in 19 French immunocompetent children (0.29-5.36 years; median: 1.52) with active tuberculosis. The rate of indeterminates results was 0/19 and the rates of positivity were 6/10 and 9/9 in <2 and 2- to 5-year-old children, respectively. QuantiFERON-TB Gold In-Tube in association with tuberculin skin test could improve diagnosis of tuberculosis even in young children. PMID:21694659

  14. Optimal intervention strategies for tuberculosis

    NASA Astrophysics Data System (ADS)

    Bowong, Samuel; Aziz Alaoui, A. M.

    2013-06-01

    This paper deals with the problem of optimal control of a deterministic model of tuberculosis (abbreviated as TB for tubercle bacillus). We first present and analyze an uncontrolled tuberculosis model which incorporates the essential biological and epidemiological features of the disease. The model is shown to exhibit the phenomenon of backward bifurcation, where a stable disease-free equilibrium co-exists with one or more stable endemic equilibria when the associated basic reproduction number is less than the unity. Based on this continuous model, the tuberculosis control is formulated and solved as an optimal control problem, indicating how control terms on the chemoprophylaxis and detection should be introduced in the population to reduce the number of individuals with active TB. Results provide a framework for designing the cost-effective strategies for TB with two intervention methods.

  15. Increased Risk of Active Tuberculosis following Acute Kidney Injury: A Nationwide, Population-Based Study

    PubMed Central

    Chang, Chia-Hsui; Huang, Hui-Yu; Huang, Tao-Min; Lai, Chun-Fu; Lin, Meng-Chun; Ko, Wen-Je; Wu, Kwan-Dun; Yu, Chong-Jen; Shu, Chin-Chung; Lee, Chih-Hsin; Wang, Jann-Yuan

    2013-01-01

    Background Profound alterations in immune responses associated with uremia and exacerbated by dialysis increase the risk of active tuberculosis (TB). Evidence of the long-term risk and outcome of active TB after acute kidney injury (AKI) is limited. Methods This population-based-cohort study used claim records retrieved from the Taiwan National Health Insurance database. We retrieved records of all hospitalized patients, more than 18 years, who underwent dialysis for acute kidney injury (AKI) during 1999–2008 and validated using the NSARF data. Time-dependent Cox proportional hazards model to adjust for the ongoing effect of end-stage renal disease (ESRD) was conducted to predict long-term de novo active TB after discharge from index hospitalization. Results Out of 2,909 AKI dialysis patients surviving 90 days after index discharge, 686 did not require dialysis after hospital discharge. The control group included 11,636 hospital patients without AKI, dialysis, or history of TB. The relative risk of active TB in AKI dialysis patients, relative to the general population, after a mean follow-up period of 3.6 years was 7.71. Patients who did (hazard ratio [HR], 3.84; p<0.001) and did not (HR, 6.39; p<0.001) recover from AKI requiring dialysis had significantly higher incidence of TB than patients without AKI. The external validated data also showed nonrecovery subgroup (HR = 4.37; p = 0.049) had high risk of developing active TB compared with non-AKI. Additionally, active TB was associated with long-term all-cause mortality after AKI requiring dialysis (HR, 1.34; p = 0.032). Conclusions AKI requiring dialysis seems to independently increase the long-term risk of active TB, even among those who weaned from dialysis at discharge. These results raise concerns that the increasing global burden of AKI will in turn increase the incidence of active TB. PMID:23936044

  16. Neuron-specific enolase as a novel biomarker reflecting tuberculosis activity and treatment response

    PubMed Central

    Nam, Sung-Jin; Jeong, Jee-Yeong; Jang, Tae-Won; Jung, Mann-Hong; Chun, Bong-Kwon; Cha, Hee-Jae; Oak, Chul-Ho

    2016-01-01

    Background/Aims: It is not clear which tests are indicative of the activity and severity of tuberculosis (TB). This study aimed to investigate the predictive value of neuron-specific enolase (NSE) and to determine the origin of NSE in TB patients. Methods: A single-center retrospective analysis was conducted on newly diagnosed TB patients between January and December 2010. Patients were categorized into one of two disease groups (focal segmental or extensive) based on chest X-ray. Pre- and post-treatment NSE concentrations were evaluated. To determine the origin of serum NSE concentration, NSE staining was compared with macrophage-specific CD68 staining in lung tissues and with a tissue microarray using immunohistochemistry and immunofluorescence. Results: A total of 60 newly diagnosed TB patients were analyzed. In TB patients, NSE serum concentration was significantly increased and NSE level decreased after treatment (p < 0.001). In proportion to serum high-sensitivity C-reactive protein concentration, the mean serum concentration of NSE in the extensive group (25.12 ng/mL) was significantly higher than that in the focal segmental group (20.23 ng/mL, p = 0.04). Immunohistochemical staining revealed a large number of macrophages that stained positively for both NSE and CD68 in TB tissues. In addition, NSE signals mostly co-localized with CD68 signals in the tissue microarray of TB patients. Conclusions: Our results suggest that NSE may be a practical parameter that can be used to monitor TB activity and treatment response. Elevated serum NSE level originates, at least in part, from macrophages in granulomatous lesions. PMID:27271274

  17. Disseminated disease severity as a measure of virulence of Mycobacterium tuberculosis in the guinea pig model.

    PubMed

    Palanisamy, Gopinath S; Smith, Erin E; Shanley, Crystal A; Ordway, Diane J; Orme, Ian M; Basaraba, Randall J

    2008-07-01

    Virulence is the measure of pathogenicity of a microorganism as determined by its ability to invade host tissues and to produce severe disease. In the low-dose aerosol guinea pig model the virulence of multiple strains of Mycobacterium tuberculosis was determined by measuring time of survival, bacterial loads in target organs, and the severity of pulmonary and extra-pulmonary lesions. Erdman K01, CSU93/CDC1551 and HN878 had shorter survival times compared to the common laboratory strain H37Rv. After 30 days of the infection bacilli had disseminated from the lungs resulting in microscopically visible lesions in peribronchial lymph nodes, peripancreatic lymph nodes, spleen, liver, pancreas, adrenal and heart. The extent of the lesion necrosis paralleled virulence when survival times were used as a measure as Erdman K01 and the two clinical isolates caused more necrosis and resulted in sooner death in infected animals than the H37Rv. The extent of extra-pulmonary lesion necrosis was a better predictor of virulence than the number of viable bacilli in the tissue. Overall, this study emphasizes the point that extra-pulmonary disease is a prominent feature of the guinea pig model and dissemination to organs not normally assayed such as the heart and adrenal glands should be taken into account in the assessment of the disease process. PMID:18321783

  18. Detection of Mycobacterium tuberculosis Peptides in the Exosomes of Patients with Active and Latent M. tuberculosis Infection Using MRM-MS

    PubMed Central

    Kruh-Garcia, Nicole A.; Wolfe, Lisa M.; Chaisson, Lelia H.; Worodria, William O.; Nahid, Payam; Schorey, Jeff S.; Davis, J. Lucian; Dobos, Karen M.

    2014-01-01

    The identification of easily measured, accurate diagnostic biomarkers for active tuberculosis (TB) will have a significant impact on global TB control efforts. Because of the host and pathogen complexities involved in TB pathogenesis, identifying a single biomarker that is adequately sensitive and specific continues to be a major hurdle. Our previous studies in models of TB demonstrated that exosomes, such as those released from infected macrophages, contain mycobacterial products, including many Mtb proteins. In this report, we describe the development of targeted proteomics assays employing multiplexed multiple reaction monitoring mass spectrometry (MRM-MS) in order to allow us to follow those proteins previously identified by western blot or shotgun mass spectrometry, and enhance biomarker discovery to include detection of Mtb proteins in human serum exosomes. Targeted MRM-MS assays were applied to exosomes isolated from human serum samples obtained from culture-confirmed active TB patients to detect 76 peptides representing 33 unique Mtb proteins. Our studies revealed the first identification of bacteria-derived biomarker candidates of active TB in exosomes from human serum. Twenty of the 33 proteins targeted for detection were found in the exosomes of TB patients, and included multiple peptides from 8 proteins (Antigen 85B, Antigen 85C, Apa, BfrB, GlcB, HspX, KatG, and Mpt64). Interestingly, all of these proteins are known mycobacterial adhesins and/or proteins that contribute to the intracellular survival of Mtb. These proteins will be included as target analytes in future validation studies as they may serve as markers for persistent active and latent Mtb infection. In summary, this work is the first step in identifying a unique and specific panel of Mtb peptide biomarkers encapsulated in exosomes and reveals complex biomarker patterns across a spectrum of TB disease states. PMID:25080351

  19. Endobronchial Tuberculosis Mimicking Asthma

    PubMed Central

    Argun Baris, Serap; Onyilmaz, Tuğba; Basyigit, Ilknur; Boyaci, Hasim

    2015-01-01

    Endobronchial tuberculosis (EBTB) is defined as tuberculosis infection of the tracheobronchial tree with microbial and histopathological evidence. The clinical symptoms of the diseases are nonspecific. Chronic cough is the major symptom of the disease. The diagnosis is often delayed due to its nonspecific presentation and misdiagnosed as bronchial asthma. This case is presented to recall the notion that the endobronchial tuberculosis can mimic asthma and the importance of bronchoscopic evaluation in a patient with chronic cough and treatment resistant asthma. PMID:26798513

  20. Treatment of Active Pulmonary Tuberculosis in Adults: Current Standards and Recent Advances

    PubMed Central

    Hall, Ronald G.; Leff, Richard D.; Gumbo, Tawanda

    2010-01-01

    Tuberculosis is a global pandemic, with 9 million new cases of the disease and approximately 2 million deaths each year. More than 98% of patients treated for tuberculosis in the United States between 1993 and 2007 had drug-susceptible strains. The standard treatment regimen for drug-susceptible tuberculosis has not changed in decades and was developed on the basis of empiric observations of different treatment regimens. Only recently has the veracity of the scientific basis for standard therapy been examined. The backbone of therapy is still isoniazid, rifampin, and pyrazinamide, although fluoroquinolones are being investigated as a replacement for isoniazid. Recent population pharmacokinetic studies have demonstrated the importance of individualized dosing of isoniazid, pyrazinamide, and rifampin. Isoniazid serum clearance differs depending on the patient’s number of N-acetyltransferase 2 gene *4 (NAT2*4) alleles. Pyrazinamide serum clearance has been shown to increase with increases in body weight. Rifampin’s volume of distribution, clearance, and absorption have wide between-patient and within-patient variability. Microbial pharmacokinetic-pharmacodynamic (PK-PD) indexes and targets to optimize microbial killing and minimize resistance have been identified for rifampin, isoniazid, pyrazinamide, and the fluoroquinolones. These PK-PD indexes suggest that different doses and dosing schedules than those currently recommended could optimize therapy and perhaps shorten duration of therapy. Efflux pump inhibition is also being investigated to enhance first-line antituberculosis drug therapy. Comorbid conditions such as diabetes mellitus and genetically determined iron overload syndromes have been associated with significantly worse patient outcomes. Therapy for these and other patient groups needs further improvement. These patient factors, the covariates for pharmacokinetic variability, and PK-PD factors suggest the need to individualize therapy for patients with

  1. Low-Density Granulocytes Are Elevated in Mycobacterial Infection and Associated with the Severity of Tuberculosis

    PubMed Central

    Luo, Qing; Huang, Zhikun; Peng, Yiping; Xiong, Guoliang; Guo, Yang; Jiang, Hong; Li, Junming

    2016-01-01

    Tuberculosis remains a global health problem caused by infection with Mycobacterium tuberculosis. Numerous studies have established a close correlation between the development of tuberculosis and the roles of neutrophils. Recently, a distinct population of CD15+ granulocytes was found to be present in the peripheral blood mononuclear cell (PBMC) fraction in humans. This population of granulocytes, termed low-density granulocytes (LDGs), was reported to be elevated and associated with disease activity or severity in a number of different conditions including SLE, asthma and HIV infection. However, both the frequency and clinical significance of LDGs associated with tuberculosis are unclear. Here we determined LDG levels and made comparisons between subjects with active pulmonary tuberculosis (PTB) and healthy controls, between PTB patients with mild-to-moderate disease and patients with advanced disease, and among PTB patients following anti-tuberculous therapy of varying durations. The direct correlation between M. tuberculosis infection and LDG levels was confirmed by in vitro infection of whole peripheral blood and isolated granulocytes with mycobacteria. Our results demonstrated that PBMCs in PTB patients contained significantly elevated percentages of LDGs compared with control subjects. LDGs in tuberculosis expressed higher levels of activation markers compared to normal-density granulocytes (NDGs). M. tuberculosis induced the generation of LDGs in both whole blood and isolated NDGs from control subjects, which suggests that LDGs associated with M. tuberculosis infection are likely to originate from in situ activation. Furthermore, our results revealed that the frequency of LDGs is associated with the severity of tuberculosis. PMID:27073889

  2. Low-Density Granulocytes Are Elevated in Mycobacterial Infection and Associated with the Severity of Tuberculosis.

    PubMed

    Deng, Yating; Ye, Jianqing; Luo, Qing; Huang, Zhikun; Peng, Yiping; Xiong, Guoliang; Guo, Yang; Jiang, Hong; Li, Junming

    2016-01-01

    Tuberculosis remains a global health problem caused by infection with Mycobacterium tuberculosis. Numerous studies have established a close correlation between the development of tuberculosis and the roles of neutrophils. Recently, a distinct population of CD15+ granulocytes was found to be present in the peripheral blood mononuclear cell (PBMC) fraction in humans. This population of granulocytes, termed low-density granulocytes (LDGs), was reported to be elevated and associated with disease activity or severity in a number of different conditions including SLE, asthma and HIV infection. However, both the frequency and clinical significance of LDGs associated with tuberculosis are unclear. Here we determined LDG levels and made comparisons between subjects with active pulmonary tuberculosis (PTB) and healthy controls, between PTB patients with mild-to-moderate disease and patients with advanced disease, and among PTB patients following anti-tuberculous therapy of varying durations. The direct correlation between M. tuberculosis infection and LDG levels was confirmed by in vitro infection of whole peripheral blood and isolated granulocytes with mycobacteria. Our results demonstrated that PBMCs in PTB patients contained significantly elevated percentages of LDGs compared with control subjects. LDGs in tuberculosis expressed higher levels of activation markers compared to normal-density granulocytes (NDGs). M. tuberculosis induced the generation of LDGs in both whole blood and isolated NDGs from control subjects, which suggests that LDGs associated with M. tuberculosis infection are likely to originate from in situ activation. Furthermore, our results revealed that the frequency of LDGs is associated with the severity of tuberculosis. PMID:27073889

  3. Impact of awareness drives and community-based active tuberculosis case finding in Odisha, India.

    PubMed

    Parija, D; Patra, T K; Kumar, A M V; Swain, B K; Satyanarayana, S; Sreenivas, A; Chadha, V K; Moonan, P K; Oeltmann, J E

    2014-09-01

    India's Revised National Tuberculosis Control programme employs passive case detection. The new sputum smear-positive case detection rate is less than 70% in Odisha State. During April-June 2012, active case finding (ACF) was conducted through awareness drives and field-based tuberculosis (TB) screening in select communities with the lowest case detection rates. During the campaign, 240 sputum smear-positive TB cases were detected. The number of smear-positive cases detected increased by 11% relative to April-June 2011 in intervention communities compared to an 0.8% increase in non-intervention communities. ACF brought TB services closer to the community and increased TB case detection. PMID:25189560

  4. A review of Vitamin D effects on common respiratory diseases: Asthma, chronic obstructive pulmonary disease, and tuberculosis.

    PubMed

    Hejazi, Mohammad Esmaeil; Modarresi-Ghazani, Faezeh; Entezari-Maleki, Taher

    2016-01-01

    Despite the classic role of Vitamin D in skeletal health, new aspects of Vitamin D have been discovered in tissues and organs other than bones. Epidemiological and observational studies demonstrate a link between Vitamin D deficiency and risk of developing respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), and tuberculosis (TB). To review the literature, we searched the terms "Vitamin D" (using the set operator) and "asthma," "COPD" and "TB" in electronic databases, including PubMed/MEDLINE, Scopus, and Google Scholar until July 2015. Non-English articles or articles with unavailable full text were excluded. Both in vivo and in vitro studies were included. All the reviewed articles state that Vitamin D deficiency is very common among patients with respiratory diseases. The present data regarding Vitamin D and asthma is still controversial, but data about COPD and TB are more encouraging. The relevant studies have been conducted in different populations therefore it is not particularly possible to compare the data due to genetic variations. In order to point out a role for Vitamin D, large clinical trials with Vitamin D deficient subjects and sufficient Vitamin D supplementation are needed. PMID:26985430

  5. A review of Vitamin D effects on common respiratory diseases: Asthma, chronic obstructive pulmonary disease, and tuberculosis

    PubMed Central

    Hejazi, Mohammad Esmaeil; Modarresi-Ghazani, Faezeh; Entezari-Maleki, Taher

    2016-01-01

    Despite the classic role of Vitamin D in skeletal health, new aspects of Vitamin D have been discovered in tissues and organs other than bones. Epidemiological and observational studies demonstrate a link between Vitamin D deficiency and risk of developing respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), and tuberculosis (TB). To review the literature, we searched the terms “Vitamin D” (using the set operator) and “asthma,” “COPD” and “TB” in electronic databases, including PubMed/MEDLINE, Scopus, and Google Scholar until July 2015. Non-English articles or articles with unavailable full text were excluded. Both in vivo and in vitro studies were included. All the reviewed articles state that Vitamin D deficiency is very common among patients with respiratory diseases. The present data regarding Vitamin D and asthma is still controversial, but data about COPD and TB are more encouraging. The relevant studies have been conducted in different populations therefore it is not particularly possible to compare the data due to genetic variations. In order to point out a role for Vitamin D, large clinical trials with Vitamin D deficient subjects and sufficient Vitamin D supplementation are needed. PMID:26985430

  6. Mycobacterium tuberculosis Rv1096 protein: gene cloning, protein expression, and peptidoglycan deacetylase activity

    PubMed Central

    2014-01-01

    Background Many bacteria modulate and evade the immune defenses of their hosts through peptidoglycan (PG) deacetylation. The PG deacetylases from Streptococcus pneumonia, Listeria monocytogenes and Lactococcus lactis have been characterized. However, thus far, the PG deacetylase of Mycobacterium tuberculosis has not been identified. Results In this study, we cloned the Rv1096 gene from the M. tuberculosis H37Rv strain and expressed Rv1096 protein in both Escherichia coli and M. smegmatis. The results showed that the purified Rv1096 protein possessed metallo-dependent PG deacetylase activity, which increased in the presence of Co2+. The kinetic parameters of the PG deacetylase towards M. smegmatis PG as a substrate were as follows: Km, 0.910 ± 0.007 mM; Vmax, 0.514 ± 0.038 μMmin-1; and Kcat = 0.099 ± 0.007 (S-1). Additionally, the viability of M. smegmatis in the presence of over-expressed Rv1096 protein was 109-fold higher than that of wild-type M. smegmatis after lysozyme treatment. Additionally, light microscopy and scanning electron microscopy showed that in the presence of over-expressed Rv1096 protein, M. smegmatis kept its regular shape, with an undamaged cell wall and smooth surface. These results indicate that Rv1096 caused deacetylation of cell wall PG, leading to lysozyme resistance in M. smegmatis. Conclusion We have determined that M. tuberculosis Rv1096 is a PG deacetylase. The PG deacetylase activity of Rv1096 contributed to lysozyme resistance in M. smegmatis. Our findings suggest that deacetylation of cell wall PG may be involved in evasion of host immune defenses by M. tuberculosis. PMID:24975018

  7. Longitudinal tracking of cytokines after acute exposure to tuberculosis: association of distinct cytokine patterns with protection and disease development.

    PubMed

    Hussain, Rabia; Talat, Najeeha; Shahid, Firdaus; Dawood, Ghaffar

    2007-12-01

    Household contacts (HCs) of patients with tuberculosis (TB) are at higher risk of infection as well as the development of active disease. Longitudinal tracking of antigen-specific cytokines after acute exposure may significantly advance our understanding of the dynamic changes in cytokine patterns associated with disease establishment. To achieve this objective, we carried out a prospective cohort study with healthy HCs after exposure to TB. The patterns of cytokines (gamma interferon [IFN-gamma] and interleukin 10 [IL-10]) in response to mycobacterial antigens (culture filtrate [CF] proteins) and nonspecific mitogens (phytohemagglutinin [PHA] and lipopolysaccharide [LPS]) were assessed at 0, 6, 12, and 24 months after exposure. Seven of 109 (6.4%) HCs developed active disease. Six of the seven individuals were females, and active disease developed between 12 and 15 months after exposure in 5/20 families. The most significant findings were the exponential increases ( approximately 1,000-fold) in both the CF protein- and the PHA- or LPS-induced IFN-gamma/IL-10 ratio in healthy HCs (n = 26), which peaked at 12 months, compared to the levels in HCs who developed disease (n = 7), in whom relatively flat responses were observed during the 24-month period. Linear trends for 0 to 12 and 0 to 24 months for the CF protein-induced IFN-gamma/IL-10 ratio showed significant differences between the two groups, as determined by the use of the Mantel extension test for chi(2) analysis (odds ratio = 0.45; 95% confidence interval = 0.295 to 0.685; P = 0.0002). Our results strongly suggest that the magnitude of the IFN-gamma/IL-10 ratio at 12 months after exposure may be a critical determinant in the resolution of infection. These studies provide new insights into the cytokine responses associated with disease establishment or the resolution of infection after natural exposure to TB and have implications for TB control programs as well vaccine efficacy studies. PMID:17928427

  8. Longitudinal Tracking of Cytokines after Acute Exposure to Tuberculosis: Association of Distinct Cytokine Patterns with Protection and Disease Development▿

    PubMed Central

    Hussain, Rabia; Talat, Najeeha; Shahid, Firdaus; Dawood, Ghaffar

    2007-01-01

    Household contacts (HCs) of patients with tuberculosis (TB) are at higher risk of infection as well as the development of active disease. Longitudinal tracking of antigen-specific cytokines after acute exposure may significantly advance our understanding of the dynamic changes in cytokine patterns associated with disease establishment. To achieve this objective, we carried out a prospective cohort study with healthy HCs after exposure to TB. The patterns of cytokines (gamma interferon [IFN-γ] and interleukin 10 [IL-10]) in response to mycobacterial antigens (culture filtrate [CF] proteins) and nonspecific mitogens (phytohemagglutinin [PHA] and lipopolysaccharide [LPS]) were assessed at 0, 6, 12, and 24 months after exposure. Seven of 109 (6.4%) HCs developed active disease. Six of the seven individuals were females, and active disease developed between 12 and 15 months after exposure in 5/20 families. The most significant findings were the exponential increases (∼1,000-fold) in both the CF protein- and the PHA- or LPS-induced IFN-γ/IL-10 ratio in healthy HCs (n = 26), which peaked at 12 months, compared to the levels in HCs who developed disease (n = 7), in whom relatively flat responses were observed during the 24-month period. Linear trends for 0 to 12 and 0 to 24 months for the CF protein-induced IFN-γ/IL-10 ratio showed significant differences between the two groups, as determined by the use of the Mantel extension test for χ2 analysis (odds ratio = 0.45; 95% confidence interval = 0.295 to 0.685; P = 0.0002). Our results strongly suggest that the magnitude of the IFN-γ/IL-10 ratio at 12 months after exposure may be a critical determinant in the resolution of infection. These studies provide new insights into the cytokine responses associated with disease establishment or the resolution of infection after natural exposure to TB and have implications for TB control programs as well vaccine efficacy studies. PMID:17928427

  9. Tuberculosis: Getting Healthy, Staying Healthy

    MedlinePlus

    Tuberculosis Getting Healthy, Staying Healthy U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Allergy and Infectious Diseases Tuberculosis Getting Healthy, Staying Healthy U.S. DEPARTMENT OF HEALTH ...

  10. Circulating Angiogenic Factors as Biomarkers of Disease Severity and Bacterial Burden in Pulmonary Tuberculosis

    PubMed Central

    Kumar, Nathella Pavan; Banurekha, Vaithilingam V.; Nair, Dina; Babu, Subash

    2016-01-01

    Background Angiogenesis and lymphangiogenesis are classical features of granuloma formation in pulmonary tuberculosis (PTB). In addition, the angiogenic factor—VEGF-A is a known biomarker for PTB. Aims/Methodology To examine the association of circulating angiogenic factors with PTB, we examined the systemic levels of VEGF-A, VEGF-C, VEGF-D, VEGF-R1, VEGF-R2 and VEGF-R3in individuals with PTB, latent TB (LTB) or no TB infection (NTB). Results Circulating levels of VEGF-A, VEGF-C andVEGF-R2 were significantly higher in PTB compared to LTB or NTB individuals. Moreover, the levels of VEGF-A, VEGF-C and VEGF-R2 were significantly higher in PTB with bilateral and/or cavitary disease. The levels of these factors also exhibited a significant positive relationship with bacterial burdens in PTB. ROC analysis revealed VEGF-A and VEGF-R2 as markers distinguishing PTB from LTB or NTB. Finally, the circulating levels of all the angiogenic factors examined were significantly reduced following successful chemotherapy. Conclusion Therefore, our data demonstrate that PTB is associated with elevated levels of circulating angiogenic factors, possibly reflecting vascular and endothelial dysfunction. In addition, some of these circulating angiogenic factors could prove useful as biomarkers to monitor disease severity, bacterial burden and therapeutic responses. PMID:26727122

  11. Proteome analysis of the macroscopically affected colonic mucosa of Crohn’s disease and intestinal tuberculosis

    PubMed Central

    Rukmangadachar, Lokesh A.; Makharia, Govind K.; Mishra, Asha; Das, Prasenjit; Hariprasad, Gururao; Srinivasan, Alagiri; Gupta, Siddhartha Datta; Ahuja, Vineet; Acharya, Subrat K.

    2016-01-01

    Differentiation between intestinal tuberculosis (ITB) and Crohn’s disease (CD) is challenging in geographical regions where both these diseases are prevalent. There is a need of biomarkers for differentiation between these two disorders. Colonic biopsies from inflamed mucosa of treatment-naive patients with ITB, CD and controls were used for analysis. Protein extracted from biopsies was digested with trypsin and resulting peptides were labeled with iTRAQ reagents. The peptides were subsequently analyzed using LC-MS/MS for identification and quantification. Gene ontology annotation for proteins was analyzed in PANTHER. Validation experiments were done for six differentially expressed proteins using immunohistochemistry. 533 proteins were identified and 241 proteins were quantified from 5 sets of iTRAQ experiments. While 63 were differentially expressed in colonic mucosa of patients with CD and ITB in at least one set of iTRAQ experiment, 11 proteins were differentially expressed in more than one set of experiments. Six proteins used for validation using immunohistochemistry in a larger cohort of patients; none of them however was differentially expressed in patients with ITB and CD. There are differentially expressed proteins in tissue proteome of CD and ITB. Further experiments are required using a larger cohort of homogeneous tissue samples. PMID:26988818

  12. Tuberculosis and chronic kidney disease: an emerging global syndemic.

    PubMed

    Romanowski, Kamila; Clark, Edward G; Levin, Adeera; Cook, Victoria J; Johnston, James C

    2016-07-01

    The link between chronic kidney disease (CKD) and tuberculosis (TB) has been known for more than 40 years, but the interaction between these 2 diseases is still poorly understood. Dialysis and renal transplant patients appear to be at a higher risk of TB, in part related to immunosuppression along with socioeconomic, demographic, and comorbid factors. Meanwhile, TB screening and diagnostic test performance is suboptimal in the CKD population, and there is limited evidence to guide protocols. Given the increasing prevalence of CKD in TB endemic areas, a merging of CKD and TB epidemics could have significant public health implications, especially in low- to middle-income countries such as India and China, that are experiencing rapid increases in CKD prevalence and account for more than one-third of global TB prevalence. To begin addressing TB-CKD, a clear understanding of the relationship between these 2 conditions needs to be established, and consistent, evidence-based screening and treatment guidelines need to be developed. PMID:27178832

  13. A real-time PCR signature to discriminate between tuberculosis and other pulmonary diseases.

    PubMed

    Laux da Costa, Lucas; Delcroix, Melaine; Dalla Costa, Elis R; Prestes, Isaías V; Milano, Mariana; Francis, Steve S; Unis, Gisela; Silva, Denise R; Riley, Lee W; Rossetti, Maria L R

    2015-07-01

    The goal of this study was to identify a host gene signature that can distinguish tuberculosis (TB) from other pulmonary diseases (OPD). We conducted real-time PCR on whole blood samples from patients in Brazil. TB and OPD patients (asthma and non-TB pneumonia) differentially expressed granzyme A (GZMA), guanylate binding protein 5 (GBP5) and Fc gamma receptor 1A (CD64). Receiver operating characteristic, tree classification and random forest analyses were applied to evaluate the discriminatory power of the three genes and find the gene panel most predictive of patients' disease classification. Tree classification produced a model based on GBP5 and CD64 expression. In random forest analysis, the combination of the three genes provided a robust biosignature to distinguish TB from OPD with 95% specificity and 93% sensitivity. Our results suggest that GBP5 and CD64 in tandem may be the most predictive combination. However, GZMA contribution to the prediction model requires further investigation. Regardless, these three genes show promise as a rapid diagnostic marker separating TB from OPD. PMID:26025597

  14. Tuberculosis: a Re-emerging Disease at the Interface of Domestic Animals and Wildlife

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In the early 20th century there were large numbers of tuberculous cattle in many countries. An association was made between the number of M. bovis infected humans and the prevalence of tuberculosis in cattle. Mandatory pasteurization of milk caused the prevalence of human tuberculosis due to M. bovi...

  15. Role of Metal Ions on the Activity of Mycobacterium tuberculosis Pyrazinamidase

    PubMed Central

    Sheen, Patricia; Ferrer, Patricia; Gilman, Robert H.; Christiansen, Gina; Moreno-Román, Paola; Gutiérrez, Andrés H.; Sotelo, Jun; Evangelista, Wilfredo; Fuentes, Patricia; Rueda, Daniel; Flores, Myra; Olivera, Paula; Solis, José; Pesaresi, Alessandro; Lamba, Doriano; Zimic, Mirko

    2012-01-01

    Pyrazinamidase of Mycobacterium tuberculosis catalyzes the conversion of pyrazinamide to the active molecule pyrazinoic acid. Reduction of pyrazinamidase activity results in a level of pyrazinamide resistance. Previous studies have suggested that pyrazinamidase has a metal-binding site and that a divalent metal cofactor is required for activity. To determine the effect of divalent metals on the pyrazinamidase, the recombinant wild-type pyrazinamidase corresponding to the H37Rv pyrazinamide-susceptible reference strain was expressed in Escherichia coli with and without a carboxy terminal. His-tagged pyrazinamidase was inactivated by metal depletion and reactivated by titration with divalent metals. Although Co2+, Mn2+, and Zn2+ restored pyrazinamidase activity, only Co2+ enhanced the enzymatic activity to levels higher than the wild-type pyrazinamidase. Cu2+, Fe2+, Fe3+, and Mg2+ did not restore the activity under the conditions tested. Various recombinant mutated pyrazinamidases with appropriate folding but different enzymatic activities showed a differential pattern of recovered activity. X-ray fluorescence and atomic absorbance spectroscopy showed that recombinant wild-type pyrazinamidase expressed in E. coli most likely contained Zn. In conclusion, this study suggests that M. tuberculosis pyrazinamidase is a metalloenzyme that is able to coordinate several ions, but in vivo, it is more likely to coordinate Zn2+. However, in vitro, the metal-depleted enzyme could be reactivated by several divalent metals with higher efficiency than Zn. PMID:22764307

  16. Pulmonary Paragonimiasis Mimicking Tuberculosis.

    PubMed

    Prasad, Kj; Basu, Arup; Khana, Shilpi; Wattal, Chand

    2015-08-01

    Paragonimiasis is a disease which is frequently misdiagnosed as pulmonary tuberculosis. In the areas where people eat crab/crayfish this disease should be considered in the differential diagnosis to avoid antituberculosis treatment for a non-tubercular condition. We are reporting a case of pulmonary paragonimiasis who had been treated for tuberculosis. PMID:27604443

  17. Effect of serial subculturing on the genetic composition and cytotoxic activity of Mycobacterium tuberculosis.

    PubMed

    Molina-Torres, C A; Castro-Garza, J; Ocampo-Candiani, J; Monot, M; Cole, S T; Vera-Cabrera, L

    2010-04-01

    Continuous subculture has been observed to produce changes in the virulence of micro-organisms, e.g. rabies virus, poliovirus and Mycobacterium bovis BCG. The latter has been used as a vaccine for tuberculosis for the last 100 years; however, in some instances its efficacy has been observed to be very low. In order to determine whether similar changes can be produced in Mycobacterium tuberculosis, we selected four isolates, M. tuberculosis H37Rv, a Beijing strain (DR-689), and two more isolates with deletion of the phospholipase C locus (plcA-plcB-plcC ), and subjected them to serial culturing on Middlebrook 7H9 medium, with or without ox bile. After 100 passages, we performed RFLP-IS6110 analysis to determine whether genomic changes were produced. We also checked their genomic composition by microarray analysis. Changes in virulence were studied by measuring the cytotoxic effect of parental and subcultured isolates on a THP-1 macrophage monolayer. The most visible change was the change of position of an IS6110 band of approximately 1400 bp to approximately 1600 bp in the Beijing isolate subcultured in the ox bile medium. Analysis by microarray and PCR confirmation did not reveal any genomic changes. Cytotoxic activity was decreased in the isolates at levels close to that of BCG, and more consistently in those subcultured in the presence of ox bile. PMID:20056774

  18. Systematic Survey of Serine Hydrolase Activity in Mycobacterium tuberculosis Defines Changes Associated with Persistence.

    PubMed

    Ortega, Corrie; Anderson, Lindsey N; Frando, Andrew; Sadler, Natalie C; Brown, Robert W; Smith, Richard D; Wright, Aaron T; Grundner, Christoph

    2016-02-18

    The transition from replication to non-replication underlies much of Mycobacterium tuberculosis (Mtb) pathogenesis, as non- or slowly replicating Mtb are responsible for persistence and poor treatment outcomes. Therapeutic targeting of non-replicating populations is a priority for tuberculosis treatment, but few drug targets in non-replicating Mtb are currently known. Here, we directly measured the activity of the highly diverse and druggable serine hydrolases (SHs) during active replication and non-replication using activity-based proteomics. We predict SH activity for 78 proteins, including 27 proteins with unknown function, and identify 37 SHs that remain active in the absence of replication, providing a set of candidate persistence targets. Non-replication was associated with major shifts in SH activity. These activity changes were largely independent of SH abundance, indicating extensive post-translational regulation of SHs. By probing a large cross-section of druggable Mtb enzyme space during replication and non-replication, we identify new SHs and suggest new persistence targets. PMID:26853625

  19. The vital activity of organisms in infralow frequency magnetic field. 4. Mycobacteria tuberculosis

    SciTech Connect

    Khizhenkov, P.K.; Noreiko, B.V.; Lepshina, S.M.

    1995-07-01

    It is shown that a periodic (0.5 or 7 h/day) application of an alternating magnetic field H (f = 8 Hz, amplitude 60-80 Oe) enhances the vital activity of tuberculosis mycobacteria (TMB), which leads to a doubling of the biocycles and a 48-h reduction in the lag-phase. The increase in the functional activity of the TMB is accompanied by a lowering of the their resistance to medication. In the experiment, the TMB exposed to the magnetic field effect completely lost their resistance to three of the four tested medicines.

  20. Study of Genetic Evolution in Mycobacterium tuberculosis Isolates from Patients with Active Pulmonary Tuberculosis in the Iran and Belarus

    PubMed Central

    Bostanabad, Saeed Zaker; Shekarabei, Mehdi; Nojoumi, Seyed Ali; Jabbarzadeh, Esmaeil; Ghalami, Mostafa; Kazemi, Vahid Molla; Beigdeli, Mostafa Gholi; Karim Rahimi, Mohammad; Bossak, Mohammad; Sagalchyk, Evgeni Romanovich; Konstantina Surkova, Larisa; Mikhaelovna Zalutska, Aksana; Slizen, Veronika; Petrovich Titov, Leonid

    2011-01-01

    Objective: This is the new comparative geogenetic molecular evolution research of M. tuberculosis in Iran and Belarus. Thus, we researched the genetic patterns of samples collected in the first survey of anti-tuberculosis drug-resistance by gene coding of RNA polymerase as part of the international project of on tuberculosis. Method: DNA extraction and amplification of rpoB gene was performed. All PCR products of gene were sequenced using the Amersham auto sequencer. For analysing phenogram has been demonstrated by method UPGMA and Neighbour-Joining. Clinical isolates (70/473) were analyzed by using sequencing gene rpoB and genotyped by program DNAMAN and MEGA. Results: The all data were compared with the international database of national center for biotechnology information website. Multi drug resistant of tuberculosis patient (MDR-TB) was 92% in never treated and 8% in previously treated. Mutations in rpoB gene and katG genes were showed in 95% and 84% of the MDR isolates, respectively. Two clusters were found to be identical by the four different analysis methods, presumably representing cases of recent transmission of MDR tuberculosis. The other isolates are divided in Iran into 2 groups: group A – similar to the Eastern strains (China, Taiwan) and group B – strains of another genotype. And 3 groups in Belarus: group A - Strains of the first group are more similar to the standard European and Eastern ones China and Taiwan) which diverged in the last 10 years (Genetic evolution rate), i.e. they are relatively new ones, and that is confirmed by the mutations, group B - Strains of the second group diverged earlier; they are older than the strains of the first group (16 years old- time and rate of evolution) and group C - Strains of the third group are similar to European strains and only circulate in Brest region. They are grouped separately on the phenogram and became prevalent in Iran (they are called Iranian residential strains and also is genetic analogy

  1. Modulation of pro- and anti-inflammatory cytokines in active and latent tuberculosis by coexistent Strongyloides stercoralis infection.

    PubMed

    George, Parakkal Jovvian; Pavan Kumar, Nathella; Jaganathan, Jeeva; Dolla, Chandrakumar; Kumaran, Paul; Nair, Dina; Banurekha, Vaithilingam V; Shen, Kui; Nutman, Thomas B; Babu, Subash

    2015-12-01

    Helminth infections are known to induce modulation of both innate and adaptive immune responses in active and latent tuberculosis (TB). However, the role of helminth infections in modulating systemic cytokine responses in active and latent tuberculosis (LTB) is not known. To define the systemic cytokine levels in helminth-TB coinfection, we measured the circulating plasma levels of Type 1, Type 2, Type 17, other pro-inflammatory and regulatory cytokines in individuals with active TB (ATB) with or without coexistent Strongyloides stercoralis (Ss) infection by multiplex ELISA. Similarly, we also measured the same cytokine levels in individuals with LTB with or without concomitant Ss infection in a cross-sectional study. Our data reveal that individuals with ATB or LTB and coexistent Ss infection have significantly lower levels of Type 1 (IFNγ, TNFα and IL-2) and Type 17 (IL-17A and IL-17F) cytokines compared to those without Ss infection. In contrast, those with ATB and LTB with Ss infection have significantly higher levels of the regulatory cytokines (IL-10 and TGFβ), and those with LTB and Ss infection also have significantly higher levels of Type 2 cytokines (IL-4, IL-5 and IL-13) as well. Finally, those with LTB (but not ATB) exhibit significantly lower levels of other pro-inflammatory cytokines (IFNα, IFNβ, IL-6, IL-12 and GM-CSF). Our data therefore reveal a profound effect of Ss infection on the systemic cytokine responses in ATB and LTB and indicate that coincident helminth infections might influence pathogenesis of TB infection and disease. PMID:26542223

  2. [Tuberculosis in Iceland. 1976].

    PubMed

    Sigurdsson, Sigurdur

    2005-01-01

    Because of signs of tuberculous lesions in old skeletons it can be stated with certainty that tuberculosis has occurred in the country shortly after the settlement. From that time and up to the seventeenth century, little or nothing is known about the occurrence of the disease. A few preserved descriptions of diseases and deaths indicate that tuberculosis has existed in the country before the advent of qualified physicians in 1760. On the basis of papers and reports from the first physicians and the first tuberculosis registers the opinions is set forth that the disease has been rare up to the latter part of the nineteenth century. During the two last decades of that century the disease began to spread more rapidly and increased steadily up to the turn of the century. Although reporting of the disease was started in the last decade of the nineteenth century the reporting was first ordered by law with the passage of the first tuberculosis Act in the year 1903. With this legislation official measures for tuberculosis control work really started in the country. The first sanatorium was built in 1910. In 1921 the tuberculosis Act was revised and since then practically all the expenses for the hospitalization and treatment of tuberculous cases has been defrayed by the state. In the year 1935 organized tuberculosis control work was begun and a special physician appointed to direct it. From then on systematic surveys were made, partly in health centers i.e. tuberculosis clinics, which were established in the main towns, and partly by means of transportable X ray units in outlying rural areas of the country. In 1939 the tuberculosis Act was again revised with special reference to the surveys and the activities of the tuberculosis clinics. This act is still in force. Some items of it are described. The procedure of the surveys and the methods of examination are described. The great majority of subjects were tuberculin tested and all positive reactors X rayed. Furthermore, X

  3. Prevalence of latent tuberculosis infection among health care workers in a hospital for pulmonary diseases

    PubMed Central

    Schablon, Anja; Beckmann, Gudrun; Harling, Melanie; Diel, Roland; Nienhaus, Albert

    2009-01-01

    Background Little is known about the prevalence of latent tuberculosis infections (LTBI) in health care workers (HCW) in low-incidence countries especially in hospitals for pulmonary diseases. With Interferon-gamma release assays (IGRA), a new method for diagnosis of LTBI is available which is more specific than the tuberculin skin test (TST). Objectives The study was designed to estimate prevalence of LTBI among 270 HCW in a Hospital of Pulmonary Diseases routinely screened for TB. Methods LTBI was assessed by the QuantiFERON-Gold In Tube (QFT-IT). Information on gender, age, workplace, job title, BCG vaccination and history of both TB and TST were collected using a standardised questionnaire. Adjusted odds ratios for potential risk factors for LTBI were calculated. Results The prevalence of LTBI was 7.2%. In HCW younger than 30 years LTBI prevalence was 3.5% and in those older than 50 years 22%. Physicians and nurses showed a higher prevalence rate than other professions (10.8% to 4.5%). The putative risk factors for LTBI were age (>50 year OR 9.3, 95%CI 2.5–33.7), working as physicians/nurses (OR 3. 95%CI 1.2–10.4) and no previous TST in medical history (OR 4.4, 95%CI 1.01–18.9) when compared to those with a negative TST. Conclusion Prevalence of LTBI assessed by QFT-IT is low, this indicates a low infection risk even in hospitals for pulmonary diseases. No statement can be made regarding the occupational risk as compared to the general population because there are no LTBI prevalence data from Germany available. The higher LTBI prevalence rate in older HCWs might be due to the cohort effect or the longer time at risk. PMID:19134168

  4. Identification and Characterization of Lipase Activity and Immunogenicity of LipL from Mycobacterium tuberculosis

    PubMed Central

    Cao, Jun; Dang, Guanghui; Li, Huafang; Li, Tiantian; Yue, Zhiguo; Li, Na; Liu, Yajun; Liu, Siguo; Chen, Liping

    2015-01-01

    Lipids and lipid-metabolizing esterases/lipases are highly important for the mycobacterial life cycle and, possibly, for mycobacterial virulence. In this study, we expressed 10 members of the Lip family of Mycobacterium tuberculosis. Among the 10 proteins, LipL displayed a significantly high enzymatic activity for the hydrolysis of long-chain lipids. The optimal temperature for the lipase activity of LipL was demonstrated to be 37°C, and the optimal pH was 8.0. The lipase active center was not the conserved motif G-x-S-x-G, but rather the S-x-x-K and GGG motifs, and the key catalytic amino acid residues were identified as G50, S88, and K91, as demonstrated through site-directed mutagenesis experiments. A three-dimensional modeling structure of LipL was constructed, which showed that the GGG motif was located in the surface of a pocket structure. Furthermore, the subcellular localization of LipL was demonstrated to be on the mycobacterial surface by Western blot analysis. Our results revealed that the LipL protein could induce a strong humoral immune response in humans and activate a CD8+ T cell-mediated response in mice. Overall, our study identified and characterized a novel lipase denoted LipL from M. tuberculosis, and demonstrated that LipL functions as an immunogen that activates both humoral and cell-mediated responses. PMID:26398213

  5. Immunotherapy for tuberculosis: future prospects

    PubMed Central

    Abate, Getahun; Hoft, Daniel F

    2016-01-01

    Tuberculosis (TB) is still a major global health problem. A third of the world’s population is infected with Mycobacterium tuberculosis. Only ~10% of infected individuals develop TB but there are 9 million TB cases with 1.5 million deaths annually. The standard prophylactic treatment regimens for latent TB infection take 3–9 months, and new cases of TB require at least 6 months of treatment with multiple drugs. The management of latent TB infection and TB has become more challenging because of the spread of multidrug-resistant and extremely drug-resistant TB. Intensified efforts to find new TB drugs and immunotherapies are needed. Immunotherapies could modulate the immune system in patients with latent TB infection or active disease, enabling better control of M. tuberculosis replication. This review describes several types of potential immunotherapies with a focus on those which have been tested in humans. PMID:27529060

  6. What's new in tuberculosis vaccines?

    PubMed Central

    Ginsberg, Ann M.

    2002-01-01

    Over the past 10 years, tuberculosis (TB) vaccine development has resurged as an active area of investigation. The renewed interest has been stimulated by the recognition that, although BCG is delivered to approximately 90% of all neonates globally through the Expanded Programme on Immunization, Mycobacterium tuberculosis continues to cause over 8 million new cases of TB and over 2 million deaths annually. Over one hundred TB vaccine candidates have been developed, using different approaches to inducing protective immunity. Candidate vaccines are typically screened in small animal models of primary TB disease for their ability to protect against a virulent strain of M. tuberculosis. The most promising are now beginning to enter human safety trials, marking real progress in this field for the first time in 80 years. PMID:12132007

  7. Miliary tuberculosis disease complicated by Pott's abscess in an infant: Seven year follow-up

    PubMed Central

    Bayhan, Gulsum Iclal; Tanir, Gonul; Gayretli Aydın, Zeynep Gokce; Yildiz, Yasemin Tasci

    2015-01-01

    A 20-month-old boy presented with 1-year history of persistent fever, cough, and progressive abdominal distention. Abdominal ultrasonography showed hepatomegaly and multiple calcifications in the liver and spleen. Thoracic computed tomography showed multiple mediastinal lymph nodes and consolidation in both lungs. Additionally, there was a 2-cm thick retroperitoneal soft tissue mass destroying the T7-8 and L1-L2 vertebral bodies. The patient was preliminarily diagnosed with miliary tuberculosis (TB) and Pott's disease, and began administering anti-TB treatment consisting of isoniazid, rifampin, ethambutol, and pyrazinamide. Acid-resistant bacilli analysis and mycobacterial culture of the biopsy specimen of Pott's abscess were positive. Mycobacterial culture and PCR of gastric aspirate were also positive. The patient's condition progressively improved with anti-TB treatment and he received 12 months of antiTB therapy. At the end of the treatment all of the patient's symptoms were relieved and he was well except for kyphosis. Miliary TB complicated by Pott's abscess is a very rare presentation of childhood TB. The presented case shows that when Pott's abscess is diagnosed and surgically corrected without delay, patients can recover without squeal. PMID:25983412

  8. Population dynamics and tuberculosis: a cross sectional study of an overlooked disease in Saudi Arabia

    PubMed Central

    Al-Bishri, Jamal; Masoodi, Ibrahim; Adnan, Mubarki; Tariq, Malik; Abdullah, Harthi; Abdulgoni, Thubaiti; Bander, Guraibi; Altalhi, Mansoor

    2014-01-01

    Background: International travel, migration and human population movements facilitate the spread of tuberculosis (TB). Objective: To study the impact of poorly screened expatriates working in Saudi Arabia on the local incidence of TBs. Patients and methods: This cross sectional study was carried out in the Chest Disease Hospital, Taif. All confirmed cases of TB from June 2009 to May 2010 admitted to the hospital were enrolled. Inclusion criteria were diagnosed cases of TB (pulmonary & extra-pulmonary) in patients between the ages of 14 to 65 years. Patients with HIV and coexistent malignancies were excluded. The age, gender and ethnic group of each patient was recorded, and patients were divided into two groups. Of the two groups, Group A consisted of Taif residents and group B of patients referred from other cities in the country. Results: Of the 686 cases studied, 370 (54%) were Saudi nationals (Group A = 80 & Group B = 290) and 316 (46%) cases were from other countries. Males outnumbered females and most of the patients were aged 20 to 29 years. The number of cases from the areas close to the pilgrimage sites, i.e. Makah (233) and Jeddah (275), outnumbered those in Taif (110). Conclusions: Our study identifies an increased prevalence of TB cases in areas close to the pilgrimage (Group B). The higher proportion of non-Saudi TB patients in group B is most likely explained by the higher number of poorly screened illegal expatriates in the region. PMID:24454274

  9. NLRP3 Activation Was Regulated by DNA Methylation Modification during Mycobacterium tuberculosis Infection

    PubMed Central

    Wei, Meili; Wang, Lu; Wu, Tao; Xi, Jun; Han, Yuze; Yang, Xingxiang; Zhang, Ding; Fang, Qiang

    2016-01-01

    Mycobacterium tuberculosis (Mtb) infection activates the NLRP3 inflammasome in macrophages and dendritic cells. Much attention has been paid to the mechanisms for regulation of NLRP3 against Mtb. However, whether epigenetic mechanisms participated in NLRP3 activation is still little known. Here we showed that NLRP3 activation was regulated by DNA methylation modification. Mtb infection promoted NLRP3 activation and inflammatory cytokines expression. NLRP3 promoter was cloned and subsequently identified by Dual-Luciferase Reporter System. The results showed that NLRP3 promoter activity was decreased after methylation by DNA methylase Sss I in vitro. Meanwhile, DNA methyltransferases inhibitor DAC could upregulate the expression of NLRP3. Furthermore, promoter region of NLRP3 gene was demethylated after Mtb H37Rv strain infection. These data revealed that DNA methylation was involved in NLRP3 inflammasome activation during Mtb infection and provided a new insight into the relationship between host and pathogens. PMID:27366746

  10. TUBERCULOSIS AND LUNG CANCER.

    PubMed

    Tamura, Atsuhisa

    2016-01-01

    The occurrence of pulmonary tuberculosis (PTB) and lung cancer as comorbidities has been extensively discussed in many studies. In the past, it was well known that lung cancer is a specific epidemiological successor of PTB and that lung cancer often develops in scars caused by PTB. In recent years, the relevance of the two diseases has drawn attention in terms of the close epidemiological connection and chronic inflammation-associated carcinogenesis. In Japanese case series studies, most lung cancer patients with tuberculous sequelae received supportive care alone in the past, but more recently, the use of aggressive lung cancer treatment is increasing. Many studies on PTB and lung cancer as comorbidities have revealed that active PTB is noted in 2-5% of lung cancer cases, whereas lung cancer is noted in 1-2% of active PTB cases. In such instances of comorbidity, many active PTB cases showed Type II (non-extensively cavitary disease) and Spread 2-3 (intermediate-extensive diseases) on chest X-rays, but standard anti-tuberculosis treatment easily eradicates negative conversion of sputum culture for M. tuberculosis; lung cancer cases were often stage III- IV and squamous cell carcinoma predominant, and the administration of aggressive treatment for lung cancer is increasing. The major clinical problems associated with PTB and lung cancer as comorbidities include delay in diagnosis (doctor's delay) and therapeutic limitations. The former involves two factors of radiographic interpretation: the principles of parsimony (Occam's razor) and visual search; the latter involves three factors of lung cancer treatment: infectivity of M.tuberculosis, anatomical limitation due to lung damage by tuberculosis, and drug-drug interactions between rifampicin and anti-cancer drugs, especially molecularly targeted drugs. The comorbidity of these two diseases is an important health-related issue in Japan. In the treatment of PTB, the possibility of concurrent lung cancer should be kept

  11. Validation of the BrockTB Stat-Pak Assay for Detection of Tuberculosis in Eurasian Badgers (Meles meles) and Influence of Disease Severity on Diagnostic Accuracy▿

    PubMed Central

    Chambers, Mark A.; Crawshaw, Tim; Waterhouse, Sue; Delahay, Richard; Hewinson, R. Glyn; Lyashchenko, Konstantin P.

    2008-01-01

    A lateral-flow immunoassay (BrockTB Stat-Pak) for detecting tuberculosis in Eurasian badgers was 49% sensitive and 93% specific against culture for M. bovis (n = 1,464) at necropsy. However, the sensitivity was significantly higher (66 to 78%) in animals with more severe tuberculosis, indicating that the BrockTB Stat-Pak may be useful for the detection of badgers with the greatest risk of transmitting disease. PMID:18272706

  12. Mycobacterium tuberculosis produces pili during human infection

    PubMed Central

    Alteri, Christopher J.; Xicohténcatl-Cortes, Juan; Hess, Sonja; Caballero-Olín, Guillermo; Girón, Jorge A.; Friedman, Richard L.

    2007-01-01

    Mycobacterium tuberculosis is responsible for nearly 3 million human deaths worldwide every year. Understanding the mechanisms and bacterial factors responsible for the ability of M. tuberculosis to cause disease in humans is critical for the development of improved treatment strategies. Many bacterial pathogens use pili as adherence factors to colonize the host. We discovered that M. tuberculosis produces fine (2- to 3-nm-wide), aggregative, flexible pili that are recognized by IgG antibodies contained in sera obtained from patients with active tuberculosis, indicating that the bacilli produce pili or pili-associated antigen during human infection. Purified M. tuberculosis pili (MTP) are composed of low-molecular-weight protein subunits encoded by the predicted M. tuberculosis H37Rv ORF, designated Rv3312A. MTP bind to the extracellular matrix protein laminin in vitro, suggesting that MTP possess adhesive properties. Isogenic mtp mutants lost the ability to produce Mtp in vitro and demonstrated decreased laminin-binding capabilities. MTP shares morphological, biochemical, and functional properties attributed to bacterial pili, especially with curli amyloid fibers. Thus, we propose that MTP are previously unidentified host-colonization factors of M. tuberculosis. PMID:17360408

  13. A Survey of Texas HIV, Sexually Transmitted Disease, Tuberculosis, and Viral Hepatitis Providers' Billing and Reimbursement Capabilities.

    PubMed

    Flynn, Matthew B; Atwood, Robin; Greenberg, Jennifer B; Ray, Tara; Harris, Karol Kaye

    2015-11-01

    The Affordable Care Act presents financial challenges and opportunities for publicly funded service providers. We assessed billing practices and anticipated barriers to third-party billing among organizations in Texas that provide publicly funded HIV, sexually transmitted diseases, tuberculosis, and viral hepatitis services. One third to one half of the organizations did not bill for medical services. The most common barrier to third-party billing was lack of staff knowledge about billing and coding. Future research must evaluate options for organizations and communities to maintain access to infectious disease services for vulnerable populations. PMID:26447911

  14. A Survey of Texas HIV, Sexually Transmitted Disease, Tuberculosis, and Viral Hepatitis Providers’ Billing and Reimbursement Capabilities

    PubMed Central

    Atwood, Robin; Greenberg, Jennifer B.; Ray, Tara; Harris, Karol Kaye

    2015-01-01

    The Affordable Care Act presents financial challenges and opportunities for publicly funded service providers. We assessed billing practices and anticipated barriers to third-party billing among organizations in Texas that provide publicly funded HIV, sexually transmitted diseases, tuberculosis, and viral hepatitis services. One third to one half of the organizations did not bill for medical services. The most common barrier to third-party billing was lack of staff knowledge about billing and coding. Future research must evaluate options for organizations and communities to maintain access to infectious disease services for vulnerable populations. PMID:26447911

  15. Activity against Mycobacterium smegmatis and M. tuberculosis by extract of South African medicinal plants.

    PubMed

    Mativandlela, Sannah Patience Nkami; Meyer, Jacob Jacobus Marion; Hussein, Ahmed A; Houghton, Peter J; Hamilton, Chris J; Lall, Namrita

    2008-06-01

    Seven ethnobotanically selected medicinal plants were screened for their antimycobacterial activity. The minimum inhibitory concentration (MIC) of four plants namely Artemisia afra, Dodonea angustifolia, Drosera capensis and Galenia africana ranged from 0.781 to 6.25 mg/mL against Mycobacterium smegmatis. G. africana showed the best activity exhibiting an MIC of 0.78 mg/mL and a minimum bactericidal concentration (MBC) of 1.56 mg/mL. The MICs of ethanol extracts of D. angustifolia and G. africana against M. tuberculosis were found to be 5.0 and 1.2 mg/mL respectively. The mammalian cytotoxicity IC(50) value of the most active antimycobacterial extract, from G. africana, was found to be 101.3 microg/mL against monkey kidney Vero cells. Since the ethanol G. africana displayed the best antimycobacterial activity, it was subjected to fractionation which led to the isolation of a flavone, 5,7,2'-trihydroxyflavone. The MIC of this compound was found to be 0.031 mg/mL against M. smegmatis and 0.10 mg/mL against M. tuberculosis. This study gives some scientific basis to the traditional use of these plants for TB-related symptoms. PMID:18412151

  16. The active site architecture in peroxiredoxins: a case study on Mycobacterium tuberculosis AhpE.

    PubMed

    Pedre, Brandán; van Bergen, Laura A H; Palló, Anna; Rosado, Leonardo A; Dufe, Veronica Tamu; Molle, Inge Van; Wahni, Khadija; Erdogan, Huriye; Alonso, Mercedes; Proft, Frank De; Messens, Joris

    2016-08-11

    Peroxiredoxins catalyze the reduction of peroxides, a process of vital importance to survive oxidative stress. A nucleophilic cysteine, also known as the peroxidatic cysteine, is responsible for this catalytic process. We used the Mycobacterium tuberculosis alkyl hydroperoxide reductase E (MtAhpE) as a model to investigate the effect of the chemical environment on the specificity of the reaction. Using an integrative structural (R116A - PDB ; F37H - PDB ), kinetic and computational approach, we explain the mutational effects of key residues in its environment. This study shows that the active site residues are specifically oriented to create an environment which selectively favours a reaction with peroxides. PMID:27471753

  17. Meropenem-Clavulanic Acid Shows Activity against Mycobacterium tuberculosis In Vivo

    PubMed Central

    England, Kathleen; Boshoff, Helena I. M.; Arora, Kriti; Weiner, Danielle; Dayao, Emmanuel; Schimel, Daniel; Via, Laura E.

    2012-01-01

    The carbapenems imipenem and meropenem in combination with clavulanic acid reduced the bacterial burden in Mycobacterium tuberculosis-infected macrophages by 2 logs over 6 days. Despite poor stability in solution and a short half-life in rodents, treatment of chronically infected mice revealed significant reductions of bacterial burden in the lungs and spleens. Our results show that meropenem has activity in two in vivo systems, but stability and pharmacokinetics of long-term administration will offer significant challenges to clinical evaluation. PMID:22450968

  18. Synthesis and Anti-Tuberculosis Activity of the Marine Natural Product Caulerpin and Its Analogues

    PubMed Central

    Canché Chay, Cristina I.; Gómez Cansino, Rocío; Espitia Pinzón, Clara I.; Torres-Ochoa, Rubén O.; Martínez, Roberto

    2014-01-01

    Caulerpin (1a), a bis-indole alkaloid from the marine algal Caulerpa sp., was synthesized in three reaction steps with an overall yield of 11%. The caulerpin analogues (1b–1g) were prepared using the same synthetic pathway with overall yields between 3% and 8%. The key reaction involved a radical oxidative aromatic substitution involving xanthate (3) and 3-formylindole compounds (4a–4g). All bis-indole compounds synthesized were evaluated against the Mycobacterium tuberculosis strain H37Rv, and 1a was found to display excellent activity (IC50 0.24 µM). PMID:24681629

  19. Tuberculosis in Children

    PubMed Central

    Marais, Ben J.; Schaaf, H. Simon

    2014-01-01

    Many clinicians regard tuberculosis as an adult pulmonary disease, but tuberculosis (TB) is a major cause of disease, both pulmonary and extrapulmonary, and death in young children from TB-endemic countries, especially in areas affected by poverty, social disruption, and human immunodeficiency virus (HIV) infection. This article reviews the disease burden and the natural history of disease in children with TB. It also provides guidance regarding the diagnosis, treatment, and prevention of TB in children. PMID:25037105

  20. Tuberculosis in children.

    PubMed

    Marais, Ben J; Schaaf, H Simon

    2014-09-01

    Many clinicians regard tuberculosis as an adult pulmonary disease, but tuberculosis (TB) is a major cause of disease, both pulmonary and extrapulmonary, and death in young children from TB-endemic countries, especially in areas affected by poverty, social disruption, and human immunodeficiency virus (HIV) infection. This article reviews the disease burden and the natural history of disease in children with TB. It also provides guidance regarding the diagnosis, treatment, and prevention of TB in children. PMID:25037105

  1. Tuberculosis and nutrition

    PubMed Central

    Gupta, Krishna Bihari; Gupta, Rajesh; Atreja, Atulya; Verma, Manish; Vishvkarma, Suman

    2009-01-01

    Malnutrition and tuberculosis are both problems of considerable magnitude in most of the underdeveloped regions of the world. These two problems tend to interact with each other. Tuberculosis mortality rates in different economic groups in a community tend to vary inversely with their economic levels. Similarly, nutritional status is significantly lower in patients with active tuberculosis compared with healthy controls. Malnutrition can lead to secondary immunodeficiency that increases the host's susceptibility to infection. In patients with tuberculosis, it leads to reduction in appetite, nutrient malabsorption, micronutrient malabsorption, and altered metabolism leading to wasting. Both, protein-energy malnutrition and micronutrients deficiencies increase the risk of tuberculosis. It has been found that malnourished tuberculosis patients have delayed recovery and higher mortality rates than well-nourished patients. Nutritional status of patients improves during tuberculosis chemotherapy. High prevalence of human immunodeficiency (HIV) infection in the underdeveloped countries further aggravates the problem of malnutrition and tuberculosis. Effect of malnutrition on childhood tuberculosis and tuberculin skin test are other important considerations. Nutritional supplementation may represent a novel approach for fast recovery in tuberculosis patients. In addition, raising nutritional status of population may prove to be an effective measure to control tuberculosis in underdeveloped areas of world. PMID:20165588

  2. The cytosolic sensor cGAS detects Mycobacterium tuberculosis DNA to induce type I interferons and activate autophagy

    PubMed Central

    MacDuff, Donna A.; Kimmey, Jacqueline M.; Diner, Elie J.; Olivas, Joanna; Vance, Russell E.; Stallings, Christina L.; Virgin, Herbert W.; Cox, Jeffery S.

    2015-01-01

    Summary Type I interferons (IFNs) are critical mediators of antiviral defense, but their elicitation by bacterial pathogens can be detrimental to hosts. Many intracellular bacterial pathogens, including Mycobacterium tuberculosis, induce type I IFNs following phagosomal membrane perturbations. Cytosolic M. tuberculosis DNA has been implicated as a trigger for IFN production, but the mechanisms remain obscure. We report that the cytosolic DNA sensor, cyclic GMP-AMP synthase (cGAS), is required for activating IFN production via the STING/TBK1/IRF3 pathway during M. tuberculosis and L. pneumophila infection of macrophages, whereas L. monocytogenes short-circuits this pathway by producing the STING agonist, c-di-AMP. Upon sensing cytosolicDNA, cGAS also activates cell-intrinsic antibacterial defenses, promoting autophagic targeting of M. tuberculosis. Importantly, we show that cGAS binds M. tuberculosis DNA during infection, providing direct evidence that this unique host-pathogen interaction occurs in vivo. These data uncover a mechanism by which IFN is likely elicited during active human infections. PMID:26048136

  3. The Cytosolic Sensor cGAS Detects Mycobacterium tuberculosis DNA to Induce Type I Interferons and Activate Autophagy.

    PubMed

    Watson, Robert O; Bell, Samantha L; MacDuff, Donna A; Kimmey, Jacqueline M; Diner, Elie J; Olivas, Joanna; Vance, Russell E; Stallings, Christina L; Virgin, Herbert W; Cox, Jeffery S

    2015-06-10

    Type I interferons (IFNs) are critical mediators of antiviral defense, but their elicitation by bacterial pathogens can be detrimental to hosts. Many intracellular bacterial pathogens, including Mycobacterium tuberculosis, induce type I IFNs following phagosomal membrane perturbations. Cytosolic M. tuberculosis DNA has been implicated as a trigger for IFN production, but the mechanisms remain obscure. We report that the cytosolic DNA sensor, cyclic GMP-AMP synthase (cGAS), is required for activating IFN production via the STING/TBK1/IRF3 pathway during M. tuberculosis and L. pneumophila infection of macrophages, whereas L. monocytogenes short-circuits this pathway by producing the STING agonist, c-di-AMP. Upon sensing cytosolic DNA, cGAS also activates cell-intrinsic antibacterial defenses, promoting autophagic targeting of M. tuberculosis. Importantly, we show that cGAS binds M. tuberculosis DNA during infection, providing direct evidence that this unique host-pathogen interaction occurs in vivo. These data uncover a mechanism by which IFN is likely elicited during active human infections. PMID:26048136

  4. Virulence factors of the Mycobacterium tuberculosis complex

    PubMed Central

    Forrellad, Marina A.; Klepp, Laura I.; Gioffré, Andrea; Sabio y García, Julia; Morbidoni, Hector R.; Santangelo, María de la Paz; Cataldi, Angel A.; Bigi, Fabiana

    2013-01-01

    The Mycobacterium tuberculosis complex (MTBC) consists of closely related species that cause tuberculosis in both humans and animals. This illness, still today, remains to be one of the leading causes of morbidity and mortality throughout the world. The mycobacteria enter the host by air, and, once in the lungs, are phagocytated by macrophages. This may lead to the rapid elimination of the bacillus or to the triggering of an active tuberculosis infection. A large number of different virulence factors have evolved in MTBC members as a response to the host immune reaction. The aim of this review is to describe the bacterial genes/proteins that are essential for the virulence of MTBC species, and that have been demonstrated in an in vivo model of infection. Knowledge of MTBC virulence factors is essential for the development of new vaccines and drugs to help manage the disease toward an increasingly more tuberculosis-free world. PMID:23076359

  5. The MprB Extracytoplasmic Domain Negatively Regulates Activation of the Mycobacterium tuberculosis MprAB Two-Component System

    PubMed Central

    Bretl, Daniel J.; Bigley, Tarin M.; Terhune, Scott S.

    2014-01-01

    Mycobacterium tuberculosis is an acid-fast pathogen of humans and the etiological agent of tuberculosis (TB). It is estimated that one-third of the world's population is latently (persistently) infected with M. tuberculosis. M. tuberculosis persistence is regulated, in part, by the MprAB two-component signal transduction system, which is activated by and mediates resistance to cell envelope stress. Here we identify MprAB as part of an evolutionarily conserved cell envelope stress response network and demonstrate that MprAB-mediated signal transduction is negatively regulated by the MprB extracytoplasmic domain (ECD). In particular, we report that deregulated production of the MprB sensor kinase, or of derivatives of this protein, negatively impacts M. tuberculosis growth. The observed growth attenuation is dependent on MprAB-mediated signal transduction and is exacerbated in strains of M. tuberculosis producing an MprB variant lacking its ECD. Interestingly, full-length MprB, and the ECD of MprB specifically, immunoprecipitates the Hsp70 chaperone DnaK in vivo, while overexpression of dnaK inhibits MprAB-mediated signal transduction in M. tuberculosis grown in the absence or presence of cell envelope stress. We propose that under nonstress conditions, or under conditions in which proteins present in the extracytoplasmic space are properly folded, signaling through the MprAB system is inhibited by the MprB ECD. Following exposure to cell envelope stress, proteins present in the extracytoplasmic space become unfolded or misfolded, leading to removal of the ECD-mediated negative regulation of MprB and subsequent activation of MprAB. PMID:24187094

  6. Lung surfactant dysfunction in tuberculosis: effect of mycobacterial tubercular lipids on dipalmitoylphosphatidylcholine surface activity.

    PubMed

    Chimote, G; Banerjee, R

    2005-11-10

    In pulmonary tuberculosis, Mycobacterium tuberculosis bacteria reside in the alveoli and are in close proximity with the alveolar surfactant. Mycolic acid in its free form and as cord factor, constitute the major lipids of the mycobacterial cell wall. They can detach from the bacteria easily and are known to be moderately surface active. We hypothesize that these surface-active mycobacterial cell wall lipids could interact with the pulmonary surfactant and result in lung surfactant dysfunction. In this study, the major phospholipid of the lung surfactant, dipalmitoylphosphatidylcholine (DPPC) and binary mixtures of DPPC:phosphatidylglycerol (PG) in 9:1 and 7:3 ratios were modelled as lung surfactant monolayers and the inhibitory potential of mycolic acid and cord factor on the surface activity of DPPC and DPPC:PG mixtures was evaluated using Langmuir monolayers. The mycobacterial lipids caused common profile changes in all the isotherms: increase in minimum surface tension, compressibility and percentage area change required for change in surface tension from 30 to 10 mN/m. Higher minimum surface tension values were achieved in the presence of mycolic acid (18.2+/-0.7 mN/m) and cord factor (13.28+/-1.2 mN/m) as compared to 0 mN/m, achieved by pure DPPC film. Similarly higher values of compressibility (0.375+/-0.005 m/mN for mycolic acid:DPPC and 0.197+/-0.003 m/mN for cord factor:DPPC monolayers) were obtained in presence of mycolic acid and cord factor. Thus, mycolic acid and cord factor were said to be inhibitory towards lung surfactant phospholipids. Higher surface tension and compressibility values in presence of tubercular lipids are suggestive of an unstable and fluid surfactant film, which will fail to achieve low surface tensions and can contribute to alveolar collapse in patients suffering from pulmonary tuberculosis. In conclusion a biophysical inhibition of lung surfactant may play a role in the pathogenesis of tuberculosis and may serve as a target for

  7. Tuberculosis-resistant transgenic cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tuberculosis is a devastating disease that affects humans and many animal species. In humans, tuberculosis (TB) is mainly caused by Mycobacterium tuberculosis, while most cases in cattle are caused by Mycobacterium bovis. However, Mb can also cause, albeit rarely, human TB. In this issue, Wu et al. ...

  8. Systematic Expression Profiling Analysis Identifies Specific MicroRNA-Gene Interactions that May Differentiate between Active and Latent Tuberculosis Infection

    PubMed Central

    Wu, Lawrence Shih-Hsin; Huang, Kai-Yao; Lee, Tzong-Yi; Hsu, Paul Wei-Che

    2014-01-01

    Tuberculosis (TB) is the second most common cause of death from infectious diseases. About 90% of those infected are asymptomatic—the so-called latent TB infections (LTBI), with a 10% lifetime chance of progressing to active TB. To further understand the molecular pathogenesis of TB, several molecular studies have attempted to compare the expression profiles between healthy controls and active TB or LTBI patients. However, the results vary due to diverse genetic backgrounds and study designs and the inherent complexity of the disease process. Thus, developing a sensitive and efficient method for the detection of LTBI is both crucial and challenging. For the present study, we performed a systematic analysis of the gene and microRNA profiles of healthy individuals versus those affected with TB or LTBI. Combined with a series of in silico analysis utilizing publicly available microRNA knowledge bases and published literature data, we have uncovered several microRNA-gene interactions that specifically target both the blood and lungs. Some of these molecular interactions are novel and may serve as potential biomarkers of TB and LTBI, facilitating the development for a more sensitive, efficient, and cost-effective diagnostic assay for TB and LTBI for the Taiwanese population. PMID:25276827

  9. Association Between Tuberculosis and Parkinson Disease: A Nationwide, Population-Based Cohort Study.

    PubMed

    Shen, Chih-Hao; Chou, Chung-Hsing; Liu, Feng-Cheng; Lin, Te-Yu; Huang, Wen-Yen; Wang, Yu-Chiao; Kao, Chia-Hung

    2016-02-01

    Few studies have investigated the association between tuberculosis (TB) and Parkinson disease (PD). This nationwide, population-based, retrospective cohort study investigated the risk of PD in patients with TB.We selected patients newly diagnosed with TB (International Classification of Diseases, Ninth Revision, Clinical Modification: 011) from 2000 to 2009 in the Taiwan National Health Insurance Database as the TB cohort. The comparison cohort (the non-TB cohort) was frequency matched to the TB cohort at a ratio of 4:1 by sex, age, and the index date. We analyzed the risks of PD by using Cox proportional hazard regression models.A total of 121,951 patients with TB and 487,800 non-TB controls were enrolled in this study. The TB cohort had a 1.38-fold risk of PD compared with the non-TB cohort after adjustment for age, sex, and comorbidities (aHR, 95% CI: 1.30-1.46). The adjusted risk of PD in the TB and non-TB cohorts increased in subgroups regardless of age, sex, and comorbidities. Combined effect of TB and comorbidities on the risk of PD were significant in patients with TB who had diabetes (aHR: 2.26, 95% CI: 2.02-2.52), hypertension (aHR: 2.23, 95% CI: 2.04-2.44), head injury (aHR: 2.32, 95% CI: 1.95-2.77), chronic kidney disease (aHR: 2.02, 95% CI: 1.49-2.72), chronic obstructive pulmonary disease (aHR: 1.84, 95% CI: 1.66-2.05), depression (aHR: 4.66, 95% CI: 3.59-6.05), dementia (aHR: 3.70, 95% CI: 2.99-4.59), and stroke (aHR: 2.56, 95% CI: 2.28-2.87). The risk of PD was higher in a follow-up within 1 year (aHR: 1.78, 95% CI: 1.58-2.00) and decreased with the follow-up period in the TB cohort.Patients with TB have an independently 1.38-fold risk of PD. The risk of PD decreased with the follow-up period in the TB cohort. Physicians should be aware of the risk of PD in patients with TB when treating such patients. PMID:26937925

  10. Epidemiology and clinical management of tuberculosis in children in Canada

    PubMed Central

    Morris, Shaun K; Demers, Anne-Marie; Lam, Ray; Pell, Lisa G; Giroux, Ryan JP; Kitai, Ian

    2015-01-01

    Although often regarded as a foreign disease, latent tuberculosis or tuberculosis disease will be encountered in many clinical situations by the Canadian child health practitioner. There are key differences between tuberculosis in children and adults. In the present article, the changing epidemiology of tuberculosis in children in Canada and around the world, the pathogenesis of infection, diagnostic tests, and clinical management of childhood latent tuberculosis and tuberculosis disease are reviewed. PMID:25838781

  11. Heterogeneous disease progression and treatment response in a C3HeB/FeJ mouse model of tuberculosis

    PubMed Central

    Lanoix, Jean-Philippe; Lenaerts, Anne J.; Nuermberger, Eric L.

    2015-01-01

    ABSTRACT Mice are the most commonly used species for non-clinical evaluations of drug efficacy against tuberculosis (TB). Unlike commonly used strains, C3HeB/FeJ mice develop caseous necrosis in the lung, which might alter the representation of drug efficacy in a way that is more like human TB. Because the development of such pathology requires time, we investigated the effect of infection incubation period on the activity of six drugs in C3HeB/FeJ and BALB/c mice. Mice were aerosol infected and held for 6, 10 or 14 weeks before receiving therapy with rifampin (RIF), rifapentine (RPT), pyrazinamide (PZA), linezolid (LZD), sutezolid (PNU) or metronidazole (MTZ) for 4-8 weeks. Outcomes included pathological assessments, pH measurements of liquefied caseum and assessment of colony-forming unit (CFU) counts from lung cultures. Remarkable heterogeneity in the timing and extent of disease progression was observed in C3HeB/FeJ mice, largely independent of incubation period. Likewise, drug efficacy in C3HeB/FeJ mice was not affected by incubation period. However, for PZA, LZD and PNU, dichotomous treatment effects correlating with the presence or absence of large caseous lesions were observed. In the case of PZA, its poor activity in the subset of C3HeB/FeJ mice with large caseous lesions might be explained by the pH of 7.36±0.09 measured in liquefied caseum. This study highlights the potential value of C3HeB/FeJ mice for non-clinical efficacy testing, especially for investigating the interaction of lesion pathology and drug effect. Careful use of this model could enhance the bridging of non-clinical results with clinical outcomes. PMID:26035868

  12. Heterogeneous disease progression and treatment response in a C3HeB/FeJ mouse model of tuberculosis.

    PubMed

    Lanoix, Jean-Philippe; Lenaerts, Anne J; Nuermberger, Eric L

    2015-06-01

    Mice are the most commonly used species for non-clinical evaluations of drug efficacy against tuberculosis (TB). Unlike commonly used strains, C3HeB/FeJ mice develop caseous necrosis in the lung, which might alter the representation of drug efficacy in a way that is more like human TB. Because the development of such pathology requires time, we investigated the effect of infection incubation period on the activity of six drugs in C3HeB/FeJ and BALB/c mice. Mice were aerosol infected and held for 6, 10 or 14 weeks before receiving therapy with rifampin (RIF), rifapentine (RPT), pyrazinamide (PZA), linezolid (LZD), sutezolid (PNU) or metronidazole (MTZ) for 4-8 weeks. Outcomes included pathological assessments, pH measurements of liquefied caseum and assessment of colony-forming unit (CFU) counts from lung cultures. Remarkable heterogeneity in the timing and extent of disease progression was observed in C3HeB/FeJ mice, largely independent of incubation period. Likewise, drug efficacy in C3HeB/FeJ mice was not affected by incubation period. However, for PZA, LZD and PNU, dichotomous treatment effects correlating with the presence or absence of large caseous lesions were observed. In the case of PZA, its poor activity in the subset of C3HeB/FeJ mice with large caseous lesions might be explained by the pH of 7.36±0.09 measured in liquefied caseum. This study highlights the potential value of C3HeB/FeJ mice for non-clinical efficacy testing, especially for investigating the interaction of lesion pathology and drug effect. Careful use of this model could enhance the bridging of non-clinical results with clinical outcomes. PMID:26035868

  13. Ion Channel Blockers as Antimicrobial Agents, Efflux Inhibitors, and Enhancers of Macrophage Killing Activity against Drug Resistant Mycobacterium tuberculosis

    PubMed Central

    Perdigão, João; Couto, Isabel; Portugal, Isabel; Martins, Marta; Amaral, Leonard; Anes, Elsa; Viveiros, Miguel

    2016-01-01

    Given the ability of M. tuberculosis to survive as an intracellular pathogen and its propensity to develop resistance to the existing antituberculosis drugs, its treatment requires new approaches. Here the antimycobacterial properties of verapamil, thioridazine, chlorpromazine, flupenthixol and haloperidol were investigated against a panel of drug resistant M. tuberculosis strains, both in vitro and on human-infected macrophages. These compounds are efflux inhibitors that share among them the characteristic of being ion channel blockers. In vitro, all compounds exhibited synergistic inhibitory activities when combined with isoniazid and rifampicin, and were able to inhibit active efflux, demonstrating their role as efflux inhibitors. Gene expression analysis showed that M. tuberculosis efflux genes were overexpressed in response to antibiotic exposure, in vitro and within macrophages, irrespective of their resistance pattern. These compounds displayed a rapid and high killing activity against M. tuberculosis, associated with a decrease in intracellular ATP levels demonstrating that the bactericidal action of the ion channel blockers against M. tuberculosis clinical strains is associated with their interference with energy metabolism. The compounds led to a decrease in the intracellular mycobacterial load by increasing phagosome acidification and activating lysosomal hydrolases. The results presented in this study enable us to propose the following mechanism of action for these compounds: a) in the bacteria, the compounds generate a cascade of events involving the inhibition of the respiratory chain complexes and energy production for efflux activity. Indirectly, this reduce the resistance level to antituberculosis drugs potentiating their activity; b) on the host cell, the treatment with the ion channel blockers increases phagosome acidification and induces the expression of phagosomal hydrolases, leading to bacterial growth restriction irrespective of their

  14. Ion Channel Blockers as Antimicrobial Agents, Efflux Inhibitors, and Enhancers of Macrophage Killing Activity against Drug Resistant Mycobacterium tuberculosis.

    PubMed

    Machado, Diana; Pires, David; Perdigão, João; Couto, Isabel; Portugal, Isabel; Martins, Marta; Amaral, Leonard; Anes, Elsa; Viveiros, Miguel

    2016-01-01

    Given the ability of M. tuberculosis to survive as an intracellular pathogen and its propensity to develop resistance to the existing antituberculosis drugs, its treatment requires new approaches. Here the antimycobacterial properties of verapamil, thioridazine, chlorpromazine, flupenthixol and haloperidol were investigated against a panel of drug resistant M. tuberculosis strains, both in vitro and on human-infected macrophages. These compounds are efflux inhibitors that share among them the characteristic of being ion channel blockers. In vitro, all compounds exhibited synergistic inhibitory activities when combined with isoniazid and rifampicin, and were able to inhibit active efflux, demonstrating their role as efflux inhibitors. Gene expression analysis showed that M. tuberculosis efflux genes were overexpressed in response to antibiotic exposure, in vitro and within macrophages, irrespective of their resistance pattern. These compounds displayed a rapid and high killing activity against M. tuberculosis, associated with a decrease in intracellular ATP levels demonstrating that the bactericidal action of the ion channel blockers against M. tuberculosis clinical strains is associated with their interference with energy metabolism. The compounds led to a decrease in the intracellular mycobacterial load by increasing phagosome acidification and activating lysosomal hydrolases. The results presented in this study enable us to propose the following mechanism of action for these compounds: a) in the bacteria, the compounds generate a cascade of events involving the inhibition of the respiratory chain complexes and energy production for efflux activity. Indirectly, this reduce the resistance level to antituberculosis drugs potentiating their activity; b) on the host cell, the treatment with the ion channel blockers increases phagosome acidification and induces the expression of phagosomal hydrolases, leading to bacterial growth restriction irrespective of their

  15. Cationic amphipathic D-enantiomeric antimicrobial peptides with in vitro and ex vivo activity against drug-resistant Mycobacterium tuberculosis.

    PubMed

    Lan, Yun; Lam, Jason T; Siu, Gilman K H; Yam, Wing Cheong; Mason, A James; Lam, Jenny K W

    2014-12-01

    Tuberculosis (TB) is the leading cause of bacterial death worldwide. Due to the emergence of multi-drug resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), and the persistence of latent infections, a safe and effective TB therapy is highly sought after. Antimicrobial peptides (AMPs) have therapeutic potential against infectious diseases and have the ability to target microbial pathogens within eukaryotic cells. In the present study, we investigated the activity of a family of six AMPs containing all-D amino acids (D-LAK peptides) against MDR and XDR clinical strains of Mycobacterium tuberculosis (Mtb) both in vitro and, using THP-1 cells as a macrophage model, cultured ex vivo. All the D-LAK peptides successfully inhibited the growth of Mtb in vitro and were similarly effective against MDR and XDR strains. D-LAK peptides effectively broke down the heavy clumping of mycobacteria in broth culture, consistent with a 'detergent-like effect' that could reduce the hydrophobic interactions between the highly lipidic cell walls of the mycobacteria, preventing bacteria cell aggregation. Furthermore, though not able to eradicate the intracellular mycobacteria, D-LAK peptides substantially inhibited the intracellular growth of drug-resistant Mtb clinical isolates at concentrations that were well tolerated by THP-1 cells. Finally, combining D-LAK peptide with isoniazid could enhance the anti-TB efficacy. D-LAK peptide, particularly D-LAK120-A, was effective as an adjunct agent at non-toxic concentration to potentiate the efficacy of isoniazid against drug-resistant Mtb in vitro, possibly by facilitating the access of isoniazid into the mycobacteria by increasing the surface permeability of the pathogen. PMID:25154927

  16. Spinal Tuberculosis

    PubMed Central

    Ekinci, Safak; Tatar, Oner; Akpancar, Serkan; Bilgic, Serkan; Ersen, Omer

    2015-01-01

    Spinal tuberculosis (TB) is a significant form of TB, causing spinal deformity and paralysis. Early diagnosis and treatment are crucial for avoiding multivertebral destruction and are critical for improving outcomes in spinal TB. We believe that appropriate treatment method should be implemented at the early stage of this disease and that the Gulhane Askeri Tıp Akademisi classification system can be considered a practical guide for spinal TB treatment planning in all countries. PMID:26609247

  17. A Note on Derivatives of Isoniazid, Rifampicin, and Pyrazinamide Showing Activity Against Resistant Mycobacterium tuberculosis.

    PubMed

    Nusrath Unissa, Ameeruddin; Hanna, Luke Elizabeth; Swaminathan, Soumya

    2016-04-01

    Drug-resistant tuberculosis (DR-TB) is a serious problem that impedes the success of the TB control program. Of note, multidrug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB have certainly complicated the scenario. One of the possible strategies to overcome drug resistance in an economic and simple manner would involve modification of existing anti-TB drugs to obtain derivatives that can work on resistant TB bacilli. These may have improved half-life and increased bioavailability, be more efficacious, and serve as cost-effective alternatives, as compared to new drugs identified through conventional methods of drug discovery and development. Although extensive literature is available on the activity of various derivatives of first-line drugs (isoniazid, rifampicin and pyrazinamide) on drug-susceptible Mycobacterium tuberculosis (MTB), reports on the activity of derivatives on resistant MTB are very limited, to our knowledge. In light of this, the present review aims to provide a concise report on the derivatives of first-line drugs that have the potential to overcome the resistance to the parental drug and could thus serve as effective alternatives. PMID:26613382

  18. Post-treatment change in Mycobacterium tuberculosis antigen-stimulated tumor necrosis factor-alpha release in patients with active tuberculosis

    PubMed Central

    Kim, Chang Ho; Yoo, Seung Soo; Lee, Shin Yup; Cha, Seung Ick; Park, Jae Yong

    2015-01-01

    Background Monitoring tuberculosis (TB) treatment response remains challenging due to lack of reliable laboratory markers. In recent years, increased efforts have been exerted toward development of new biomarkers reflecting treatment response appropriately. While performance of interferon-gamma release assays (IGRAs) to monitor anti-TB treatment has been extensively evaluated, there is no data about post-treatment changes in Mycobacterium tuberculosis (MTB) antigen-stimulated tumor necrosis factor-alpha (TNF-α) release in active TB patients. Herein, we explored whether the MTB antigen-stimulated TNF-α release would be useful for monitoring responses to anti-TB treatment. Methods We compared unstimulated (TNF-αNil), MTB antigen-stimulated (TNF-αAg), and MTB antigen-stimulated minus unstimulated TNF-α levels (TNF-αAg-Nil) in supernatants from QuantiFERON-TB Gold In-Tube tests before and after treatment in 16 active TB patients, 25 latent TB infection (LTBI) subjects, and 10 healthy controls (HC). Results TNF-αAg and TNF-αAg-Nil levels decreased significantly after treatment in patients with active TB. In addition, TNF-αNil, TNF-αAg, and TNF-αAg-Nil levels were significantly higher in untreated active TB patients compared to LTBI subjects and HC. Conclusions This finding cautiously suggests that MTB Ag-stimulated TNF-α response may be a potential adjunctive marker for monitoring treatment response in active TB patients. PMID:26101647

  19. Transcriptional Blood Signatures Distinguish Pulmonary Tuberculosis, Pulmonary Sarcoidosis, Pneumonias and Lung Cancers

    PubMed Central

    Bloom, Chloe I.; Graham, Christine M.; Berry, Matthew P. R.; Rozakeas, Fotini; Redford, Paul S.; Wang, Yuanyuan; Xu, Zhaohui; Wilkinson, Katalin A.; Wilkinson, Robert J.; Kendrick, Yvonne; Devouassoux, Gilles; Ferry, Tristan; Miyara, Makoto; Bouvry, Diane; Dominique, Valeyre; Gorochov, Guy; Blankenship, Derek; Saadatian, Mitra; Vanhems, Phillip; Beynon, Huw; Vancheeswaran, Rama; Wickremasinghe, Melissa; Chaussabel, Damien; Banchereau, Jacques; Pascual, Virginia; Ho, Ling-pei; Lipman, Marc; O’Garra, Anne

    2013-01-01

    Rationale New approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations. Objectives To determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases. Methods We compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations. Measurements and Main Results An Interferon-inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls. Conclusions Tuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the

  20. Inflammasome genetics contributes to the development and control of active pulmonary tuberculosis.

    PubMed

    Souza de Lima, D; Ogusku, M M; Sadahiro, A; Pontillo, A

    2016-07-01

    Tuberculosis (TB) continues to be a major public health problem. An estimated one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb) but remains asymptomatic (latent TB) and only 5% to 10% of these latent individuals will develop active pulmonary TB. Factors affecting the balance between latent and active TB are mostly unknown, even if host genome has been shown to contribute to the outcome of Mtb response. Acute inflammation and Th1 response are important in the early clearance of the bacteria as it was emphasized by the association between immune genes (i.e.: HLA, IFNG, TNF, NRPAM1, IL10) variants and the development of active pulmonary TB. Recently, the role of the inflammasome in experimental TB has been demonstrated, however, to our knowledge, no data still exist about the contribution of inflammasome genetics to Mtb susceptibility and/or to the development of active TB. For this reason, selected polymorphisms in inflammasome genes were analysed in a case/control cohort of individuals with active pulmonary TB from an endemic area of Brazil Amazon. Our data evidence the novel association between polymorphisms in NLRP3-inflammasome encoding genes and active pulmonary TB, and replicated the association between P2X7 and TB observed in other populations. These results emphasize the role of NLRP3-inflammasome also in human TB, and contribute to our knowledge about pathways involved in the development of active TB, even if deeper investigation are needed to fully elucidate the role of the complex in Mtb infection. PMID:27101784

  1. Mycobacterium microti tuberculosis in its maintenance host, the field vole (Microtus agrestis): characterization of the disease and possible routes of transmission.

    PubMed

    Kipar, A; Burthe, S J; Hetzel, U; Rokia, M Abo; Telfer, S; Lambin, X; Birtles, R J; Begon, M; Bennett, M

    2014-09-01

    The field vole (Microtus agrestis) is a known maintenance host of Mycobacterium microti. Previous studies have shown that infected animals develop tuberculosis. However, the disease is also known in cats and is sporadically reported from humans and other mammalian species. We examined trapped field voles from an endemic area, using a range of diagnostic approaches. These confirmed that a combination of gross and histological examination with culture is most appropriate to identify the true prevalence of the disease, which was shown to be more than 13% at times when older animals that have previously been shown to be more likely to develop the disease dominate the population. The thorough pathological examination of diseased animals showed that voles generally develop systemic disease with most frequent involvement of spleen and liver, followed by skin, lymph nodes, and lungs. The morphology of the lesions was consistent with active disease, and their distribution suggested skin wounds or oral and/or aerogenic infection as the main portal of entry. The demonstration of mycobacteria in open skin lesions, airways, and salivary glands indicated bacterial shedding from the skin and with sputum and saliva. This suggests not only the environment but also direct contact and devouring as likely sources of infection. PMID:24334995

  2. Mycobacterium microti Tuberculosis in Its Maintenance Host, the Field Vole (Microtus agrestis): Characterization of the Disease and Possible Routes of Transmission

    PubMed Central

    Kipar, A.; Burthe, S. J.; Hetzel, U.; Abo Rokia, M.; Telfer, S.; Lambin, X.; Birtles, R. J.; Begon, M.; Bennett, M.

    2014-01-01

    The field vole (Microtus agrestis) is a known maintenance host of Mycobacterium microti. Previous studies have shown that infected animals develop tuberculosis. However, the disease is also known in cats and is sporadically reported from humans and other mammalian species. We examined trapped field voles from an endemic area, using a range of diagnostic approaches. These confirmed that a combination of gross and histological examination with culture is most appropriate to identify the true prevalence of the disease, which was shown to be more than 13% at times when older animals that have previously been shown to be more likely to develop the disease dominate the population. The thorough pathological examination of diseased animals showed that voles generally develop systemic disease with most frequent involvement of spleen and liver, followed by skin, lymph nodes, and lungs. The morphology of the lesions was consistent with active disease, and their distribution suggested skin wounds or oral and/or aerogenic infection as the main portal of entry. The demonstration of mycobacteria in open skin lesions, airways, and salivary glands indicated bacterial shedding from the skin and with sputum and saliva. This suggests not only the environment but also direct contact and devouring as likely sources of infection. PMID:24334995

  3. [National surveys of the prevalence of tuberculosis disease--overview, progress and lessons learnt].

    PubMed

    Onozaki, Ikushi

    2013-12-01

    This is a summary of an invited lecture at the 88th annual assembly of the Japanese Society for Tuberculosis on 28 March 2013. The lecture was carried out in Japanese. The WHO's Global Task Force on TB Impact Measurement was established in June 2006 to produce a robust, rigorous and widely-endorsed assessment of whether the 2015 targets for reductions in TB incidence, prevalence and mortality are achieved at global and regional levels and in individual countries; to regularly report on progress towards these targets in the years leading up to 2015; and strengthen national capacity in monitoring and evaluation of TB control. Three major and inter-related areas of work were defined and working groups were established to cover each of these areas, Surveillance, Prevalence surveys, and Estimates of TB burden, in 2007. x-ray screening and culture diagnosis between 2007 and today (March 2013). At least six countries are expected to launch a survey in 2013, and seven are already in a pipeline to launch one in 2014. These surveys provide an unbiased estimation of disease burden that is often higher than it was thought when the survey was planned especially in Asian countries. Surveys are also providing a rich source of data to inform programme policy and strategy: In this lecture, lessons learnt from surveys in China, Cambodia and Myanmar were discussed to show impact of DOTS as well as its limitations and challenges caused by rapidly ageing populations in Asia. An overall synthesis of the main implications of the results from recent prevalence surveys implemented in Asia and Africa for post-2015 global TB policy and strategy is also in the pipeline. The summary results and implications will be widely disseminated from 2014 when the results of the surveys in African countries are finalized. PMID:24551951

  4. Baseline assessment of collaborative tuberculosis/HIV activities in Kinshasa, the Democratic Republic of Congo.

    PubMed

    Martinot, Amanda; Van Rie, Annelies; Mulangu, Sabue; Mbulula, Marie; Jarrett, Nikki; Behets, Frieda; Bola, Valentin; Bahati, Etienne

    2008-07-01

    Ninety-two clinics were surveyed in 2005 as part of a baseline assessment of HIV activities in Tuberculosis (TB) clinics in Kinshasa, Democratic Republic of Congo. Some HIV activities were implemented in 58% of TB clinics. The majority of health had > or = 1 health care worker (HCW) trained in either HIV counseling or testing (71%). Fifty-three clinics offered counseling and testing to TB patients; twenty-two (42%) routinely offered HIV CT to all patients, while others used selective criteria. While most offered on-site counseling (92%) and testing (77%), not all 53 clinics had a HCW trained in counseling and only 31 had access to a counseling room. Cotrimoxazole prophylaxis was offered in 51% of clinics; antiretroviral treatment in 17%. Shortcomings in human resources, infrastructure and quality of services were revealed. Strengthening those clinics already implementing HIV activities could be prioritized to achieve the goals set forward by the Global Plan to Stop TB. PMID:18628533

  5. Tuberculosis: medico-legal aspects.

    PubMed

    Vetrugno, G; De-Giorgio, F; D'Alessandro, F; Scafetta, I; Berloco, F; Buonsenso, D; Abbate, F; Scalise, G; Pascali, V L; Valentini, P

    2014-01-01

    Tuberculosis is a diffusive infectious disease whose typical behaviour differentiates it from other infectious diseases spread by human-to-human transmission (flu, chicken pox, cholera, etc.) that follow a classic epidemic pattern. Indeed, in the presence of a known source of Koch bacilli that is capable of spreading the bacteria by air, not all exposed individuals inhale the bacteria, not all those who inhale them absorb them, not all those who absorb the bacteria are unable to eliminate them, not all who are able to eliminate them do so using delayed hypersensitivity, not all those who react with delayed hypersensitivity suffer lasting tissue damage (among other things, minor), not all who suffer tissue damage have anatomical sequelae, and not all those who have anatomical sequelae, however minimal, become carriers of bacilli in the latent period. The vast majority (90-95%) of the latter - which are in any case a portion, not the totality of those exposed - remain asymptomatic throughout their lives and never develop active tuberculosis. Based on these biological characteristics and the legal concepts of "epidemic" and "disease," it becomes highly problematic, if not impossible, to assert both that tuberculosis can cause events of sufficient magnitude to be associated with the crime of "epidemic," and that the mere diagnosis of a latent tuberculosis infection is sufficient to assume the presence of an illness legally prosecutable in criminal proceedings or a disability prosecutable in civil proceedings. Furthermore, clinically apparent tuberculosis is a temporarily-and in some cases permanently-disabling condition, and in certain work environments, even with the difficulties caused by the lack of available effective diagnostic tools and the insidious behaviour of the disease in the early stages, targeted monitoring to identify other persons who may become ill is appropriate. PMID:24804006

  6. A framework and toolkit for capturing the communicable disease programmes within health systems: tuberculosis control as an illustrative example.

    PubMed

    Atun, R A; Lennox-Chhugani, N; Drobniewski, F; Samyshkin, Y A; Coker, R J

    2004-09-01

    The frameworks and methods used for analysis, monitoring and evaluation of communicable disease control vary greatly. Although a number of manuals exist instruments for a detailed analysis of wider health system context are lacking. This is surprising given that the success of vertical programmes is often determined by the constraints of health systems. The importance of the context and the health system in determining the successful implementation of national tuberculosis programmes is well recognized by the WHO, which recommends analysis of national tuberculosis programmes within the context of health care system, health reform and the economic status of the country. However, current approaches inadequately capture intelligence on the health systems variables impacting on programme efficacy, limiting the ability of policy makers to draw lessons for wider use. A recent WHO report highlights the major systemic constraints to DOTS implementation and recommends a comprehensive and multi-sectoral approach to tuberculosis control. This obviates the need for tools that take into account health systems issues as well as focusing on a particular vertical programme but no such comprehensive tool exists. This paper outlines the conceptual basis for a model and a toolkit for rapid assessment, monitoring, and evaluation of the context, the elements of the health system and vertical communicable disease programme. It describes the framework, the potential strengths and weaknesses, approach and piloting of the toolkit and its two elements: first for 'horizontal assessment' of the health system within which the programme is embedded and second for 'vertical assessment' of the infectious disease-specific programme. PMID:15369032

  7. Evaluation of the anti-mycobacterium tuberculosis activity and in vivo acute toxicity of Annona sylvatic

    PubMed Central

    2014-01-01

    Background The recent emergence of extensively multidrug-resistant Mycobacterium tuberculosis strains has further complicated the control of tuberculosis. There is an urgent need for the development of new molecular candidates antitubercular drugs. Medicinal plants have been an excellent source of leads for the development of drugs. The aim of this study was to evaluate the in vitro activity of 28 alcoholic extracts and essential oils of native and exotic Brazilian plants against Mycobacterium tuberculosis and to further study these extracts through chemical fractionation, the isolation of their constituents, and an evaluation of the in vivo acute toxicity of the active extracts. To the best of our knowledge this is the first chemical characterization, antituberculosis activity and acute toxicity evaluation of Annona sylvatica. Methods The anti-mycobacterial activity of these extracts and their constituent compounds was evaluated using the resazurin reduction microtiter assay (REMA). To investigate the acute toxicity of these extracts in vivo, female Swiss mice were treated with the extracts at doses of 500, 1000 and 2000 mg · kg-1 of body weight. The extracts were characterized by LC-MS, and the constituents were isolated and identified by chromatographic analysis of spectroscopic data. Results Of the 28 extracts, the methanol extract obtained from the leaves of Annona sylvatica showed anti-mycobacterial activity with an minimal inhibitory concentration (MIC) of 184.33 μg/mL, and the ethyl acetate fraction (EAF) resulting from liquid-liquid partitioning of the A. sylvatica extract showed an MIC of 115.2 μg/mL. The characterization of this extract by LC-MS identified flavonoids and acetogenins as its main constituents. The phytochemical study of the A. sylvatica EAF resulted in the isolation of quercetin, luteolin, and almunequin. Conclusions Among the compounds isolated from the EAF, luteolin and almunequin were the most promising, with MICs of 236.8

  8. New strain multidrug resistant tuberculosis G24767 in Puerto Rico: Old disease a continuous threat.

    PubMed

    Maldonado, Hiram José; Cruz, Michael; Nieves, Joel; Rivera, Kelvin; Fernández, Ricardo; Colón, Miguel; Fernández, Francisco

    2016-01-01

    Multidrug resistant tuberculosis (MDR-TB) is defined as a Mycobacterium tuberculosis strain resistant to two or more first-line anti-tuberculous drugs. Tuberculosis (TB) is a global threat to society despite improvement in therapy as it continues to be an economic burden especially in underdeveloped countries. The downfall of global economics and growing travel destinations in developing countries has escalade the exposure of organism not previously encountered in industrialized nations. Most cases of MDR-TB are reported on immunosuppressed patients with risk factors and from endemic areas. Nevertheless new strains with higher transmission degree are emerging as a threat in patients who have low risk factors for the development of MDR-TB. PMID:27547724

  9. [Experience in joint activities of the Central Research Institute of Tuberculosis, USSR Ministry of Health, with therapeutic-preventive institutions of a Kazakhstan rural area].

    PubMed

    Ivanova, E S; Fisher, Iu Ia; Fedorov, L P; Utepkaliev, M M; Akpanov, Z A; Temresheva, G T; Polosukhin, S M

    1991-01-01

    The joint activity of the Institute staff together with local health institutions has favoured qualified tuberculosis care to become more accessible to the rural population. Favourable changes in the epidemiological situation have been registered in a high tuberculosis incidence area. PMID:1837927

  10. Access channel residues Ser315 and Asp137 in Mycobacterium tuberculosis catalase-peroxidase (KatG) control peroxidatic activation of the pro-drug isoniazid

    PubMed Central

    Zhao, Xiangbo; Hersleth, Hans-Petter; Zhu, Janan; Andersson, K. Kristoffer; Magliozzo, Richard S.

    2013-01-01

    Peroxidatic activation of the anti-tuberculosis pro-drug isoniazid by Mycobacterium tuberculosis catalase-peroxidase (KatG) is regulated by gating residues of a heme access channel. The steric restriction at the bottleneck of this channel is alleviated by replacement of residue Asp137 with Ser, according to crystallographic and kinetic studies. PMID:24185282

  11. Association of Strong Immune Responses to PPE Protein Rv1168c with Active Tuberculosis

    PubMed Central

    Khan, Nooruddin; Alam, Kaiser; Nair, Shiny; Valluri, Vijaya Lakshmi; Murthy, Kolluri J. R.; Mukhopadhyay, Sangita

    2008-01-01

    Accurate diagnosis of tuberculosis (TB) infection is critical for the treatment, prevention, and control of TB. Conventional diagnostic tests based on purified protein derivative (PPD) do not achieve the required diagnostic sensitivity. Therefore, in this study, we have evaluated the immunogenic properties of Rv1168c, a member of the PPE family, in comparison with PPD, which is routinely used in the tuberculin test, and Hsp60 and ESAT-6, well-known immunodominant antigens of Mycobacterium tuberculosis. In a conventional enzyme immunoassay, the recombinant Rv1168c protein displayed stronger immunoreactivity against the sera obtained from patients with clinically active TB than did PPD, Hsp60, or ESAT-6 and could distinguish TB patients from Mycobacterium bovis BCG-vaccinated controls. Interestingly, Rv1168c antigen permits diagnosis of smear-negative pulmonary TB as well as extrapulmonary TB cases, which are often difficult to diagnose by conventional tests. The immunodominant nature of Rv1168c makes it a promising candidate to use in serodiagnosis of TB. In addition, our studies also show that Rv1168c is a potent T-cell antigen which elicits a strong gamma interferon response in sensitized peripheral blood mononuclear cells obtained from TB patients. PMID:18400969

  12. Mycobacterium tuberculosis PE9 protein has high activity binding peptides which inhibit target cell invasion.

    PubMed

    Díaz, Diana P; Ocampo, Marisol; Pabón, Laura; Herrera, Chonny; Patarroyo, Manuel A; Munoz, Marina; Patarroyo, Manuel E

    2016-05-01

    PE/PPE proteins are involved in several processes during Mycobacterium tuberculosis (Mtb) infection of target cells; studying them is extremely interesting as they are the only ones from the Mycobacterium genus, they abound in pathogenic species such as Mtb and their function remains yet unknown. The PE9 protein (Rv1088) was characterised, the rv1088 gene was identified by PCR in Mtb complex strains and its expression and localisation on mycobacterial surface was confirmed by Western blot and immunoelectron microscopy. Bioinformatics tools were used for predicting PE9 protein structural aspects and experimental study involved the circular dichroism of synthetic peptides. The peptides were tested in binding assays involving U937 and A549 cells; two high activity binding peptides (HABPs) were found for both cell lines (39226-(1)MSYMIATPAALTAAATDIDGI(21) and 39232-(125)YQRHFGTGGQPEFRQHSEHRR(144)), one for U937 (39231-(104)YAGAGRRQRRRRSGDGQWRLRQ(124)) and one for A549 (39230-(83)YGTGVFRRRRGRQTVTAAEHRA(103)). HABP 39232 inhibited mycobacterial entry to A549 cells (∼70%) and U937 cells (∼50%), peptides 39226 and 39231 inhibited entry to U937 cells (∼60% and 80%, respectively) and peptide 39230 inhibited entry to A549 cells (∼60%). This emphasised HABPs' functional importance in recognition between Mtb H37Rv and target cell receptors. These peptide sequences could be involved in invasion and were recognised by the host's immune system, thereby highlighting their use when designing an efficient anti-tuberculosis multiantigenic vaccine. PMID:26851205

  13. The association between sterilizing activity and drug distribution into tuberculosis lesions

    PubMed Central

    Prideaux, Brendan; Via, Laura E.; Zimmerman, Matthew D.; Eum, Seokyong; Sarathy, Jansy; O’Brien, Paul; Chen, Chao; Kaya, Firat; Weiner, Danielle M.; Chen, Pei-Yu; Song, Taeksun; Lee, Myungsun; Shim, TaeSun; Cho, Jeong Su; Kim, Wooshik; Cho, Sang Nae; Olivier, Kenneth N.; Barry, Clifton E.; Dartois, Véronique

    2015-01-01

    Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a MALDI mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside1. In contrast, moxifloxacin which is active in vitro against persisters, a sub-population of Mycobacterium tuberculosis that persists in specific niches under drug pressure, and achieved treatment shortening in mice2, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We also suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration contributes to treatment outcome has wide implications for TB. PMID:26343800

  14. Rifapentine Is Not More Active than Rifampin against Chronic Tuberculosis in Guinea Pigs

    PubMed Central

    Dutta, Noton K.; Illei, Peter B.; Peloquin, Charles A.; Pinn, Michael L.; Mdluli, Khisimuzi E.; Nuermberger, Eric L.; Grosset, Jacques H.

    2012-01-01

    Rifamycins are key sterilizing drugs in the current treatment of active tuberculosis (TB). Daily dosing of rifapentine (P), a potent rifamycin with high intracellular accumulation, in place of rifampin (R) in the standard antitubercular regimen significantly shortens the duration of treatment needed to prevent relapse in a murine model of active TB. We undertook the current study to compare directly the activities of human-equivalent doses of P and R in a guinea pig model of chronic TB, in which bacilli are predominantly extracellular within human-like necrotic granulomas. Hartley strain guinea pigs were aerosol infected with ∼200 bacilli of Mycobacterium tuberculosis H37Rv, and treatment given 5 days/week was initiated 6 weeks later. R at 100 mg/kg of body weight and P at 100 mg/kg were given orally alone or in combination with isoniazid (H) at 60 mg/kg and pyrazinamide (Z) at 300 mg/kg. Culture-positive relapse was assessed in subgroups of guinea pigs after completion of 1 and 2 months of treatment. Human-equivalent doses of R and P showed equivalent bactericidal activity when used alone and in combination therapy. In guinea pigs treated with rifampin, isoniazid, and pyrazinamide (RHZ) or PHZ, microbiological relapse occurred in the lungs of 8/10 animals treated for 1 month and in 0/10 animals treated for 2 months. Substitution of P for R in the standard antitubercular regimen did not shorten the time to cure in this guinea pig model of chronic TB. Data from ongoing clinical trials comparing the activity of these two drugs are awaited to determine the relevance of the guinea pig TB model in preclinical drug screening. PMID:22547623

  15. [Lessons learned from tuberculosis outbreak cases].

    PubMed

    Kato, Seiya; Kuwabara, Katsuhiro

    2014-02-01

    Teishin Hospital), Toru MORI (Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association) The index case was a patient who was admitted to a general hospital where she was treated with pulsed corticosteroid therapy and then put on a respirator. Soon after, she developed tuberculosis (TB) and died. Immediately after her death, the healthcare workers who had close contact with the index case were given the QuantiFERON TB Gold (QFT) test, which indicated that all staff except one were negative. However, a QFT test administered eight weeks later had a positive rate of 18.6%. Subsequently, a total of five workers, including a doctor, nurses, and radiology technicians, developed TB. The bacterial isolates from five of them exhibited an RFLP pattern identical to that of the index case. These secondary cases of TB included a case who had contact of less than 5 minutes, a case whose QFT was negative ("doubtful" in the Japanese criterion of the QFT), and a case who was QFT-positive but declined to be treated for latent TB infection (LTBI). No other workers nor hospitalized patients developed TB. The healthcare worker contacts were further examined with the QFT 6, 9 and 12 months after the contact. The QFT results revealed four additional positive reactors and four "doubtful" reactors who were indicated for LTBI treatment. Among them were seven subjects who turned positive six months after the contact. TB prevention in hospital settings and contact investigations were discussed with the hospital staff, with special reference to the application of QFT. 3. Summary and issues of concern relating to a tuberculosis outbreak in a prison: Mitsunobu HOMMA, Takefumi ITOH (Department of Respiratory Medicine, Akita City Hospital) We report a tuberculosis outbreak that occurred in a prison in the spring of 2011, resulting in 11 cases of active disease and 40 cases of infection. The primary cause of the outbreak is thought to be the delay in identifying the index case, where the

  16. [The temporary work incapacity caused by respiratory diseases and tuberculosis in Romania and Dolj county in year 2000].

    PubMed

    Didilescu, Cr; Niţu, Mimi

    2002-01-01

    The temporary work incapacity caused by disease make yearly the consumption of billions of lei from the Social Care budget of our country. The Gravity Index (number of days of medical vacation/100 employers) was 627 days in 1989 and reached 948 in 2000. The high frequency of superior airways pulmonary parenchyma and pleural disease set the respiratory pathology on the first place in the structure of general morbidity and subsequently, it's the first cause generating temporary work incapacity (16.1%). 45% of medical vacation days paid in 2000 were due to respiratory and osteo-articular diseases and to accidents. In Dolj county gravity index is situated below the country average, being 785 days in 2000 versus 570 in 1989. In same production departments as in charcoal industry, the gravity index reaches 1714 days and above 1400 in other departments such as leather, furs, footwear and textile industries. In health care units the gravity index was 533.7 days in 2000. The "balance" of tuberculosis in temporary work incapacity structure diminished, as a result of introducing new treatment formula, from 4.4% in 1989 to 3.3% in 2000. In Dolj county, with higher TB incidence 4.5% of temporary work incapacity was due to tuberculosis. PMID:12693167

  17. A preliminary investigation of tuberculosis and other diseases in African buffalo (Syncerus caffer) in Queen Elizabeth National Park, Uganda.

    PubMed

    Kalema-Zikusoka, G; Bengis, R G; Michel, A L; Woodford, M H

    2005-06-01

    A survey to determine the prevalence of bovine tuberculosis caused by Mycobacterium bovis and certain other infectious diseases was conducted on 42 free-ranging African buffaloes, (Syncerus caffer) from May to June 1997 in the Queen Elizabeth National Park, Uganda. Using the gamma interferon test, exposure to M. bovis was detected in 21.6% of the buffaloes. One dead buffalo and an emaciated warthog (Phacochoerus aethiopicus) that was euthanased, were necropsied; both had miliary granulomas from which M. bovis was isolated. None of the buffaloes sampled in Sector A of the park, which has no cattle interface, tested positive for bovine tuberculosis (BTB) exposure. The prevalence and distribution of BTB does not appear to have changed significantly since the 1960s, but this may be due to fluxes in the buffalo population. Serological testing for foot-and-mouth disease (FMD) demonstrated positive exposure of 57.1% of the buffaloes sampled, with types A, O and SAT 1-3, which is the first known report of FMD antibodies to A and O types in free ranging African buffaloes. Foot-and-mouth disease virus types SAT 1 and SAT 3 were isolated from buffalo probang samples. Two percent of the buffaloes had been exposed to brucellosis. None of the buffaloes tested had antibodies to rinderpest, leptospirosis or Q fever. PMID:16137132

  18. A VSEIR model for transmission of tuberculosis (TB) disease in North Sumatera, Indonesia

    NASA Astrophysics Data System (ADS)

    Rangkuti, Yulita M.; Sinaga, Marlina S.; Marpaung, F.; Side, Syafruddin

    2014-12-01

    In this work, Vaccination (V), Susceptible (S) Infected (I), and Recovered (R) (VSIR) model for transmission of Tuberculosis in North Sumatera is modified. An exposed class is adopted to VSIR model so called VSEIR to determine the probability of people who infectious before infected. This model is written in ordinary differential equation (ODEs) in five classes. Determination the equilibrium point and stability analysis of the model is discussed to determine the dynamic behaviour of systems. A simulation is also discussed to see the suitable model to North Sumatera data. The simulation of VSEIR model indicates Tuberculosis has not endemic in North Sumatera.

  19. Phytoconstituents from Alpinia purpurata and their in vitro inhibitory activity against Mycobacterium tuberculosis

    PubMed Central

    Villaflores, Oliver B.; Macabeo, Allan Patrick G.; Gehle, Dietmar; Krohn, Karsten; Franzblau, Scott G.; Aguinaldo, Alicia M.

    2010-01-01

    Alpinia purpurata or red ginger was studied for its phytochemical constituents as part of our growing interest on Philippine Zingiberaceae plants that may exhibit antimycobacterial activity. The hexane and dichloromethane subextracts of the leaves were fractionated and purified using silica gel chromatography to afford a mixture of C28–C32 fatty alcohols, a 3-methoxyflavone and two steroidal glycosides. The two latter metabolites were spectroscopically identified as kumatakenin (1), sitosteryl-3-O-6-palmitoyl-β-D-glucoside (2) and b-sitosteryl galactoside (3) using ultraviolet (UV), infrared (IR), electron impact mass spectrometer (EIMS) and nuclear magnetic resonance (NMR) experiments, and by comparison with literature data. This study demonstrates for the first time the isolation of these constituents from A. purpurata. In addition to the purported anti-inflammatory activity, its phytomedicinal potential to treat tuberculosis is also described. PMID:21120040

  20. All-trans retinoic acid-triggered antimicrobial activity against Mycobacterium tuberculosis is dependent on NPC2.

    PubMed

    Wheelwright, Matthew; Kim, Elliot W; Inkeles, Megan S; De Leon, Avelino; Pellegrini, Matteo; Krutzik, Stephan R; Liu, Philip T

    2014-03-01

    A role for vitamin A in host defense against Mycobacterium tuberculosis has been suggested through epidemiological and in vitro studies; however, the mechanism is unclear. In this study, we demonstrate that vitamin A-triggered antimicrobial activity against M. tuberculosis requires expression of NPC2. Comparison of monocytes stimulated with all-trans retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3 (1,25D3), the biologically active forms of vitamin A and vitamin D, respectively, indicates that ATRA and 1,25D3 induce mechanistically distinct antimicrobial activities. Stimulation of primary human monocytes with ATRA did not result in expression of the antimicrobial peptide cathelicidin, which is required for 1,25D3 antimicrobial activity. In contrast, ATRA triggered a reduction in the total cellular cholesterol concentration, whereas 1,25D3 did not. Blocking ATRA-induced cellular cholesterol reduction inhibits antimicrobial activity as well. Bioinformatic analysis of ATRA- and 1,25D3-induced gene profiles suggests that NPC2 is a key gene in ATRA-induced cholesterol regulation. Knockdown experiments demonstrate that ATRA-mediated decrease in total cellular cholesterol content and increase in lysosomal acidification are both dependent upon expression of NPC2. Expression of NPC2 was lower in caseous tuberculosis granulomas and M. tuberculosis-infected monocytes compared with normal lung and uninfected cells, respectively. Loss of NPC2 expression ablated ATRA-induced antimicrobial activity. Taken together, these results suggest that the vitamin A-mediated antimicrobial mechanism against M. tuberculosis requires NPC2-dependent expression and function, indicating a key role for cellular cholesterol regulation in the innate immune response. PMID:24501203

  1. Pulmonary tuberculosis: clinical features and patient management.

    PubMed

    Gough, Andrea; Kaufman, Gerri

    Pulmonary tuberculosis (TB) is a common infectious disease and a major cause of illness and death throughout the world, particularly in developing countries. This article explores the difference between latent TB infection and active TB disease, and discusses the pharmacological management of TB and issues around adherence to medication. Although TB is usually managed by specialist teams it is essential that all practitioners have an understanding of the signs and symptoms of the disease to ensure early referral and accurate diagnosis. PMID:21888103

  2. Learning from outbreaks of bovine tuberculosis near Riding Mountain National Park: Applications to a foreign animal disease outbreak

    PubMed Central

    2004-01-01

    Abstract Riding Mountain National Park, Manitoba, is home to a population of free-roaming elk (Cervus elaphus manitobensis) that have been found to be infected with Mycobacterium bovis, the agent of bovine tuberculosis (TB). The disease has also been found in a number of cattle herds near the Park and, as a result, Manitoba has been assigned a split status for bovine TB. A number of government agencies, with input from representatives from the wildlife and agricultural sectors, have responded by devising a program to detect, investigate, control, eradicate, and prevent TB in both wild and domestic animals. Experience from these efforts can be applied to the control of other diseases, such a foreign animal disease, elsewhere in Canada. PMID:14992251

  3. Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in Hiv-positive adults

    PubMed Central

    Shah, Maunank; Hanrahan, Colleen; Wang, Zhuo Yu; Dendukuri, Nandini; Lawn, Stephen D; Denkinger, Claudia M; Steingart, Karen R

    2016-01-01

    Background Rapid detection of tuberculosis (TB) among people living with human immunodeficiency virus (HIV) is a global health priority. HIV-associated TB may have different clinical presentations and is challenging to diagnose. Conventional sputum tests have reduced sensitivity in HIV-positive individuals, who have higher rates of extrapulmonary TB compared with HIV-negative individuals. The lateral flow urine lipoarabinomannan assay (LF-LAM) is a new, commercially available point-of-care test that detects lipoarabinomannan (LAM), a lipopolysaccharide present in mycobacterial cell walls, in people with active TB disease. Objectives To assess the accuracy of LF-LAM for the diagnosis of active TB disease in HIV-positive adults who have signs and symptoms suggestive of TB (TB diagnosis).To assess the accuracy of LF-LAM as a screening test for active TB disease in HIV-positive adults irrespective of signs and symptoms suggestive of TB (TB screening). Search methods We searched the following databases without language restriction on 5 February 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE (PubMed,1966); EMBASE (OVID, from 1980); Science Citation Index Expanded (SCI-EXPANDED, from 1900), Conference Proceedings Citation Index-Science (CPCI-S, from 1900), and BIOSIS Previews (from 1926) (all three using the Web of Science platform; MEDION; LILACS (BIREME, from 1982); SCOPUS (from 1995); the metaRegister of Controlled Trials (mRCT); the search portal of the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP); and ProQuest Dissertations & Theses A&l (from 1861). Selection criteria Eligible study types included randomized controlled trials, cross-sectional studies, and cohort studies that determined LF-LAM accuracy for TB against a microbiological reference standard (culture or nucleic acid amplification test from any body site). A higher quality reference standard was one in which two or more specimen types were

  4. Tuberculosis peritonitis: gallium-67 scintigraphic appearance.

    PubMed

    Sumi, Y; Ozaki, Y; Hasegawa, H; Shindoh, N; Katayama, H; Tamamoto, F

    1999-06-01

    Tuberculosis peritonitis is a rare manifestation of extrapulmonary tuberculosis. The results of gallium-67 scintigraphy of three patients with tuberculosis peritonitis were reviewed to assess its usefulness in the diagnosis of this condition. Tuberculosis peritonitis was associated with diffuse or focal abdominal localization and decreased hepatic accumulation of gallium-67. These gallium-67 scan features of tuberculosis peritonitis may help to optimize the diagnosis and management of this disease. PMID:10435380

  5. Crystal Structures of the Kinase Domain of the Sulfate-Activating Complex in Mycobacterium tuberculosis

    PubMed Central

    Poyraz, Ömer; Brunner, Katharina; Lohkamp, Bernhard; Axelsson, Hanna; Hammarström, Lars G. J.; Schnell, Robert; Schneider, Gunter

    2015-01-01

    In Mycobacterium tuberculosis the sulfate activating complex provides a key branching point in sulfate assimilation. The complex consists of two polypeptide chains, CysD and CysN. CysD is an ATP sulfurylase that, with the energy provided by the GTPase activity of CysN, forms adenosine-5’-phosphosulfate (APS) which can then enter the reductive branch of sulfate assimilation leading to the biosynthesis of cysteine. The CysN polypeptide chain also contains an APS kinase domain (CysC) that phosphorylates APS leading to 3’-phosphoadenosine-5’-phosphosulfate, the sulfate donor in the synthesis of sulfolipids. We have determined the crystal structures of CysC from M. tuberculosis as a binary complex with ADP, and as ternary complexes with ADP and APS and the ATP mimic AMP-PNP and APS, respectively, to resolutions of 1.5 Å, 2.1 Å and 1.7 Å, respectively. CysC shows the typical APS kinase fold, and the structures provide comprehensive views of the catalytic machinery, conserved in this enzyme family. Comparison to the structure of the human homolog show highly conserved APS and ATP binding sites, questioning the feasibility of the design of specific inhibitors of mycobacterial CysC. Residue Cys556 is part of the flexible lid region that closes off the active site upon substrate binding. Mutational analysis revealed this residue as one of the determinants controlling lid closure and hence binding of the nucleotide substrate. PMID:25807013

  6. Tuberculosis among Children in Alaska.

    ERIC Educational Resources Information Center

    Gessner, Bradford D.

    1997-01-01

    The incidence of tuberculosis among Alaskan children under 15 was more than twice the national rate, with Alaska Native children showing a much higher incidence. Children with household exposure to adults with active tuberculosis had a high risk of infection. About 22 percent of pediatric tuberculosis cases were identified through school…

  7. Targeting Drug-Sensitive and -Resistant Strains of Mycobacterium tuberculosis by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology

    PubMed Central

    Chandra, Pallavi; Rajmani, R. S.; Verma, Garima; Bhavesh, Neel Sarovar

    2016-01-01

    ABSTRACT In view of emerging drug resistance among bacterial pathogens, including Mycobacterium tuberculosis, the development of novel therapeutic strategies is increasingly being sought. A recent paradigm in antituberculosis (anti-TB) drug development is to target the host molecules that are crucial for intracellular survival of the pathogen. We previously showed the importance of Src tyrosine kinases in mycobacterial pathogenesis. Here, we report that inhibition of Src significantly reduced survival of H37Rv as well as multidrug-resistant (MDR) and extremely drug-resistant (XDR) strains of M. tuberculosis in THP-1 macrophages. Src inhibition was also effective in controlling M. tuberculosis infection in guinea pigs. In guinea pigs, reduced M. tuberculosis burden due to Src inhibition also led to a marked decline in the disease pathology. In agreement with the theoretical framework of host-directed approaches against the pathogen, Src inhibition was equally effective against an XDR strain in controlling infection in guinea pigs. We propose that Src inhibitors could be developed into effective host-directed anti-TB drugs, which could be indiscriminately used against both drug-sensitive and drug-resistant strains of M. tuberculosis. IMPORTANCE The existing treatment regimen for tuberculosis (TB) suffers from deficiencies like high doses of antibiotics, long treatment duration, and inability to kill persistent populations in an efficient manner. Together, these contribute to the emergence of drug-resistant tuberculosis. Recently, several host factors were identified which help intracellular survival of Mycobacterium tuberculosis within the macrophage. These factors serve as attractive targets for developing alternate therapeutic strategies against M. tuberculosis. This strategy promises to be effective against drug-resistant strains. The approach also has potential to considerably lower the risk of emergence of new drug-resistant strains. We explored tyrosine kinase

  8. Targeting Drug-Sensitive and -Resistant Strains of Mycobacterium tuberculosis by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology.

    PubMed

    Chandra, Pallavi; Rajmani, R S; Verma, Garima; Bhavesh, Neel Sarovar; Kumar, Dhiraj

    2016-01-01

    In view of emerging drug resistance among bacterial pathogens, including Mycobacterium tuberculosis, the development of novel therapeutic strategies is increasingly being sought. A recent paradigm in antituberculosis (anti-TB) drug development is to target the host molecules that are crucial for intracellular survival of the pathogen. We previously showed the importance of Src tyrosine kinases in mycobacterial pathogenesis. Here, we report that inhibition of Src significantly reduced survival of H37Rv as well as multidrug-resistant (MDR) and extremely drug-resistant (XDR) strains of M. tuberculosis in THP-1 macrophages. Src inhibition was also effective in controlling M. tuberculosis infection in guinea pigs. In guinea pigs, reduced M. tuberculosis burden due to Src inhibition also led to a marked decline in the disease pathology. In agreement with the theoretical framework of host-directed approaches against the pathogen, Src inhibition was equally effective against an XDR strain in controlling infection in guinea pigs. We propose that Src inhibitors could be developed into effective host-directed anti-TB drugs, which could be indiscriminately used against both drug-sensitive and drug-resistant strains of M. tuberculosis. IMPORTANCE The existing treatment regimen for tuberculosis (TB) suffers from deficiencies like high doses of antibiotics, long treatment duration, and inability to kill persistent populations in an efficient manner. Together, these contribute to the emergence of drug-resistant tuberculosis. Recently, several host factors were identified which help intracellular survival of Mycobacterium tuberculosis within the macrophage. These factors serve as attractive targets for developing alternate therapeutic strategies against M. tuberculosis. This strategy promises to be effective against drug-resistant strains. The approach also has potential to considerably lower the risk of emergence of new drug-resistant strains. We explored tyrosine kinase Src as a

  9. Seasonality of Tuberculosis in the United States, 1993–2008

    PubMed Central

    Willis, Matthew D.; Winston, Carla A.; Heilig, Charles M.; Cain, Kevin P.; Walter, Nicholas D.; Mac Kenzie, William R.

    2016-01-01

    Background Although seasonal variation in tuberculosis incidence has been described in several recent studies, the mechanism underlying this seasonality remains unknown. Seasonality of tuberculosis disease may indicate the presence of season-specific risk factors that could potentially be controlled if they were better understood. We conducted this study to determine whether tuberculosis is seasonal in the United States and to describe patterns of seasonality in specific populations. Methods We performed a time series decomposition analysis of tuberculosis cases reported to the Centers for Disease Control and Prevention from 1993 through 2008. Seasonal amplitude of tuberculosis disease (the difference between the months with the highest and lowest mean case counts), was calculated for the population as a whole and for populations with select demographic, clinical, and epidemiologic characteristics. Results A total of 243 432 laboratory-confirmed tuberculosis cases were reported over a period of 16 years. A mean of 21.4% more cases were diagnosed in March, the peak month, compared with November, the trough month. The magnitude of seasonality did not vary with latitude. The greatest seasonal amplitude was found among children aged <5 years and in cases associated with disease clusters. Conclusions Tuberculosis is a seasonal disease in the United States, with a peak in spring and trough in late fall. The latitude independence of seasonality suggests that reduced winter sunlight exposure may not be a strong contributor to tuberculosis risk. Increased seasonality among young children and clustered cases suggests that disease that is the result of recent transmission is more influenced by season than disease resulting from activation of latent infection. PMID:22474225

  10. Recent tuberculosis diagnosis toward the end TB strategy.

    PubMed

    Cheon, Seon Ah; Cho, Hyun Hee; Kim, Jeonghyo; Lee, Jaebeom; Kim, Hwa-Jung; Park, Tae Jung

    2016-04-01

    Tuberculosis (TB) is an infectious bacterial disease caused by Mycobacterium tuberculosis. Despite global TB eradication efforts, it is still a global public health concern, especially in low- and middle-income countries. Most of the active TB infections are curable with early diagnosis and appropriate treatment, but drug-resistant TB is difficult and expensive to treat in immunocompetent as well as immunocompromised individuals. Thus, rapid, economic, and accurate point-of care tools for TB diagnosis are required urgently. This review describes the history of M. tuberculosis detection methods up to date and the recent advances using nanotechnology for point-of-care testing of TB diagnosis. PMID:26853124

  11. Urinary tuberculosis: modern issues.

    PubMed

    Wise, Gilbert J

    2009-07-01

    Tuberculosis remains an epidemic that affects one third of the world's population. The persistence of this disease is caused by a large pool of immune-compromised and lower socioeconomic populations. The advent of rapid transportation and migration has contributed to the persistence of this disease in developed and less developed nations. The emergence of drug-resistant strains has added an additional factor for the pervasiveness of tuberculosis. The genitourinary system is a primary target for hematogenous infections. This paper reviews the contemporary issues that affect the diagnosis and treatment of urinary tuberculosis. PMID:19570494

  12. Two enzymes with redundant fructose bisphosphatase activity sustain gluconeogenesis and virulence in Mycobacterium tuberculosis

    PubMed Central

    Ganapathy, Uday; Marrero, Joeli; Calhoun, Susannah; Eoh, Hyungjin; de Carvalho, Luiz Pedro Sorio; Rhee, Kyu; Ehrt, Sabine

    2015-01-01

    The human pathogen Mycobacterium tuberculosis (Mtb) likely utilizes host fatty acids as a carbon source during infection. Gluconeogenesis is essential for the conversion of fatty acids into biomass. A rate-limiting step in gluconeogenesis is the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate by a fructose bisphosphatase (FBPase). The Mtb genome contains only one annotated FBPase gene, glpX. Here we show that, unexpectedly, an Mtb mutant lacking GLPX grows on gluconeogenic carbon sources and has detectable FBPase activity. We demonstrate that the Mtb genome encodes an alternative FBPase (GPM2, Rv3214) that can maintain gluconeogenesis in the absence of GLPX. Consequently, deletion of both GLPX and GPM2 is required for disruption of gluconeogenesis and attenuation of Mtb in a mouse model of infection. Our work affirms a role for gluconeogenesis in Mtb virulence and reveals previously unidentified metabolic redundancy at the FBPase-catalysed reaction step of the pathway. PMID:26258286

  13. Synthetic Long Peptide Derived from Mycobacterium tuberculosis Latency Antigen Rv1733c Protects against Tuberculosis

    PubMed Central

    Coppola, Mariateresa; van den Eeden, Susan J. F.; Wilson, Louis; Franken, Kees L. M. C.; Ottenhoff, Tom H. M.

    2015-01-01

    Responsible for 9 million new cases of active disease and nearly 2 million deaths each year, tuberculosis (TB) remains a global health threat of overwhelming dimensions. Mycobacterium bovis BCG, the only licensed vaccine available, fails to confer lifelong protection and to prevent reactivation of latent infection. Although 15 new vaccine candidates are now in clinical trials, an effective vaccine against TB remains elusive, and new strategies for vaccination are vital. BCG vaccination fails to induce immunity against Mycobacterium tuberculosis latency antigens. Synthetic long peptides (SLPs) combined with adjuvants have been studied mostly for therapeutic cancer vaccines, yet not for TB, and proved to induce efficient antitumor immunity. This study investigated an SLP derived from Rv1733c, a major M. tuberculosis latency antigen which is highly expressed by “dormant” M. tuberculosis and well recognized by T cells from latently M. tuberculosis-infected individuals. In order to assess its in vivo immunogenicity and protective capacity, Rv1733c SLP in CpG was administered to HLA-DR3 transgenic mice. Immunization with Rv1733c SLP elicited gamma interferon-positive/tumor necrosis factor-positive (IFN-γ+/TNF+) and IFN-γ+ CD4+ T cells and Rv1733c-specific antibodies and led to a significant reduction in the bacterial load in the lungs of M. tuberculosis-challenged mice. This was observed both in a pre- and in a post-M. tuberculosis challenge setting. Moreover, Rv1733c SLP immunization significantly boosted the protective efficacy of BCG, demonstrating the potential of M. tuberculosis latency antigens to improve BCG efficacy. These data suggest a promising role for M. tuberculosis latency antigen Rv1733c-derived SLPs as a novel TB vaccine approach, both in a prophylactic and in a postinfection setting. PMID:26202436

  14. Noninvasive Test for Tuberculosis Detection among Primates

    PubMed Central

    Mugisha, Lawrence; Shoyama, Fernanda Miyagaki; O’Malley, Melanie J.; Flynn, JoAnne L.; Asiimwe, Benon; Travis, Dominic A.; Singer, Randall S.; Sreevatsan, Srinand

    2015-01-01

    Traditional testing methods have limited epidemiologic studies of tuberculosis among free-living primates. PCR amplification of insertion element IS6110 of Mycobacterium tuberculosis from fecal samples was evaluated as a noninvasive screening test for tuberculosis in primates. Active tuberculosis was detected among inoculated macaques and naturally exposed chimpanzees, demonstrating the utility of this test. PMID:25695329

  15. The Mycobacterium tuberculosis Proteasome Active Site Threonine Is Essential for Persistence Yet Dispensable for Replication and Resistance to Nitric Oxide

    PubMed Central

    Gandotra, Sheetal; Lebron, Maria B.; Ehrt, Sabine

    2010-01-01

    Previous work revealed that conditional depletion of the core proteasome subunits PrcB and PrcA impaired growth of Mycobacterium tuberculosis in vitro and in mouse lungs, caused hypersusceptibility to nitric oxide (NO) and impaired persistence of the bacilli during chronic mouse infections. Here, we show that genetic deletion of prcBA led to similar phenotypes. Surprisingly, however, an active site mutant proteasome complemented the in vitro and in vivo growth defects of the prcBA knockout (ΔprcBA) as well as its NO hypersensitivity. In contrast, long-term survival of M. tuberculosis in stationary phase and during starvation in vitro and in the chronic phase of mouse infection required a proteolytically active proteasome. Inhibition of inducible nitric oxide synthase did not rescue survival of ΔprcBA, revealing a function beyond NO defense, by which the proteasome contributes to M. tuberculosis fitness during chronic mouse infections. These findings suggest that proteasomal proteolysis facilitates mycobacterial persistence, that M. tuberculosis faces starvation during chronic mouse infections and that the proteasome serves a proteolysis-independent function. PMID:20711362

  16. Structural analysis of the dodecameric proteasome activator PafE in Mycobacterium tuberculosis.

    PubMed

    Bai, Lin; Hu, Kuan; Wang, Tong; Jastrab, Jordan B; Darwin, K Heran; Li, Huilin

    2016-04-01

    The human pathogen Mycobacterium tuberculosis (Mtb) requires a proteasome system to cause lethal infections in mice. We recently found that proteasome accessory factor E (PafE, Rv3780) activates proteolysis by the Mtb proteasome independently of adenosine triphosphate (ATP). Moreover, PafE contributes to the heat-shock response and virulence of Mtb Here, we show that PafE subunits formed four-helix bundles similar to those of the eukaryotic ATP-independent proteasome activator subunits of PA26 and PA28. However, unlike any other known proteasome activator, PafE formed dodecamers with 12-fold symmetry, which required a glycine-XXX-glycine-XXX-glycine motif that is not found in previously described activators. Intriguingly, the truncation of the PafE carboxyl-terminus resulted in the robust binding of PafE rings to native proteasome core particles and substantially increased proteasomal activity, suggesting that the extended carboxyl-terminus of this cofactor confers suboptimal binding to the proteasome core particle. Collectively, our data show that proteasomal activation is not limited to hexameric ATPases in bacteria. PMID:27001842

  17. Structural analysis of the dodecameric proteasome activator PafE in Mycobacterium tuberculosis

    DOE PAGESBeta

    Bai, Lin; Hu, Kuan; Wang, Tong; Jastrab, Jordan B.; Darwin, K. Heran; Li, Huilin

    2016-03-21

    Here, the human pathogen Mycobacterium tuberculosis (Mtb) requires a proteasome system to cause lethal infections in mice. We recently found that proteasome accessory factor E (PafE, Rv3780) activates proteolysis by the Mtb proteasome independently of adenosine triphosphate (ATP). Moreover, PafE contributes to the heat-shock response and virulence of Mtb. Here, we show that PafE subunits formed four-helix bundles similar to those of the eukaryotic ATP-independent proteasome activator subunits of PA26 and PA28. However, unlike any other known proteasome activator, PafE formed dodecamers with 12-fold symmetry, which required a glycine-XXX-glycine-XXX-glycine motif that is not found in previously described activators. Intriguingly, themore » truncation of the PafE carboxyl-terminus resulted in the robust binding of PafE rings to native proteasome core particles and substantially increased proteasomal activity, suggesting that the extended carboxyl-terminus of this cofactor confers suboptimal binding to the proteasome core particle. Collectively, our data show that proteasomal activation is not limited to hexameric ATPases in bacteria.« less

  18. Hypoxia and classical activation limits Mycobacterium tuberculosis survival by Akt-dependent glycolytic shift in macrophages

    PubMed Central

    Matta, S K; Kumar, D

    2016-01-01

    Cellular reactive oxygen species (ROS) is a major antibacterial defense mechanism used by macrophages upon activation. Exposure of Mycobacterium tuberculosis (Mtb)-infected macrophages to hypoxia is known to compromise the survival of the pathogen. Here we report that the hypoxia-induced control of intracellular Mtb load in RAW 264.7 macrophages was mediated by regulating the cellular ROS levels. We show that similar to classical activation, hypoxia incubation of macrophages resulted in decreased mitochondrial outer membrane potential (MOMP) and a concomitant increase in the cellular ROS levels. Mitochondrial depolarization and consequently higher ROS could be blocked by knocking down Akt using siRNAs, which acted by inhibiting the switch to glycolytic mode of metabolism, an essential adaptive response upon classical activation or hypoxic incubation of macrophages. Moreover, in the classically activated macrophages or in the macrophages under hypoxia incubation, supplementation with additional glucose had similar effects as Akt knockdown. Interestingly, in both the cases, the reversal of phenotype was linked with the ability of the mitochondrial F0–F1 ATP synthase activity to maintain the MOMP in the absence of oxidative phosphorylation. Both Akt knockdown and glucose supplementation were also able to rescue Mtb survival in these macrophages upon classical activation or hypoxia incubation. These results provide a framework for better understanding of how the interplay between oxygen supply, which is limiting in the human tubercular granulomas, and nutrient availability could together direct the outcome of infections in vivo. PMID:27551515

  19. IL-4Rα-Dependent Alternative Activation of Macrophages Is Not Decisive for Mycobacterium tuberculosis Pathology and Bacterial Burden in Mice

    PubMed Central

    Savvi, Suzana; Logan, Erin; Schwegmann, Anita; Roy, Sugata; Nieuwenhuizen, Natalie E.; Ozturk, Mumin; Schmeier, Sebastian; Suzuki, Harukazu; Brombacher, Frank

    2015-01-01

    Classical activation of macrophages (caMph or M1) is crucial for host protection against Mycobacterium tuberculosis (Mtb) infection. Evidence suggests that IL-4/IL-13 alternatively activated macrophages (aaMph or M2) are exploited by Mtb to divert microbicidal functions of caMph. To define the functions of M2 macrophages during tuberculosis (TB), we infected mice deficient for IL-4 receptor α on macrophages (LysMcreIL-4Rα-/lox) with Mtb. We show that absence of IL-4Rα on macrophages does not play a major role during infection with Mtb H37Rv, or the clinical Beijing strain HN878. This was demonstrated by similar mortality, bacterial burden, histopathology and T cell proliferation between infected wild-type (WT) and LysMcreIL-4Rα-/lox mice. Interestingly, we observed no differences in the lung expression of inducible nitric oxide synthase (iNOS) and Arginase 1 (Arg1), well-established markers for M1/M2 macrophages among the Mtb-infected groups. Kinetic expression studies of IL-4/IL-13 activated bone marrow-derived macrophages (BMDM) infected with HN878, followed by gene set enrichment analysis, revealed that the MyD88 and IL-6, IL-10, G-CSF pathways are significantly enriched, but not the IL-4Rα driven pathway. Together, these results suggest that IL-4Rα-macrophages do not play a central role in TB disease progression. PMID:25790379

  20. Cytokine and chemokine expression profiles in response to Mycobacterium tuberculosis stimulation are altered in HIV-infected compared to HIV-uninfected subjects with active tuberculosis.

    PubMed

    Waruk, Jillian L M; Machuki, Zipporah; Mesa, Christine; Juno, Jennifer A; Anzala, Omu; Sharma, Meenu; Ball, T Blake; Oyugi, Julius; Kiazyk, Sandra

    2015-09-01

    Mycobacterium tuberculosis (Mtb) infects nearly 2 million people annually and is the most common cause of death in HIV-infected individuals. Tuberculosis (TB) diagnostics cater to HIV-uninfected individuals in non-endemic countries, are expensive, slow, and lack sensitivity for those most affected. Patterns of soluble immune markers from Mtb-stimulated immune cells are not well defined in HIV co-infection. We assessed immune differences between HIV-infected and HIV-uninfected individuals with active TB utilizing IFNγ-based QuantiFERON®-TB Gold In-Tube (QFT) testing in Nairobi, Kenya. Excess QFT supernatants were used to measure cytokine and chemokine responses by a 17-plex bead array. Mtb/HIV co-infected participants were significantly less likely to be QFT+ (47.2% versus 84.2% in the HIV-uninfected group), and demonstrated lower expression of all cytokines except for IFNα2. Receiver operator characteristic analyses identified IL-1α as a potential marker of co-infection. Among HIV-infected individuals, CD4+ T cell count correlated weakly with the expression of several analytes. Co-expression analysis highlighted differences in immune profiles between the groups. These data suggest that there is a unique and detectable Mtb-specific immune response in co-infection. A better understanding of Mtb immunology can translate into much needed immunodiagnostics with enhanced sensitivity in HIV-infected individuals, facilitating their opportunity to obtain live-saving treatment. PMID:26073895

  1. B in TB: B Cells as Mediators of Clinically Relevant Immune Responses in Tuberculosis

    PubMed Central

    Rao, Martin; Valentini, Davide; Poiret, Thomas; Dodoo, Ernest; Parida, Shreemanta; Zumla, Alimuddin; Brighenti, Susanna; Maeurer, Markus

    2015-01-01

    The protective role of B cells and humoral immune responses in tuberculosis infection has been regarded as inferior to cellular immunity directed to the intracellular pathogen Mycobacterium tuberculosis. However, B-cell–mediated immune responses in tuberculosis have recently been revisited in the context of B-cell physiology and antigen presentation. We discuss in this review the diverse functions of B cells in tuberculosis, with a focus on their biological and clinical relevance to progression of active disease. We also present the peptide microarray platform as a promising strategy to discover unknown antigenic targets of M. tuberculosis that could contribute to the better understanding of epitope focus of the humoral immune system against M. tuberculosis. PMID:26409285

  2. Psychiatry and Tuberculosis

    PubMed Central

    Fantl, Kurt

    1950-01-01

    Studies on the psychosomatic aspects of tuberculosis have not brought to light a clearcut correlation between a specific personality structure and susceptibility to the illness. The recommendation is made to look for several rather than for one personality type. It is suggested that people should be studied who react to stress with loss of appetite and loss of sleep. This character structure in contrast to that where the person withdraws into sleep and overeats might make a person prone to tuberculosis. The somatopsychic influence of tuberculosis needs to be interpreted in terms of the localization of the lesion as well as infectiousness and conspicuousness of the disease. Some common sociopsychological factors of tuberculosis have been mentioned. Reports on mental illness and tuberculosis and on diet were reviewed. PMID:14792351

  3. Activity of Medicinal Plant Extracts on Multiplication of Mycobacterium tuberculosis under Reduced Oxygen Conditions Using Intracellular and Axenic Assays

    PubMed Central

    Bhatter, Purva D.; Gupta, Pooja D.; Birdi, Tannaz J.

    2016-01-01

    Aim. Test the activity of selected medicinal plant extracts on multiplication of Mycobacterium tuberculosis under reduced oxygen concentration which represents nonreplicating conditions. Material and Methods. Acetone, ethanol and aqueous extracts of the plants Acorus calamus L. (rhizome), Ocimum sanctum L. (leaf), Piper nigrum L. (seed), and Pueraria tuberosa DC. (tuber) were tested on Mycobacterium tuberculosis H37Rv intracellularly using an epithelial cell (A549) infection model. The extracts found to be active intracellularly were further studied axenically under reducing oxygen concentrations. Results and Conclusions. Intracellular multiplication was inhibited ≥60% by five of the twelve extracts. Amongst these 5 extracts, in axenic culture, P. nigrum (acetone) was active under aerobic, microaerophilic, and anaerobic conditions indicating presence of multiple components acting at different levels and P. tuberosa (aqueous) showed bactericidal activity under microaerophilic and anaerobic conditions implying the influence of anaerobiosis on its efficacy. P. nigrum (aqueous) and A. calamus (aqueous and ethanol) extracts were not active under axenic conditions but only inhibited intracellular growth of Mycobacterium tuberculosis, suggesting activation of host defense mechanisms to mediate bacterial killing rather than direct bactericidal activity. PMID:26941797

  4. Activity of Medicinal Plant Extracts on Multiplication of Mycobacterium tuberculosis under Reduced Oxygen Conditions Using Intracellular and Axenic Assays.

    PubMed

    Bhatter, Purva D; Gupta, Pooja D; Birdi, Tannaz J

    2016-01-01

    Aim. Test the activity of selected medicinal plant extracts on multiplication of Mycobacterium tuberculosis under reduced oxygen concentration which represents nonreplicating conditions. Material and Methods. Acetone, ethanol and aqueous extracts of the plants Acorus calamus L. (rhizome), Ocimum sanctum L. (leaf), Piper nigrum L. (seed), and Pueraria tuberosa DC. (tuber) were tested on Mycobacterium tuberculosis H37Rv intracellularly using an epithelial cell (A549) infection model. The extracts found to be active intracellularly were further studied axenically under reducing oxygen concentrations. Results and Conclusions. Intracellular multiplication was inhibited ≥60% by five of the twelve extracts. Amongst these 5 extracts, in axenic culture, P. nigrum (acetone) was active under aerobic, microaerophilic, and anaerobic conditions indicating presence of multiple components acting at different levels and P. tuberosa (aqueous) showed bactericidal activity under microaerophilic and anaerobic conditions implying the influence of anaerobiosis on its efficacy. P. nigrum (aqueous) and A. calamus (aqueous and ethanol) extracts were not active under axenic conditions but only inhibited intracellular growth of Mycobacterium tuberculosis, suggesting activation of host defense mechanisms to mediate bacterial killing rather than direct bactericidal activity. PMID:26941797

  5. Drug-drug interactions in inmates treated for human immunodeficiency virus and Mycobacterium tuberculosis infection or disease: an institutional tuberculosis outbreak.

    PubMed

    Spradling, P; Drociuk, D; McLaughlin, S; Lee, L M; Peloquin, C A; Gallicano, K; Pozsik, C; Onorato, I; Castro, K G; Ridzon, R

    2002-11-01

    The use of rifamycins is limited by drug interactions in human immunodeficiency virus (HIV)-infected persons who are receiving highly active antiretroviral therapy (HAART). During a tuberculosis (TB) outbreak at a prison housing HIV-infected inmates, rifabutin was used to treat 238 men (13 case patients and 225 contacts). Steady-state peak plasma rifabutin concentrations were obtained after rifabutin dosages were adjusted for men receiving single-interacting HAART (with either 1 protease inhibitor [PI] or efavirenz), multi-interacting HAART (with either 2 PIs or > or =1 PI with efavirenz), and for noninteracting HAART (>1 nucleoside reverse-transcriptase inhibitor or no HAART) without rifabutin dose adjustments. Low rifabutin concentrations occurred in 9% of those receiving noninteracting HAART, compared with 19% of those receiving single-interacting and 29% of those receiving multi-interacting HAART (chi2, 3.76; P=.05). Of 225 contacts treated with rifabutin-pyrazinamide, 158 (70%) completed treatment while incarcerated. Rifabutin-pyrazinamide therapy was difficult to implement, because of the need for dosage adjustments and expert clinical management. PMID:12384845

  6. In Vitro Activity of Copper(II) Complexes, Loaded or Unloaded into a Nanostructured Lipid System, against Mycobacterium tuberculosis

    PubMed Central

    da Silva, Patricia B.; de Souza, Paula C.; Calixto, Giovana Maria Fioramonti; Lopes, Erica de O.; Frem, Regina C. G.; Netto, Adelino V. G.; Mauro, Antonio E.; Pavan, Fernando R.; Chorilli, Marlus

    2016-01-01

    Tuberculosis (TB) is an infectious disease caused mainly by the bacillus Mycobacterium tuberculosis (Mtb), presenting 9.5 million new cases and 1.5 million deaths in 2014. The aim of this study was to evaluate a nanostructured lipid system (NLS) composed of 10% phase oil (cholesterol), 10% surfactant (soy phosphatidylcholine, sodium oleate), and Eumulgin® HRE 40 ([castor oil polyoxyl-40-hydrogenated] in a proportion of 3:6:8), and an 80% aqueous phase (phosphate buffer pH = 7.4) as a tactic to enhance the in vitro anti-Mtb activity of the copper(II) complexes [CuCl2(INH)2]·H2O (1), [Cu(NCS)2(INH)2]·5H2O (2) and [Cu(NCO)2(INH)2]·4H2O (3). The Cu(II) complex-loaded NLS displayed sizes ranging from 169.5 ± 0.7095 to 211.1 ± 0.8963 nm, polydispersity index (PDI) varying from 0.135 ± 0.0130 to 0.236 ± 0.00100, and zeta potential ranging from −0.00690 ± 0.0896 to −8.43 ± 1.63 mV. Rheological analysis showed that the formulations behave as non-Newtonian fluids of the pseudoplastic and viscoelastic type. Antimycobacterial activities of the free complexes and NLS-loaded complexes against Mtb H37Rv ATCC 27294 were evaluated by the REMA methodology, and the selectivity index (SI) was calculated using the cytotoxicity index (IC50) against Vero (ATCC® CCL-81), J774A.1 (ATCC® TIB-67), and MRC-5 (ATCC® CCL-171) cell lines. The data suggest that the incorporation of the complexes into NLS improved the inhibitory action against Mtb by 52-, 27-, and 4.7-fold and the SI values by 173-, 43-, and 7-fold for the compounds 1, 2 and 3, respectively. The incorporation of the complexes 1, 2 and 3 into the NLS also resulted in a significant decrease of toxicity towards an alternative model (Artemia salina L.). These findings suggest that the NLS may be considered as a platform for incorporation of metallic complexes aimed at the treatment of TB. PMID:27196901

  7. In Vitro Activity of Copper(II) Complexes, Loaded or Unloaded into a Nanostructured Lipid System, against Mycobacterium tuberculosis.

    PubMed

    Silva, Patricia B da; Souza, Paula C de; Calixto, Giovana Maria Fioramonti; Lopes, Erica de O; Frem, Regina C G; Netto, Adelino V G; Mauro, Antonio E; Pavan, Fernando R; Chorilli, Marlus

    2016-01-01

    Tuberculosis (TB) is an infectious disease caused mainly by the bacillus Mycobacterium tuberculosis (Mtb), presenting 9.5 million new cases and 1.5 million deaths in 2014. The aim of this study was to evaluate a nanostructured lipid system (NLS) composed of 10% phase oil (cholesterol), 10% surfactant (soy phosphatidylcholine, sodium oleate), and Eumulgin(®) HRE 40 ([castor oil polyoxyl-40-hydrogenated] in a proportion of 3:6:8), and an 80% aqueous phase (phosphate buffer pH = 7.4) as a tactic to enhance the in vitro anti-Mtb activity of the copper(II) complexes [CuCl₂(INH)₂]·H₂O (1), [Cu(NCS)₂(INH)₂]·5H₂O (2) and [Cu(NCO)₂(INH)₂]·4H₂O (3). The Cu(II) complex-loaded NLS displayed sizes ranging from 169.5 ± 0.7095 to 211.1 ± 0.8963 nm, polydispersity index (PDI) varying from 0.135 ± 0.0130 to 0.236 ± 0.00100, and zeta potential ranging from -0.00690 ± 0.0896 to -8.43 ± 1.63 mV. Rheological analysis showed that the formulations behave as non-Newtonian fluids of the pseudoplastic and viscoelastic type. Antimycobacterial activities of the free complexes and NLS-loaded complexes against Mtb H37Rv ATCC 27294 were evaluated by the REMA methodology, and the selectivity index (SI) was calculated using the cytotoxicity index (IC50) against Vero (ATCC(®) CCL-81), J774A.1 (ATCC(®) TIB-67), and MRC-5 (ATCC(®) CCL-171) cell lines. The data suggest that the incorporation of the complexes into NLS improved the inhibitory action against Mtb by 52-, 27-, and 4.7-fold and the SI values by 173-, 43-, and 7-fold for the compounds 1, 2 and 3, respectively. The incorporation of the complexes 1, 2 and 3 into the NLS also resulted in a significant decrease of toxicity towards an alternative model (Artemia salina L.). These findings suggest that the NLS may be considered as a platform for incorporation of metallic complexes aimed at the treatment of TB. PMID:27196901

  8. Prevalence of Latent and Active Tuberculosis among Dairy Farm Workers Exposed to Cattle Infected by Mycobacterium bovis

    PubMed Central

    Torres-Gonzalez, Pedro; Soberanis-Ramos, Orbelin; Martinez-Gamboa, Areli; Chavez-Mazari, Barbara; Barrios-Herrera, Ma Teresa; Torres-Rojas, Martha; Cruz-Hervert, Luis Pablo; Garcia-Garcia, Lourdes; Singh, Mahavir; Gonzalez-Aguirre, Adrian; Ponce de Leon-Garduño, Alfredo; Sifuentes-Osornio, José; Bobadilla-del-Valle, Miriam

    2013-01-01

    Background Human tuberculosis caused by M. bovis is a zoonosis presently considered sporadic in developed countries, but remains a poorly studied problem in low and middle resource countries. The disease in humans is mainly attributed to unpasteurized dairy products consumption. However, transmission due to exposure of humans to infected animals has been also recognized. The prevalence of tuberculosis infection and associated risk factors have been insufficiently characterized among dairy farm workers (DFW) exposed in settings with poor control of bovine tuberculosis. Methodology/Principal Findings Tuberculin skin test (TST) and Interferon-gamma release assay (IGRA) were administered to 311 dairy farm and abattoir workers and their household contacts linked to a dairy production and livestock facility in Mexico. Sputa of individuals with respiratory symptoms and samples from routine cattle necropsies were cultured for M. bovis and resulting spoligotypes were compared. The overall prevalence of latent tuberculosis infection (LTBI) was 76.2% (95% CI, 71.4–80.9%) by TST and 58.5% (95% CI, 53.0–64.0%) by IGRA. Occupational exposure was associated to TST (OR 2.72; 95% CI, 1.31–5.64) and IGRA (OR 2.38; 95% CI, 1.31–4.30) adjusting for relevant variables. Two subjects were diagnosed with pulmonary tuberculosis, both caused by M. bovis. In one case, the spoligotype was identical to a strain isolated from bovines. Conclusions We documented a high prevalence of latent and pulmonary TB among workers exposed to cattle infected with M. bovis, and increased risk among those occupationally exposed in non-ventilated spaces. Interspecies transmission is frequent and represents an occupational hazard in this setting. PMID:23638198

  9. Ocular tuberculosis: current perspectives

    PubMed Central

    Shakarchi, Faiz I

    2015-01-01

    The World Health Organization currently estimates that nearly two billion people, or one-third of the world’s population, are infected by tuberculosis, and that roughly 10% of the infected people are symptomatic. Tuberculosis affects the lungs in 80% of patients, while in the remaining 20% the disease may affect other organs, including the eye. Uveitis can be seen concurrently with tuberculosis, but a direct association is difficult to prove. Ocular tuberculosis is usually not associated with clinical evidence of pulmonary tuberculosis, as up to 60% of extrapulmonary tuberculosis patients may not have pulmonary disease. The diagnosis of tuberculous uveitis is often problematic and in nearly all reported cases, the diagnosis was only presumptive. Tuberculous uveitis is a great mimicker of various uveitis entities and it can be considered in the differential diagnosis of any type of intraocular inflammation. It is still unknown if ocular manifestations result from a direct mycobacterium infection or hypersensitivity reaction and this is reflected on the management of tuberculous uveitis. Prevalence of tuberculosis as an etiology of uveitis may reach up to 10% in endemic areas. Tuberculous uveitis is a vision-threatening disease that inevitably leads to blindness if not properly diagnosed and treated. The aim of this review is to illustrate the various clinical features and management of presumed tuberculous uveitis. The current review focuses on the diagnostic criteria, significance of tuberculin skin test, and use of systemic corticosteroids in the management of tuberculous uveitis as recommended in recent publications. PMID:26648690

  10. Tuberculosis DALY-Gap: Spatial and Quantitative Comparison of Disease Burden Across Urban Slum and Non-slum Census Tracts.

    PubMed

    Marlow, Mariel A; Maciel, Ethel Leonor Noia; Sales, Carolina Maia Martins; Gomes, Teresa; Snyder, Robert E; Daumas, Regina Paiva; Riley, Lee W

    2015-08-01

    To quantitatively assess disease burden due to tuberculosis between populations residing in and outside of urban informal settlements in Rio de Janeiro, Brazil, we compared disability-adjusted life years (DALYs), or "DALY-gap." Using the 2010 Brazilian census definition of informal settlements as aglomerados subnormais (AGSN), we allocated tuberculosis (TB) DALYs to AGSN vs non-AGSN census tracts based on geocoded addresses of TB cases reported to the Brazilian Information System for Notifiable Diseases in 2005 and 2010. DALYs were calculated based on the 2010 Global Burden of Disease methodology. DALY-gap was calculated as the difference between age-adjusted DALYs/100,000 population between AGSN and non-AGSN. Total TB DALY in Rio in 2010 was 16,731 (266 DALYs/100,000). DALYs were higher in AGSN census tracts (306 vs 236 DALYs/100,000), yielding a DALY-gap of 70 DALYs/100,000. Attributable DALY fraction for living in an AGSN was 25.4%. DALY-gap was highest for males 40-59 years of age (501 DALYs/100,000) and in census tracts with <60% electricity (12,327 DALYs/100,000). DALY-gap comparison revealed spatial and quantitative differences in TB burden between slum vs non-slum census tracts that were not apparent using traditional measures of incidence and mortality. This metric could be applied to compare TB burden or burden for other diseases in mega-cities with large informal settlements for more targeted resource allocation and evaluation of intervention programs. PMID:25840553

  11. Interleukin 17-Producing γδ T Cells Increased in Patients with Active Pulmonary Tuberculosis

    PubMed Central

    Peng, Meiyu; Wang, Zhaohua; Yao, Chunyan; Jiang, Lina; Jin, Qili; Wang, Jing; Li, Baiqing

    2008-01-01

    Although it has been known that γδ T cells may play an important role in the immune response to infection of Mycobacterium tuberculosis (M. tb), the mechanisms by which the γδ T cells participate in the innate and/or acquired immunity to tuberculosis (TB) have not been full elucidated. In the present study, 27 patients with active pulmonary TB and 16 healthy donors (HD) were performed. We found that proportion of IL-17-producing cells among lymphocyte was similar between TB patients and HD, whereas the proportions of γδ T cells in IL-17-producing cells (59.2%) and IL-17-producing cells in γδ T cells (19.4%) in peripheral blood were markedly increased in TB patients when compared to those in HD (43.9% and 7.7%, respectively). In addition, the proportions of IFN-γ-producing γδ T cells in TB patients were obviously lower than that in HD. Upon re-stimulated with M. tb heat-treated antigen (M. tb-HAg) in vitro, fewer IL-17-producing γδ T cells were generated from HD and TB patients, whereas IFN-γ-producing γδ T cells were increased in TB patients compared to that in HD. Our findings in TB patients and healthy human were consistent with other murine investigation that the IL-17-producing γδ T cells were main source of IL-17 in mouse model of BCG infection, suggesting that γδ T cells might be involved in the formation of tubercular granuloma in pulmonary TB patients, but need further identification. PMID:18582402

  12. Activity against Mycobacterium tuberculosis with concomitant induction of cellular immune responses by a tetraaza-macrocycle with acetate pendant arms.

    PubMed

    David, S; Ordway, D; Arroz, M J; Costa, J; Delgado, R

    2001-01-01

    The novel tetraaza-macrocyclic compound 3,7,11-tris(carboxymethyl)-3,7,11,17-tetraaza-bicyclo[11.3.1]heptadeca-1(17),13,15-triene, abbreviated as ac3py14, was investigated for its activity against Mycobacterium tuberculosis and for induction of protective cellular immune responses. Perspective results show that ac3py14 and its Fe3+ 1:1 complex, [Fe(ac3py14)], inhibited radiometric growth of several strains of M. tuberculosis. Inhibition with 25 microg/mL varied from 99% for H37Rv to 80% and above for multiple drug-resistant clinical isolates. The capacity of ac3py14 to elicit a beneficial immune response without cellular apoptosis was assessed and compared to the effects of virulent M. tuberculosis. The present study produces evidence that after stimulation with ac3py14 there was significant production of interferon gamma (IFN-gamma), whereas the production of interleukin-5 (IL-5) remained low, and there was development of a memory population (CD45RO). The level of binding of Annexin V, a marker of apoptosis, was not sufficient to result in toxic effects toward alphabeta and gammadelta T cells and CD14+ macrophages. This preliminary study is the first report of a compound that simultaneously exerts an inhibitory effect against M. tuberculosis and induces factors associated with protective immune responses. PMID:11501675

  13. A comparative study of anxiety and depression in patients with bronchial asthma, chronic obstructive pulmonary disease and tuberculosis in a general hospital of chest diseases

    PubMed Central

    Moussas, Georgios; Tselebis, Athanasios; Karkanias, Athanasios; Stamouli, Dimitra; Ilias, Ioannis; Bratis, Dionisios; Vassila-Demi, Kalliopi

    2008-01-01

    Background Depression necessitating assistance from health professionals has a lifetime prevalence of 10%. Chronic disease increases comorbidity with mood and/or anxiety disorders. Patients with chronic pulmonary disease present with severely impaired functionality, chronic somatic and psychogenic pain, require frequent hospitalizations and have a dependency upon medical and nursing personnel. In the present study we assessed anxiety and depression in patients hospitalized for pulmonary disease in a pulmonary disease hospital. Methods We assessed anxiety, using the Spielberger state-trait anxiety scale, and depression, using the Beck Depression Inventory, in 132 patients with pulmonary disease. Results A total of 49.2% of the sample had moderate or severe depression and 26.5% had anxiety. Women had higher depression and anxiety scores than men (t test, p < 0.05). Depression was positively correlated with anxiety, age and time from diagnosis. Anxiety was positively correlated with depression and time from diagnosis (Pearson r = 0.62 and 0.29, p < 0.01). Patients with chronic obstructive pulmonary disease and bronchial asthma had higher depression scores than patients with tuberculosis (t test, p < 0.01). Conclusion Depression and anxiety are very prevalent in patients with pulmonary disease, especially chronic disease. This may be a very important negative factor in patients' adaptation to the chronic course of their disease. PMID:18495038

  14. Tuberculosis, advanced - chest x-rays (image)

    MedlinePlus

    Tuberculosis is an infectious disease that causes inflammation, the formation of tubercules and other growths within tissue, ... death. These chest x-rays show advanced pulmonary tuberculosis. There are multiple light areas (opacities) of varying ...

  15. Vitamin D Status in Botswana Children Under 2 Years Old With and Without Active Tuberculosis.

    PubMed

    Ludmir, Jonathan; Mazhani, Loeto; Cary, Mark S; Chakalisa, Unoda A; Pettifor, John M; Molefi, Mooketsi; Redwood, Abiona; Stallings, Virginia A; Gross, Robert; Steenhoff, Andrew P

    2016-05-01

    Additional strategies are needed to prevent and treat tuberculosis (TB). Although vitamin D may have antimycobacterial effects, it is unknown whether low vitamin D status confers a risk for active TB in African children. This case-control study assessed serum 25-hydroxyvitamin D (25(OH)D) concentration in children with and without active TB in Gaborone, Botswana. A total of 80 children under 2 years old with and without active TB, seen at hospitals and clinics in the greater Gaborone area between September 2010 and November 2012, were enrolled. Of these, 39 cases did not differ from the 41 controls in median 25(OH)D levels (P = 0.84). The 25(OH)D was < 20 ng/mL in 8/39 (21%) cases and 7/41 (17%) controls (P = 0.69, χ(2)). Univariate analyses of subject clinical characteristics (other than 25(OH)D levels) showed that any degree of weight loss was associated with a diagnosis of TB (P = 0.047). Other clinical characteristics, including age (P = 0.08) or weight below third percentile (P = 0.58), showed no association with TB. There was no significant difference in vitamin D status between children under 2 years old with and without active TB. Lower vitamin D status did not appear to be a risk factor for TB in this small Gaborone cohort. PMID:26976889

  16. Prevalence, Risk Factors and Social Context of Active Pulmonary Tuberculosis among Prison Inmates in Tajikistan

    PubMed Central

    Winetsky, Daniel E.; Almukhamedov, Olga; Pulatov, Dilshod; Vezhnina, Natalia; Dooronbekova, Aizhan; Zhussupov, Baurzhan

    2014-01-01

    Setting Tuberculosis (TB) is highly prevalent in prisons of the former Soviet Union. Objective To understand the behavioral, demographic and biological factors placing inmates in Tajikistan at risk for active TB. Design We administered a behavioral and demographic survey to 1317 inmates in two prison facilities in Sughd province, Tajikistan along with radiographic screening for pulmonary TB. Suspected cases were confirmed bacteriologically. Inmates undergoing TB treatment were also surveyed. In-depth interviews were conducted with former prisoners to elicit relevant social and behavioral characteristics. Results We identified 59 cases of active pulmonary TB (prevalence 4.5%). Factors independently associated with increased prevalence of active TB were: HIV-infection by self-report (PR 7.88; 95%CI 3.40–18.28), history of previous TB (PR 10.21; 95%CI 6.27–16.63) and infrequent supplemental nutrition beyond scheduled meals (PR 3.00; 95%CI 1.67–5.62). Access to supplemental nutrition was associated with frequency of visits from friends and family and ability to rely on other inmates for help. Conclusion In prison facilities of Tajikistan, HIV-infection, injection drug use and low access to supplemental nutrition were associated with prevalent cases of active pulmonary TB. Policies that reduce HIV transmission among injection drug users and improve the nutritional status of socially isolated inmates may alleviate the TB burden in Tajikistan’s prisons. PMID:24465861

  17. T-SPOT.TB in Detection of Active Tuberculosis During Pregnancy: A Retrospective Study in China

    PubMed Central

    Chen, Qiaopei; Guo, Xuxiao; Wang, Xinfeng; Wang, Maoshui

    2016-01-01

    Background Interferon-gamma release assays have not been validated in active TB among pregnant women. Therefore, the objective of this retrospective study was to estimate the diagnostic value of T-SPOT.TB in active TB among pregnant women. Material/Methods Between May 2012 and May 2015, 26 consecutive pregnant women with suspected TB were enrolled in our study. The clinicopathological characteristics and T-SPOT.TB results were reviewed and analyzed. Results Pregnant patients were divided into a TB group (n=21) and a Non-TB group (n=5). In the TB group, 5 patients had pulmonary TB, 5 had pulmonary TB+ extrapulmonary TB, and 11 had exclusively extrapulmonary TB. The most common site of extrapulmonary TB was pleural (n=11). Statistical analysis showed that the lymphocyte count in the TB group was lower than in the Non-TB group (P<0.05). For detection of active TB during pregnancy, T-SPOT.TB had a high sensitivity of 100.0% (84.5%–100.0%) and a specificity of 80.0% (37.6–96.4%). Conclusions T-SPOT.TB shows good performance in detection of active tuberculosis during pregnancy. Interferon gamma release assay for TB screening of pregnant women is recommended in clinical practice because it may be a more appropriate diagnostic tool than the tuberculin skin test. PMID:26732770

  18. Active Tuberculosis Is Associated with Worse Clinical Outcomes in HIV-Infected African Patients on Antiretroviral Therapy

    PubMed Central

    Siika, Abraham M.; Yiannoutsos, Constantin T.; Wools-Kaloustian, Kara K.; Musick, Beverly S.; Mwangi, Ann W.; Diero, Lameck O.; Kimaiyo, Sylvester N.; Tierney, William M.; Carter, Jane E.

    2013-01-01

    Objective This cohort study utilized data from a large HIV treatment program in western Kenya to describe the impact of active tuberculosis (TB) on clinical outcomes among African patients on antiretroviral therapy (ART). Design We included all patients initiating ART between March 2004 and November 2007. Clinical (signs and symptoms), radiological (chest radiographs) and laboratory (mycobacterial smears, culture and tissue histology) criteria were used to record the diagnosis of TB disease in the program’s electronic medical record system. Methods We assessed the impact of TB disease on mortality, loss to follow-up (LTFU) and incident AIDS-defining events (ADEs) through Cox models and CD4 cell and weight response to ART by non-linear mixed models. Results We studied 21,242 patients initiating ART–5,186 (24%) with TB; 62% female; median age 37 years. There were proportionately more men in the active TB (46%) than in the non-TB (35%) group. Adjusting for baseline HIV-disease severity, TB patients were more likely to die (hazard ratio – HR = 1.32, 95% CI 1.18–1.47) or have incident ADEs (HR = 1.31, 95% CI: 1.19–1.45). They had lower median CD4 cell counts (77 versus 109), weight (52.5 versus 55.0 kg) and higher ADE risk at baseline (CD4-adjusted odds ratio = 1.55, 95% CI: 1.31–1.85). ART adherence was similarly good in both groups. Adjusting for gender and baseline CD4 cell count, TB patients experienced virtually identical rise in CD4 counts after ART initiation as those without. However, the overall CD4 count at one year was lower among patients with TB (251 versus 269 cells/µl). Conclusions Clinically detected TB disease is associated with greater mortality and morbidity despite salutary response to ART. Data suggest that identifying HIV patients co-infected with TB earlier in the HIV-disease trajectory may not fully address TB-related morbidity and mortality. PMID:23301015

  19. The global emergency of tuberculosis: what is the cause?

    PubMed

    Grange, J M; Zumla, A

    2002-06-01

    The treatment of tuberculosis is cheap and highly effective, yet worldwide the disease remains a serious cause of illness and death; so serious as to have been declared a 'global emergency' in 1993. It is principally a disease of poverty, with 95% of cases and 98% of deaths occurring in developing countries. The incidence of tuberculosis is increasing worldwide, partly due to poverty and inequity and partly to the HIV/AIDS pandemic, which greatly increases the risk of infection proceeding to overt disease. Around 30% of AIDS-related deaths are due to tuberculosis. The emergence of multidrug resistant tuberculosis (MDRTB) is an increasing threat to tuberculosis control. Although treatable with alternative drugs, the cost is enormous and, accordingly, not undertaken in many poor nations. While the overall global incidence of MDRTB is low, it occurs in certain 'hotspots' including Russian prisons. Due to adverse socio-economic factors, London has not escaped the general rise in incidence and, without the introduction of active control strategies, there could be a serious epidemic as occurred in New York City ten years ago which required an enormous financial outlay for its control. In view of the global emergency of tuberculosis, the WHO 'Stop TB' campaign has called for the universal adoption of its directly observed therapy, short course (DOTS) strategy. Also, though the Massive Effort Against Diseases of Poverty, several international agencies are urging the establishment of effective control programmes worldwide. London should take the lead and set an example. PMID:12134771

  20. Autophagy in the Fight Against Tuberculosis

    PubMed Central

    Bento, Carla F.; Empadinhas, Nuno

    2015-01-01

    Tuberculosis (TB), a chronic infectious disease mainly caused by the tubercle bacillus Mycobacterium tuberculosis, is one of the world's deadliest diseases that has afflicted humanity since ancient times. Although the number of people falling ill with TB each year is declining, its incidence in many developing countries is still a major cause of concern. Upon invading host cells by phagocytosis, M. tuberculosis can replicate within infected cells by arresting the maturation of the phagosome whose function is to target the pathogen for elimination. Host cells have mechanisms of controlling this evasion by inducing autophagy, an elaborate cellular process that targets bacteria for progressive elimination, decreasing bacterial loads within infected cells. In addition, autophagy activation also aids in the control of inflammation, contributing to a more efficient innate immune response against M. tuberculosis. Several innovative TB therapies have been envisaged based on autophagy manipulation, with some of them revealing high potential for future clinical trials and eventual implementation in healthcare systems. Thus, this review highlights the recent advances on the innate immune response regulation by autophagy upon M. tuberculosis infection and the promising new autophagy-based therapies for TB. PMID:25607549

  1. Comparison of ranging behaviour in a multi-species complex of free-ranging hosts of bovine tuberculosis in relation to their use as disease sentinels.

    PubMed

    Yockney, I J; Nugent, G; Latham, M C; Perry, M; Cross, M L; Byrom, A E

    2013-07-01

    Sentinel species are increasingly used by disease managers to detect and monitor the prevalence of zoonotic diseases in wildlife populations. Characterizing home-range movements of sentinel hosts is thus important for developing improved disease surveillance methods, especially in systems where multiple host species co-exist. We studied ranging activity of major hosts of bovine tuberculosis (TB) in an upland habitat of New Zealand: we compared home-range coverage by ferrets (Mustela furo), wild deer (Cervus elaphus), feral pigs (Sus scrofa), brushtail possums (Trichosurus vulpecula) and free-ranging farmed cattle (Bos taurus). We also report in detail the proportional utilization of a seasonal (4-monthly) range area for the latter four species. Possums covered the smallest home range (<30 ha), ferrets covered ~100 ha, pigs ~4 km(2), deer and cattle both >30 km2. For any given weekly period, cattle, deer and pigs were shown to utilize 37–45% of their estimated 4-month range, while possums utilized 62% during any weekly period and 85% during any monthly period of their estimated 4-month range. We suggest that present means for estimating TB detection kernels, based on long-term range size estimates for possums and sentinel species, probably overstate the true local surveillance coverage per individual. PMID:23433406

  2. Being active when you have heart disease

    MedlinePlus

    Heart disease - activity ... Getting regular exercise when you have heart disease is important. Exercise can make your heart muscle stronger. It may also help you be more active without chest pain or ...

  3. Predominance of modern Mycobacterium tuberculosis strains and active transmission of Beijing sublineage in Jayapura, Indonesia Papua.

    PubMed

    Chaidir, Lidya; Sengstake, Sarah; de Beer, Jessica; Oktavian, Antonius; Krismawati, Hana; Muhapril, Erfin; Kusumadewi, Inri; Annisa, Jessi; Anthony, Richard; van Soolingen, Dick; Achmad, Tri Hanggono; Marzuki, Sangkot; Alisjahbana, Bachti; van Crevel, Reinout

    2016-04-01

    Mycobacterium tuberculosis genotype distribution is different between West and Central Indonesia, but there are no data on the most Eastern part, Papua. We aimed to identify the predominant genotypes of M. tuberculosis responsible for tuberculosis in coastal Papua, their transmission, and the association with patient characteristics. A total of 199 M. tuberculosis isolates were collected. Spoligotyping was applied to describe the population structure of M. tuberculosis, lineage identification was performed using a combination of lineage-specific markers, and genotypic clusters were identified using a combination of 24-locus-MIRU-VNTR and spoligotyping. A high degree of genetic diversity was observed among isolates based on their spoligopatterns. Strains from modern lineage 4 made up almost half of strains (46.9%), being more abundant than the ancient lineage 1 (33.7%), and modern lineage 2 (19.4%). Thirty-five percent of strains belonged to genotypic clusters, especially strains in the Beijing genotype. Previous TB treatment and mutations associated with drug resistance were more common in patients infected with strains of the Beijing genotype. Papua shows a different distribution of M. tuberculosis genotypes compared to other parts of Indonesia. Clustering and drug resistance of modern strains recently introduced to Papua may contribute to the high tuberculosis burden in this region. PMID:26825253

  4. Identification of a small molecule with activity against drug-resistant and persistent tuberculosis

    PubMed Central

    Wang, Feng; Sambandan, Dhinakaran; Halder, Rajkumar; Wang, Jianing; Batt, Sarah M.; Weinrick, Brian; Ahmad, Insha; Yang, Pengyu; Zhang, Yong; Kim, John; Hassani, Morad; Huszar, Stanislav; Trefzer, Claudia; Ma, Zhenkun; Kaneko, Takushi; Mdluli, Khisi E.; Franzblau, Scott; Chatterjee, Arnab K.; Johnsson, Kai; Mikusova, Katarina; Besra, Gurdyal S.; Fütterer, Klaus; Robbins, Scott H.; Barnes, S. Whitney; Walker, John R.; Jacobs, William R.; Schultz, Peter G.

    2013-01-01

    A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-β-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1. These in vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents. PMID:23776209

  5. IL-27 and TGFβ mediated expansion of Th1 and adaptive regulatory T cells expressing IL-10 correlates with bacterial burden and disease severity in pulmonary tuberculosis

    PubMed Central

    Kumar, Nathella P; Moideen, Kadar; Banurekha, Vaithilingam V; Nair, Dina; Sridhar, Rathinam; Nutman, Thomas B; Babu, Subash

    2015-01-01

    CD4+ T cell expression of IL-10 is an important mechanism controlling immunity to tuberculosis (TB). To identify the CD4+ T cell subsets producing IL-10 in human TB, we enumerated the frequencies of IL-10 expressing CD4+ T cell subsets following TB—antigen stimulation of cells from individuals with pulmonary (PTB) and latent TB (LTB). We first demonstrate that TB antigens induce an expansion of IL-10 expressing Th1 (IL-10+, IFNγ+, T-bet+), Th2 (IL-10+, IL-4+, GATA-3+), Th9 (IL-10+, IL-9+, IL-4−), Th17 (IL-10+, IL-17+, IFNγ−), and natural and adaptive regulatory T cells [nTregs; IL-10+, CD4+, CD25+, Foxp3+ and aTregs; IL-10 single+, CD4+, CD25−, Foxp3−] in PTB and LTB individuals, with frequencies being significantly higher in the former. However, only Th1 cells and adaptive Tregs expressing IL-10 exhibit a positive relationship with bacterial burdens and extent of disease in PTB. Finally, we show that IL-27 and TGFβ play an important role in the regulation of IL-10+ Th cell subsets. Thus, active PTB is characterized by an IL-27 and TGFβ mediated expansion of IL-10 expressing CD4+ T cell subsets, with IL-10+ Th1 and IL-10+ aTreg cells playing a potentially pivotal role in the pathogenesis of active disease. PMID:26417443

  6. IL-27 and TGFβ mediated expansion of Th1 and adaptive regulatory T cells expressing IL-10 correlates with bacterial burden and disease severity in pulmonary tuberculosis.

    PubMed

    Kumar, Nathella P; Moideen, Kadar; Banurekha, Vaithilingam V; Nair, Dina; Sridhar, Rathinam; Nutman, Thomas B; Babu, Subash

    2015-09-01

    CD4(+) T cell expression of IL-10 is an important mechanism controlling immunity to tuberculosis (TB). To identify the CD4(+) T cell subsets producing IL-10 in human TB, we enumerated the frequencies of IL-10 expressing CD4(+) T cell subsets following TB-antigen stimulation of cells from individuals with pulmonary (PTB) and latent TB (LTB). We first demonstrate that TB antigens induce an expansion of IL-10 expressing Th1 (IL-10(+), IFNγ(+), T-bet(+)), Th2 (IL-10(+), IL-4(+), GATA-3(+)), Th9 (IL-10(+), IL-9(+), IL-4(-)), Th17 (IL-10(+), IL-17(+), IFNγ(-)), and natural and adaptive regulatory T cells [nTregs; IL-10(+), CD4(+), CD25(+), Foxp3(+) and aTregs; IL-10 single(+), CD4(+), CD25(-), Foxp3(-)] in PTB and LTB individuals, with frequencies being significantly higher in the former. However, only Th1 cells and adaptive Tregs expressing IL-10 exhibit a positive relationship with bacterial burdens and extent of disease in PTB. Finally, we show that IL-27 and TGFβ play an important role in the regulation of IL-10(+) Th cell subsets. Thus, active PTB is characterized by an IL-27 and TGFβ mediated expansion of IL-10 expressing CD4(+) T cell subsets, with IL-10(+) Th1 and IL-10(+) aTreg cells playing a potentially pivotal role in the pathogenesis of active disease. PMID:26417443

  7. Biochemical characterization of quinolinic acid phosphoribosyltransferase from Mycobacterium tuberculosis H37Rv and inhibition of its activity by pyrazinamide.

    PubMed

    Kim, Hyun; Shibayama, Keigo; Rimbara, Emiko; Mori, Shigetarou

    2014-01-01

    Quinolinic acid phosphoribosyltransferase (QAPRTase, EC 2.4.2.19) is a key enzyme in the de novo pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis and a target for the development of new anti-tuberculosis drugs. QAPRTase catalyzes the synthesis of nicotinic acid mononucleotide from quinolinic acid (QA) and 5-phosphoribosyl-1-pyrophosphate (PRPP) through a phosphoribosyl transfer reaction followed by decarboxylation. The crystal structure of QAPRTase from Mycobacterium tuberculosis H37Rv (MtQAPRTase) has been determined; however, a detailed functional analysis of MtQAPRTase has not been published. Here, we analyzed the enzymatic activities of MtQAPRTase and determined the effect on catalysis of the anti-tuberculosis drug pyrazinamide (PZA). The optimum temperature and pH for MtQAPRTase activity were 60°C and pH 9.2. MtQAPRTase required bivalent metal ions and its activity was highest in the presence of Mg2+. Kinetic analyses revealed that the Km values for QA and PRPP were 0.08 and 0.39 mM, respectively, and the kcat values for QA and PRPP were 0.12 and 0.14 [s-1], respectively. When the amino acid residues of MtQAPRTase, which may interact with QA, were substituted with alanine residues, catalytic activity was undetectable. Further, PZA, which is an anti-tuberculosis drug and a structural analog of QA, markedly inhibited the catalytic activity of MtQAPRTase. The structure of PZA may provide the basis for the design of new inhibitors of MtQAPRTase. These findings provide new insights into the catalytic properties of MtQAPRTase. PMID:24949952

  8. The Effects of Socioeconomic Status, Clinical Factors, and Genetic Ancestry on Pulmonary Tuberculosis Disease in Northeastern Mexico

    PubMed Central

    Young, Bonnie N.; Rendón, Adrian; Rosas-Taraco, Adrian; Baker, Jack; Healy, Meghan; Gross, Jessica M.; Long, Jeffrey; Burgos, Marcos; Hunley, Keith L.

    2014-01-01

    Diverse socioeconomic and clinical factors influence susceptibility to tuberculosis (TB) disease in Mexico. The role of genetic factors, particularly those that differ between the parental groups that admixed in Mexico, is unclear. The objectives of this study are to identify the socioeconomic and clinical predictors of the transition from latent TB infection (LTBI) to pulmonary TB disease in an urban population in northeastern Mexico, and to examine whether genetic ancestry plays an independent role in this transition. We recruited 97 pulmonary TB disease patients and 97 LTBI individuals from a public hospital in Monterrey, Nuevo León. Socioeconomic and clinical variables were collected from interviews and medical records, and genetic ancestry was estimated for a subset of 142 study participants from 291,917 single nucleotide polymorphisms (SNPs). We examined crude associations between the variables and TB disease status. Significant predictors from crude association tests were analyzed using multivariable logistic regression. We also compared genetic ancestry between LTBI individuals and TB disease patients at 1,314 SNPs in 273 genes from the TB biosystem in the NCBI BioSystems database. In crude association tests, 12 socioeconomic and clinical variables were associated with TB disease. Multivariable logistic regression analyses indicated that marital status, diabetes, and smoking were independently associated with TB status. Genetic ancestry was not associated with TB disease in either crude or multivariable analyses. Separate analyses showed that LTBI individuals recruited from hospital staff had significantly higher European genetic ancestry than LTBI individuals recruited from the clinics and waiting rooms. Genetic ancestry differed between individuals with LTBI and TB disease at SNPs located in two genes in the TB biosystem. These results indicate that Monterrey may be structured with respect to genetic ancestry, and that genetic differences in TB

  9. [Multidrug-resistant tuberculosis associated with AIDS (kinetics of nosocomial epidemics of multidrug-resistant tuberculosis associated with AIDS. Possible transformation into endemic disease].

    PubMed

    Gonzàlez Montaner, L J; Alberti, F; Palmero, D

    1999-01-01

    The increase in the incidence of AIDS-related tuberculosis over the last decades has fueled the dissemination of multiple drug resistance tuberculosis (including resistant strains to INH and rifampin). This has now been recognized in a variety of settings including hospitals, prisons and shelters. We have identified a nosocomial epidemic at the Muñiz Hospital in the city of Buenos Aires, Argentina. This has evolved as one of the largest institutional outbreaks yet to be recognized. The purpose of this paper is to characterize the evolution of this outbreak which at the end of 1997 had involved in excess of 500 cases. Among the 3,322 patients discharged at the Muñiz Hospital during the years 1996-1997 with the diagnosis of tuberculosis, 440 (13.24%) were discharged with the diagnosis of multiple drug resistance tuberculosis. The immediate mortality (during the ensuing four months following the bacteriological diagnosis) was of 91.3% of cases in 1995 and decreased progressively to 65.9% in 1996 and 55.9% in 1997. The bacteriological confirmation of the diagnosis was made after the patients death in a decreasing number of cases, going from 72.5% of the cases in 1995 to 28.3% of the cases in 1997. Despite the significant progress achieved with regard to the diagnosis and treatment of multiple drug resistance tuberculosis, the measures undertaken to decrease the spread of the cases have had limited success. This is chiefly attributable to the inability to isolate cases. This has continued to promote nosocomial spread of multiple drug resistance tuberculosis in our environment. PMID:10560164

  10. IL-32 is a molecular marker of a host defense network in human tuberculosis

    PubMed Central

    Montoya, Dennis; Inkeles, Megan S.; Liu, Phillip T.; Realegeno, Susan; Teles, Rosane M. B.; Vaidya, Poorva; Munoz, Marcos A.; Schenk, Mirjam; Swindell, William R.; Chun, Rene; Zavala, Kathryn; Hewison, Martin; Adams, John S.; Horvath, Steve; Pellegrini, Matteo; Bloom, Barry R.; Modlin, Robert L.

    2014-01-01

    Tuberculosis is a leading cause of infectious disease–related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets for M. tuberculosis therapies. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify potential human candidate markers of host defense by studying gene expression profiles of macrophages, cells that, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene coexpression network analysis revealed an association between the cytokine interleukin-32 (IL-32) and the vitamin D antimicrobial pathway in a network of interferon-γ– and IL-15–induced “defense response” genes. IL-32 induced the vitamin D–dependent antimicrobial peptides cathelicidin and DEFB4 and to generate antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. In addition, the IL-15–induced defense response macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent compared with active tuberculosis or healthy controls and a coexpression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15–induced gene network. As maintaining M. tuberculosis in a latent state and preventing transition to active disease may represent a form of host resistance, these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis. PMID:25143364

  11. Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome.

    PubMed

    Tan, Hong Yien; Yong, Yean Kong; Shankar, Esaki M; Paukovics, Geza; Ellegård, Rada; Larsson, Marie; Kamarulzaman, Adeeba; French, Martyn A; Crowe, Suzanne M

    2016-05-15

    Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) complicates combination antiretroviral therapy (cART) in up to 25% of patients with HIV/TB coinfection. Monocytes and IL-18, a signature cytokine of inflammasome activation, are implicated in TB-IRIS pathogenesis. In this study, we investigated inflammasome activation both pre- and post-cART in TB-IRIS patients. HIV/TB patients exhibited higher proportions of monocytes expressing activated caspase-1 (casp1) pre-cART, compared with HIV patients without TB, and patients who developed TB-IRIS exhibited the greatest increase in casp1 expression. CD64(+) monocytes were a marker of increased casp1 expression. Furthermore, IL-1β, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation of NLRP3 and AIM2 inflammasome mRNA, compared with controls. Analysis of plasma mitochondrial DNA levels showed that TB-IRIS patients experienced greater cell death, especially pre-cART. Plasma NO levels were lower both pre- and post-cART in TB-IRIS patients, providing evidence of inadequate inflammasome regulation. Plasma IL-18 levels pre-cART correlated inversely with NO levels but positively with monocyte casp1 expression and mitochondrial DNA levels, and expression of IL-18Rα on CD4(+) T cells and NK cells was higher in TB-IRIS patients, providing evidence that IL-18 is a marker of inflammasome activation. We propose that inflammasome activation in monocytes/macrophages of HIV/TB patients increases with ineffective T cell-dependent activation of monocytes/macrophages, priming them for an excessive inflammatory response after cART is commenced, which is greatest in patients with TB-IRIS. PMID:27076678

  12. Respiratory infections: pulmonary tuberculosis.

    PubMed

    Choby, Beth A; Hunter, Paul

    2015-02-01

    Family physicians can prevent mortality and disability due to pulmonary tuberculosis (TB) by identifying high-risk patients. Recognition of symptoms (eg, cough for 3 weeks or longer) helps prevent overlooked diagnoses because results of tuberculin skin tests and interferon-gamma release assays are negative in up to 25% and 21%, respectively, of severe acute cases. The typical x-ray findings of cavities, infiltrates, and lymphadenopathy are minimal among immunosuppressed patients. Cases of active TB must be reported to local or state health departments within 24 hours of diagnosis. Sputum acid-fast bacillus tests provide results within hours and help quantify bacterial load but are not highly sensitive, and infection with nontuberculous mycobacteria can cause positive test results. Sputum cultures are adequately sensitive, identify mycobacterial species, and provide organisms for antibiotic susceptibility testing but require weeks for results. Molecular detection of Mycobacterium tuberculosis and of antibiotic-resistant mutations can expedite diagnosis and management of drug-resistant TB. Management of active TB should include directly observed therapy. Standard 6-month therapy with rifampin, isoniazid, pyrazinamide, and ethambutol resolves infection in nearly all immunocompetent adults with pansensitive TB. Multidrug-resistant TB requires second-line antibiotics (eg, fluoroquinolones, linezolid) in individualized regimens lasting 2 years. Management of latent TB infection prevents progression to active TB disease, particularly if management is completed within 2 years of infection. PMID:25685923

  13. Rifabutin encapsulated in liposomes exhibits increased therapeutic activity in a model of disseminated tuberculosis.

    PubMed

    Gaspar, M M; Cruz, A; Penha, A F; Reymão, J; Sousa, A C; Eleutério, C V; Domingues, S A; Fraga, A G; Filho, A Longatto; Cruz, M E M; Pedrosa, J

    2008-01-01

    Tuberculosis (TB) is a leading cause of death amongst infectious diseases. The low permeation of antimycobacterial agents and their difficult access to infected macrophages necessitate long-term use of high drug doses. Liposomes preferentially accumulate in macrophages, increasing the efficacy of antibiotics against intracellular parasites. In the present work, several rifabutin (RFB) liposomal formulations were developed and characterised and their in vivo profile was compared with free RFB following intravenous administration. With the RFB liposomal formulations tested, higher concentrations of the antibiotic were achieved in liver, spleen and lungs 24h post administration compared with free RFB. The concentration of RFB in these organs was dependent on the rigidity of liposomal lipids. The liposomal RFB formulation prepared with dipalmitoyl phosphatidylcholine:dipalmitoyl phosphatidylglycerol (DPPC:DPPG) was the most effective and was selected for biological evaluation in a mouse model of disseminated TB. Compared with mice treated with free RFB, mice treated with the DPPC:DPPG RFB formulation exhibited lower bacterial loads in the spleen (5.53 log(10) vs. 5.18 log(10)) and liver (5.79 log(10) vs. 5.41 log(10)). In the lung, the level of pathology was lower in mice treated with encapsulated RFB. These results suggest that liposomal RFB is a promising approach for the treatment of extrapulmonary TB in human immunodeficiency virus co-infected patients. PMID:18006283

  14. Tuberculosis control activities before and after Hurricane Sandy--northeast and mid-Atlantic states, 2012.

    PubMed

    2013-03-22

    On October 29, 2012, Hurricane Sandy struck the U.S. northeast and mid-Atlantic seaboard; the effects of the storm extended to southeastern and midwestern states and to eastern Canada. At the time, 1,899 residents in the most affected areas were undergoing treatment for tuberculosis (TB) disease or infection. To ascertain the operational abilities of state and local TB programs during and after the storm and to determine whether lessons learned from a previous hurricane were effective in ensuring continuity of TB patient care, CDC interviewed staff members at all of the affected state and city TB control programs, including those in areas with power outages and flooded streets, tunnels, and subway lines. The interviews determined that continuity of care for TB patients in programs affected by Hurricane Sandy was better preserved than it had been during and after Hurricane Katrina in August 2005. This improvement might be attributed to 1) preparedness measures learned from Hurricane Katrina (e.g., preparing line lists of patients, providing patients with as-needed medications, and making back-up copies of patient records in advance of the storm) and 2) less widespread displacement of persons after Hurricane Sandy than occurred after Hurricane Katrina. Maintaining readiness among clinicians and TB control programs to respond to natural disasters remains essential to protecting public health and preserving TB patients' continuity of care. PMID:23515057

  15. 2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains.

    PubMed

    Pissinate, Kenia; Villela, Anne Drumond; Rodrigues-Junior, Valnês; Giacobbo, Bruno Couto; Grams, Estêvão Silveira; Abbadi, Bruno Lopes; Trindade, Rogério Valim; Roesler Nery, Laura; Bonan, Carla Denise; Back, Davi Fernando; Campos, Maria Martha; Basso, Luiz Augusto; Santos, Diógenes Santiago; Machado, Pablo

    2016-03-10

    2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 μM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC50s ≥ 20 μM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug-drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 μM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment. PMID:26985307

  16. Granulocytic Myeloid Derived Suppressor Cells Expansion during Active Pulmonary Tuberculosis Is Associated with High Nitric Oxide Plasma Level

    PubMed Central

    El Daker, Sary; Sacchi, Alessandra; Tempestilli, Massimo; Carducci, Claudia; Goletti, Delia; Vanini, Valentina; Colizzi, Vittorio; Lauria, Francesco Nicola; Martini, Federico; Martino, Angelo

    2015-01-01

    Tuberculosis (TB) is still the principal cause of death caused by a single infectious agent, and the balance between the bacillus and host defense mechanisms reflects the different manifestations of the pathology. The aim of this work was to study the role of myeloid-derived suppressor cells (MDSCs) during active pulmonary tuberculosis at the site of infection. We observed an expansion of MDSCs in the lung and blood of patients with active TB, which are correlated with an enhanced amount of nitric oxide in the plasma. We also found that these cells have the remarkable ability to suppress T-cell response, suggesting an important role in the modulation of the immune response against TB. Interestingly, a trend in the diminution of MDSCs was found after an efficacious anti-TB therapy, suggesting that these cells may be used as a potential biomarker for monitoring anti-TB therapy efficacy. PMID:25879532

  17. The Three Mycobacterium tuberculosis Antigen 85 Isoforms Have Unique Substrates and Activities Determined by Non-active Site Regions*

    PubMed Central

    Backus, Keriann M.; Dolan, Michael A.; Barry, Conor S.; Joe, Maju; McPhie, Peter; Boshoff, Helena I. M.; Lowary, Todd L.; Davis, Benjamin G.; Barry, Clifton E.

    2014-01-01

    The three isoforms of antigen 85 (A, B, and C) are the most abundant secreted mycobacterial proteins and catalyze transesterification reactions that synthesize mycolated arabinogalactan, trehalose monomycolate (TMM), and trehalose dimycolate (TDM), important constituents of the outermost layer of the cellular envelope of Mycobacterium tuberculosis. These three enzymes are nearly identical at the active site and have therefore been postulated to exist to evade host immunity. Distal to the active site is a second putative carbohydrate-binding site of lower homology. Mutagenesis of the three isoforms at this second site affected both substrate selectivity and overall catalytic activity in vitro. Using synthetic and natural substrates, we show that these three enzymes exhibit unique selectivity; antigen 85A more efficiently mycolates TMM to form TDM, whereas C (and to a lesser extent B) has a higher rate of activity using free trehalose to form TMM. This difference in substrate selectivity extends to the hexasaccharide fragment of cell wall arabinan. Mutation of secondary site residues from the most active isoform (C) into those present in A or B partially interconverts this substrate selectivity. These experiments in combination with molecular dynamics simulations reveal that differences in the N-terminal helix α9, the adjacent Pro216–Phe228 loop, and helix α5 are the likely cause of changes in activity and substrate selectivity. These differences explain the existence of three isoforms and will allow for future work in developing inhibitors. PMID:25028517

  18. [Imaging and Laboratory Diagnostics for Tuberculosis].

    PubMed

    Bauer, C M; Schmähl, A; Kreuter, M

    2016-05-01

    Diagnosis of tuberculosis (TB) is difficult, since symptoms are often very unspecific or lacking. However active, prompt and accurate diagnosis is the key element in the public health response to tuberculosis and the cornerstone of tuberculosis control. Different diagnostic methods for an assured diagnosis of TB are necessary. Chest radiography is a useful keystone to identify tuberculosis, but diagnosis of tuberculosis cannot be established by radiography alone. CT scanning is used in patients without pathological chest radiography but clinically suspected active TB and to differentiate TB from other diseases. Radiological appearance is primarily determined by the immune status of patients and caverns and disseminated disease foci are often observed. Laboratory diagnostic methods include microscopic identification of acid-fast mycobacteria from any body fluid (especially sputum), as well as isolation and characterisation of mycobacteria in culture. It is then possible to type the pathogens by the shape of their colony, their growth behavior and their biochemical characteristics. These methods are regarded as the gold standard in diagnosis of active TB. In patients who are highly suspected of having TB, but whose sputum specimens tested negative for mycobacteria, a nucleic acid amplification test is additionally performed. Moreover, sensitivity testing with first and second line antitubercular drugs is applied as standard. Laboratory diagnostic testing of cellular immunity against pathogenic mycobacteria employs the tuberculin skin test (TST, Mantoux tuberculin test) or the more specific interferon γ test to determine γ interferon released by T lymphocytes stimulated in vitro. The new ELISA and ELISPOT procedures exhibit higher test specificity and less cross reactivity to NTM (non-tuberculosis mycobacteria), are independent of BCG-vaccination status and correlate better with the degree of exposure than does the TST. PMID:27187878

  19. Addressing poverty through disease control programmes: examples from Tuberculosis control in India

    PubMed Central

    2012-01-01

    Introduction Tuberculosis remains a major public health problem in India with the country accounting for one-fifth or 21% of all tuberculosis cases reported globally. The purpose of the study was to obtain an understanding on pro-poor initiatives within the framework of tuberculosis control programme in India and to identify mechanisms to improve the uptake and access to TB services among the poor. Methodology A national level workshop was held with participation from all relevant stakeholder groups. This study conducted during the stakeholder workshop adopted participatory research methods. The data was elicited through consultative and collegiate processes. The research study also factored information from primary and secondary sources that included literature review examining poverty headcount ratios and below poverty line population in the country; and quasi-profiling assessments to identify poor, backward and tribal districts as defined by the TB programme in India. Results Results revealed that current pro-poor initiatives in TB control included collaboration with private providers and engaging community to improve access among the poor to TB diagnostic and treatment services. The participants identified gaps in existing pro-poor strategies that related to implementation of advocacy, communication and social mobilisation; decentralisation of DOT; and incentives for the poor through the available schemes for public-private partnerships and provided key recommendations for action. Synergies between TB control programme and centrally sponsored social welfare schemes and state specific social welfare programmes aimed at benefitting the poor were unclear. Conclusion Further in-depth analysis and systems/policy/operations research exploring pro-poor initiatives, in particular examining service delivery synergies between existing poverty alleviation schemes and TB control programme is essential. The understanding, reflection and knowledge of the key stakeholders

  20. Detection of Mycobacterium tuberculosis with nested polymerase chain reaction analysis in enucleated eye ball in Eales' disease.

    PubMed

    Verma, Aditya; Biswas, Jyotirmay; Dhanurekha, L; Gayathri, R; Lily Therese, K

    2016-06-01

    Nested polymerase chain reaction (nPCR) was performed on enucleated eyeball for detection of Mycobacterium tuberculosis (M. tb) genome in a patient with Eales' disease. PCR analysis in all previous studies has been done mainly using aqueous, vitreous and epiretinal membranes from these patients. Paraffin wax embedded tissue section of the enucleated eyeball was analyzed by histopathology and nPCR targeting MPB64 gene and IS6110 region of M. tb genome. Lymphocytic infiltration was seen in the vitreous, iris and the retinal tissue. Ziehl Neelsen stain was negative for acid fast bacilli. Caseation necrosis was not seen in any section. Agarose gel electrophoretogram showed positive results with 200 bp specific amplified product targeting MPB64 gene, whereas nPCR targeting IS6110 region was negative. Since biopsy proven M. tb is extremely difficult in ocular tissues due to extensive necrosis, the nPCR technique aided in the diagnosis. PMID:26499903

  1. Effect of Active Case Finding on Prevalence and Transmission of Pulmonary Tuberculosis in Dhaka Central Jail, Bangladesh

    PubMed Central

    Banu, Sayera; Rahman, Md. Toufiq; Uddin, Mohammad Khaja Mafij; Khatun, Razia; Khan, Md. Siddiqur Rahman; Rahman, Md. Mojibur; Uddin, Syed Iftekhar; Ahmed, Tahmeed; Heffelfinger, James D.

    2015-01-01

    Background Understanding tuberculosis (TB) transmission dynamics is essential for establishing effective TB control strategies in settings where the burden and risk of transmission are high. The objectives of this study were to evaluate the effect of active screening on controlling TB transmission and also to characterize Mycobacterium tuberculosis strains for investigating transmission dynamics in a correctional setting. Methods The study was carried out in Dhaka Central Jail (DCJ), from October 2005 to February 2010. An active case finding strategy for pulmonary TB was established both at the entry point to the prison and inside the prison. Three sputum specimens were collected from all pulmonary TB suspects and subjected to smear microscopy, culture, and drug susceptibility testing as well as genotyping which included deletion analysis, spoligotyping and analysis of mycobacterial interspersed repetitive units (MIRU). Results A total of 60,585 inmates were screened during the study period. We found 466 inmates with pulmonary TB of whom 357 (77%) had positive smear microscopy results and 109 (23%) had negative smear microscopy results but had positive results on culture. The number of pulmonary TB cases declined significantly, from 49 cases during the first quarter to 8 cases in the final quarter of the study period (p=0.001). Deletion analysis identified all isolates as M. tuberculosis and further identified 229 (70%) strains as ‘modern’ and 100 (30%) strains as ‘ancestral’. Analysis of MIRU showed that 347 strains (85%) exhibited unique patterns, whereas 61 strains (15%) clustered into 22 groups. The largest cluster comprised eight strains of the Beijing M. tuberculosis type. The rate of recent transmission was estimated to be 9.6%. Conclusions Implementation of active screening for TB was associated with a decline in TB cases in DCJ. Implementation of active screening in prison settings might substantially reduce the national burden of TB in Bangladesh

  2. Parasite Infection and Tuberculosis Disease among Children: A Case–Control Study

    PubMed Central

    Franke, Molly F.; del Castillo, Hernán; Pereda, Ynés; Lecca, Leonid; Fuertes, Jhoelma; Cárdenas, Luz; Becerra, Mercedes C.; Bayona, Jaime; Murray, Megan

    2014-01-01

    We conducted a case–control study to examine associations between parasite infection, including protozoa infection, and tuberculosis (TB) in children in Lima, Peru. We enrolled 189 matched-pairs. In multivariable conditional logistic regression analyses, Blastocystis hominis infection (rate ratio = 0.30, 95% confidence interval = 0.14–0.64, P = 0.002) was strongly associated with a lower risk of TB. We observed a statistically significant inverse linear dose-response relationship between Blastocystis hominis infection and TB. These findings should be confirmed in future prospective studies. PMID:24379242

  3. 38 CFR 4.88b - Schedule of ratings-infectious diseases, immune disorders and nutritional deficiencies.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., cerebrospinal syphilis, DC 8014, meningovascular syphilis, DC 8015, tabes dorsalis, and DC 9301, dementia associated with central nervous system syphilis) 6311Tuberculosis, miliary: As active disease 100...

  4. 38 CFR 4.88b - Schedule of ratings-infectious diseases, immune disorders and nutritional deficiencies.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., cerebrospinal syphilis, DC 8014, meningovascular syphilis, DC 8015, tabes dorsalis, and DC 9301, dementia associated with central nervous system syphilis) 6311Tuberculosis, miliary: As active disease 100...

  5. 38 CFR 4.88b - Schedule of ratings-infectious diseases, immune disorders and nutritional deficiencies.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., cerebrospinal syphilis, DC 8014, meningovascular syphilis, DC 8015, tabes dorsalis, and DC 9301, dementia associated with central nervous system syphilis) 6311Tuberculosis, miliary: As active disease 100...

  6. UvrD2 is essential in Mycobacterium tuberculosis, but its helicase activity is not required.

    PubMed

    Williams, Alan; Güthlein, Carolin; Beresford, Nicola; Böttger, Erik C; Springer, Burkhard; Davis, Elaine O

    2011-09-01

    UvrD is an SF1 family helicase involved in DNA repair that is widely conserved in bacteria. Mycobacterium tuberculosis has two annotated UvrD homologues; here we investigate the role of UvrD2. The uvrD2 gene at its native locus could be knocked out only in the presence of a second copy of the gene, demonstrating that uvrD2 is essential. Analysis of the putative protein domain structure of UvrD2 shows a distinctive domain architecture, with an extended C terminus containing an HRDC domain normally found in SF2 family helicases and a linking domain carrying a tetracysteine motif. Truncated constructs lacking the C-terminal domains of UvrD2 were able to compensate for the loss of the chromosomal copy, showing that these C-terminal domains are not essential. Although UvrD2 is a functional helicase, a mutant form of the protein lacking helicase activity was able to permit deletion of uvrD2 at its native locus. However, a mutant protein unable to hydrolyze ATP or translocate along DNA was not able to compensate for lack of the wild-type protein. Therefore, we concluded that the essential role played by UvrD2 is unlikely to involve its DNA unwinding activity and is more likely to involve DNA translocation and, possibly, protein displacement. PMID:21725019

  7. Serological markers of hepatitis B and C in patients with HIV/AIDS and active tuberculosis.

    PubMed

    Araújo-Mariz, Carolline; Lopes, Edmundo Pessoa; Ximenes, Ricardo A A; Lacerda, Heloísa R; Miranda-Filho, Demócrito B; Montarroyos, Ulisses R; Barreto, Silvana; Salustiano, Daniela Medeiros; Albuquerque, Maria Fátima Pessoa Militão

    2016-06-01

    Infection with hepatitis B virus (HBV) and C virus (HCV) are common in patients with HIV/AIDS and tuberculosis (TB). This is a cross-sectional study with patients infected with HIV/AIDS and active TB in Recife, Brazil, aiming to verify the prevalence of markers for HBV: antibody to hepatitis B core antigen (anti-HBc); and HCV: antibody to hepatitis C virus (anti-HCV) by chemiluminescence, and to identify the frequency of associated factors. Data were collected through questionnaires, and blood was drawn from patients for analysis. We used the chi-square test and the Fisher exact test when necessary. We conducted a bivariate logistic regression analysis and the magnitude of the associations was expressed as odds ratio (OR) with a confidence interval of 95%. Among 166 patients studied with HIV/AIDS and active TB, anti-HBc was positive in 61 patients [36.7%; 95%CI (29.4-44.6%)] and anti-HCV in 11[6.6%; 95%CI (3.4-11.5%)]. In the logistic regression analysis, male sex, and age ≥40 years were independent factors associated with the occurrence of anti-HBc. In conclusion, we verified a high frequency of HBV contact marker and a low frequency of HCV markers in patients with HIV/AIDS and TB in Recife. J. Med. Virol. 88:996-1002, 2016. © 2015 Wiley Periodicals, Inc. PMID:26580855

  8. Active Tuberculosis Case Finding Interventions Among Immigrants, Refugees and Asylum Seekers in Italy

    PubMed Central

    Schepisi, Monica Sañé; Gualano, Gina; Piselli, Pierluca; Mazza, Marta; D’Angelo, Donatella; Fasciani, Francesca; Barbieri, Alberto; Rocca, Giorgia; Gnolfo, Filippo; Olivani, Piefranco; Ferrarese, Maurizio; Codecasa, Luigi Ruffo; Palmieri, Fabrizio; Girardi, Enrico

    2016-01-01

    In Italy tuberculosis (TB) is largely concentrated in vulnerable groups such as migrants and in urban settings. We analyzed three TB case finding interventions conducted at primary centers and mobile clinics for regular/irregular immigrants and refugees/asylum seekers performed over a four-year period (November 2009-March 2014) at five different sites in Rome and one site in Milan, Italy. TB history and presence of symptoms suggestive of active TB were investigated by verbal screening through a structured questionnaire in migrants presenting for any medical condition to out-patient and mobile clinics. Individuals reporting TB history or symptoms were referred to a TB clinic for diagnostic workup. Among 6347 migrants enrolled, 891 (14.0%) reported TB history or symptoms suggestive of active TB and 546 (61.3%) were referred to the TB clinic. Of them, 254 (46.5%) did not present for diagnostic evaluation. TB was diagnosed in 11 individuals representing 0.17% of those screened and 3.76% of those evaluated. The overall yield of this intervention was in the range reported for other TB screening programs for migrants, although we recorded an unsatisfactory adherence to diagnostic workup. Possible advantages of this intervention include low cost and reduced burden of medical procedures for the screened population. PMID:27403270

  9. Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis

    PubMed Central

    Park, Sae Woong; Casalena, Dominick; Wilson, Daniel; Dai, Ran; Nag, Partha; Liu, Feng; Boyce, Jim P.; Bittker, Joshua; Schreiber, Stuart; Finzel, Barry C.; Schnappinger, Dirk; Aldrich, Courtney C.

    2014-01-01

    SUMMARY Biotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high-throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counter-screen in either biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counter-screen proved crucial to filter out compounds whose whole-cell activity was off-target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were co-crystallized with BioA to provide a framework for future structure-based drug design efforts. PMID:25556942

  10. A novel molecule with notable activity against multi-drug resistant tuberculosis.

    PubMed

    Nair, Vasu; Okello, Maurice O; Mangu, Naveen K; Seo, Byung I; Gund, Machhindra G

    2015-03-15

    Multi-drug resistant tuberculosis (MDR-TB) is emerging as a serious global health problem, which has been elevated through co-infection involving HIV and MDR-Mtb. The discovery of new compounds with anti-MDR TB efficacy and favorable metabolism profiles is an important scientific challenge. Using computational biology and ligand docking data, we have conceived a multifunctional molecule, 2, as a potential anti-MDR TB agent. This compound was produced through a multi-step synthesis. It exhibited significant in vitro activity against MDR-TB (MIC 1.56μg/mL) and its half-life (t1/2) in human liver microsomes was 14.4h. The metabolic profiles of compound 2 with respect to human cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) isozymes were favorable. Compound 2 also had relatively low in vitro cytotoxicity in uninfected macrophages. It displayed synergistic behavior against MDR-TB in combination with PA-824. Interestingly, compound 2 also displayed in vitro anti-HIV activity. PMID:25677656

  11. Increased mortality associated with treated active tuberculosis in HIV-infected adults in Tanzania.

    PubMed

    Kabali, Conrad; Mtei, Lillian; Brooks, Daniel R; Waddell, Richard; Bakari, Muhammad; Matee, Mecky; Arbeit, Robert D; Pallangyo, Kisali; von Reyn, C Fordham; Horsburgh, C Robert

    2013-07-01

    Active tuberculosis (TB) among HIV-infected patients, even when successfully treated, may be associated with excess mortality. We conducted a prospective cohort study nested in a randomized TB vaccine trial to compare mortality between HIV-infected patients diagnosed and treated for TB (TB, n = 77) and HIV-infected patients within the same CD4 range, who were not diagnosed with or treated for active TB (non-TB, n = 308) in the period 2001-2008. Only twenty four subjects (6%) were on antiretroviral therapy at the beginning of this study. After accounting for covariate effects including use of antiretroviral therapy, isoniazid preventive therapy, and receipt of vaccine, we found a four-fold increase in mortality in TB patients compared with non-TB patients (adjusted Hazard Ratio 4.61; 95% Confidence Interval (CI): 1.63, 13.05). These findings suggest that treatment for TB alone is not sufficient to avert the excess mortality associated with HIV-related TB and that prevention of TB may provide a mortality benefit. PMID:23523641

  12. Increased mortality associated with treated active tuberculosis in HIV-infected adults in Tanzania

    PubMed Central

    Kabali, Conrad; Mtei, Lillian; Brooks, Daniel R.; Waddell, Richard; Bakari, Muhammad; Matee, Mecky; Arbeit, Robert D.; Pallangyo, Kisali; von Reyn, C. Fordham; Horsburgh, C. Robert

    2013-01-01

    SUMMARY Active tuberculosis (TB) among HIV-infected patients, even when successfully treated, may be associated with excess mortality. We conducted a prospective cohort study nested in a randomized TB vaccine trial to compare mortality between HIV-infected patients diagnosed and treated for TB (TB, n=77) and HIV-infected patients within the same CD4 range, who were not diagnosed with or treated for active TB (non-TB, n=308) in the period 2001–2008. Only twenty four subjects (6%) were on antiretroviral therapy at the beginning of this study. After accounting for covariate effects including use of antiretroviral therapy, isoniazid preventive therapy, and receipt of vaccine, we found a four-fold increase in mortality in TB patients compared with non-TB patients (adjusted Hazard Ratio 4.61; 95% Confidence Interval (CI): 1.63, 13.05). These findings suggest that treatment for TB alone is not sufficient to avert the excess mortality associated with HIV-related TB and that prevention of TB may provide a mortality benefit. PMID:23523641

  13. NF-κB Repressing Factor Inhibits Chemokine Synthesis by Peripheral Blood Mononuclear Cells and Alveolar Macrophages in Active Pulmonary Tuberculosis

    PubMed Central

    Huang, Kuo-Hsiung; Wang, Chun-Hua; Lee, Kang-Yun; Lin, Shu-Min

    2013-01-01

    NF-κB repressing factor (NRF) is a transcriptional silencer implicated in the basal silencing of specific NF-κB targeting genes, including iNOS, IFN-β and IL-8/CXCL8. IP-10/CXCL10 and IL-8/CXCL8 are involved in neutrophil and lymphocyte recruitment against M. tuberculosis (MTb) and disease progression of pulmonary tuberculosis (TB). Alveolar macrophages (AM) and peripheral blood mononuclear cells (PBMC) were used to study the regulatory role of NRF in pulmonary TB. AM and PBMC were purified from 19 TB patients and 15 normal subjects. To study the underlying mechanism, PBMC were exposed to heated TB bacilli. The regulation role of NRF in IP-10/CXCL10 and IL-8/CXCL8 was determined by NRF knock-down or over-expression. NRF binding capabilities in promoter sites were measured by chromatin immunoprecipitation (ChIP) assay. The levels of IP-10/CXCL10, IL-8/CXCL8 and NRF were significantly higher in AM and PBMC in patients with active TB. NRF played an inhibitory role in IP-10/CXCL10 and IL-8/CXCL8 inductions. We delineate the role of NRF in pulmonary TB, which inhibits the expressions of IP-10/CXCL10 and IL-8/CXCL8 in AM and PBMC of patients with high bacterial load. NRF may serve as an endogenous repressor to prevent robust increase in IP-10/CXCL10 and IL-8/CXCL8 when TB bacterial load is high. PMID:24223729

  14. A Broad Profile of Co-Dominant Epitopes Shapes the Peripheral Mycobacterium tuberculosis Specific CD8+ T-Cell Immune Response in South African Patients with Active Tuberculosis

    PubMed Central

    Axelsson-Robertson, Rebecca; Loxton, André G.; Walzl, Gerhard; Ehlers, Marthie M.; Kock, Marleen M.; Zumla, Alimuddin; Maeurer, Markus

    2013-01-01

    We studied major histocompatibility complex (MHC) class I peptide-presentation and nature of the antigen-specific CD8+ T-cell response from South African tuberculosis (TB) patients with active TB. 361 MHC class I binding epitopes were identified from three immunogenic TB proteins (ESAT-6 [Rv3875], Ag85B [Rv1886c], and TB10.4 [Rv0288], including amino acid variations for Rv0288, i.e., A10T, G13D, S27N, and A71S for MHC allotypes common in a South African population (e.g., human leukocyte antigen [HLA]-A*30, B*58, and C*07). Inter-allelic differences were identified regarding the broadness of the peptide-binding capacity. Mapping of frequencies of Mycobacterium tuberculosis (M. tb) antigen-specific CD8+ T-cells using 48 different multimers, including the newly constructed recombinant MHC class I alleles HLA-B*58:01 and C*0701, revealed a low frequency of CD8+ T-cell responses directed against a broad panel of co-dominant M. tb epitopes in the peripheral circulation of most patients. The antigen-specific responses were dominated by CD8+ T-cells with a precursor-like phenotype (CD45RA+CCR7+). The data show that the CD8+ T-cell response from patients with pulmonary TB (prior to treatment) is directed against subdominant epitopes derived from secreted and non-secreted M. tb antigens and that variant, natural occurring M. tb Rv0288 ligands, have a profound impact on T-cell recognition. PMID:23555576

  15. Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection.

    PubMed

    Kimmey, Jacqueline M; Huynh, Jeremy P; Weiss, Leslie A; Park, Sunmin; Kambal, Amal; Debnath, Jayanta; Virgin, Herbert W; Stallings, Christina L

    2015-12-24

    Mycobacterium tuberculosis, a major global health threat, replicates in macrophages in part by inhibiting phagosome-lysosome fusion, until interferon-γ (IFNγ) activates the macrophage to traffic M. tuberculosis to the lysosome. How IFNγ elicits this effect is unknown, but many studies suggest a role for macroautophagy (herein termed autophagy), a process by which cytoplasmic contents are targeted for lysosomal degradation. The involvement of autophagy has been defined based on studies in cultured cells where M. tuberculosis co-localizes with autophagy factors ATG5, ATG12, ATG16L1, p62, NDP52, BECN1 and LC3 (refs 2-6), stimulation of autophagy increases bacterial killing, and inhibition of autophagy increases bacterial survival. Notably, these studies reveal modest (~1.5-3-fold change) effects on M. tuberculosis replication. By contrast, mice lacking ATG5 in monocyte-derived cells and neutrophils (polymorponuclear cells, PMNs) succumb to M. tuberculosis within 30 days, an extremely severe phenotype similar to mice lacking IFNγ signalling. Importantly, ATG5 is the only autophagy factor that has been studied during M. tuberculosis infection in vivo and autophagy-independent functions of ATG5 have been described. For this reason, we used a genetic approach to elucidate the role for multiple autophagy-related genes and the requirement for autophagy in resistance to M. tuberculosis infection in vivo. Here we show that, contrary to expectation, autophagic capacity does not correlate with the outcome of M. tuberculosis infection. Instead, ATG5 plays a unique role in protection against M. tuberculosis by preventing PMN-mediated immunopathology. Furthermore, while Atg5 is dispensable in alveolar macrophages during M. tuberculosis infection, loss of Atg5 in PMNs can sensitize mice to M. tuberculosis. These findings shift our understanding of the role of ATG5 during M. tuberculosis infection, reveal new outcomes of ATG5 activity, and shed light on early events in innate

  16. Disease, predation and demography: Assessing the impacts of bovine tuberculosis on African buffalo by monitoring at individual and population levels

    USGS Publications Warehouse

    Cross, P.C.; Heisey, D.M.; Bowers, J.A.; Hay, C.T.; Wolhuter, J.; Buss, P.; Hofmeyr, M.; Michel, A.L.; Bengis, Roy G.; Bird, T.L.F.; Du Toit, J.T.; Getz, W.M.

    2009-01-01

    1. Understanding the effects of disease is critical to determining appropriate management responses, but estimating those effects in wildlife species is challenging. We used bovine tuberculosis (BTB) in the African buffalo Syncerus caffer population of Kruger National Park, South Africa, as a case study to highlight the issues associated with estimating chronic disease effects in a long-lived host. 2. We used known and radiocollared buffalo, aerial census data, and a natural gradient in pathogen prevalence to investigate if: (i) at the individual level, BTB infection reduces reproduction; (ii) BTB infection increases vulnerability to predation; and (iii) at the population level, increased BTB prevalence causes reduced population growth. 3. There was only a marginal reduction in calving success associated with BTB infection, as indexed by the probability of sighting a known adult female with or without a calf (P = 0??065). 4. Since 1991, BTB prevalence increased from 27 to 45% in the southern region and from 4 to 28% in the central region of Kruger National Park. The prevalence in the northern regions was only 1??5% in 1998. Buffalo population growth rates, however, were neither statistically different among regions nor declining over time. 5. Lions Panthera leo did not appear to preferentially kill test-positive buffalo. The best (Akaike's Information Criterion corrected for small sample size) AICc model with BTB as a covariate [exp(??) = 0??49; 95% CI = (0??24-1??02)] suggested that the mortality hazard for positive individuals was no greater than for test-negative individuals. 6. Synthesis and applications. Test accuracy, time-varying disease status, and movement among populations are some of the issues that make the detection of chronic disease impacts challenging. For these reasons, the demographic impacts of bovine tuberculosis in the Kruger National Park remain undetectable despite 6 years of study on known individuals and 40 years of population counts

  17. HMGB1/RAGE Signaling and Pro-Inflammatory Cytokine Responses in Non-HIV Adults with Active Pulmonary Tuberculosis

    PubMed Central

    Ip, Margaret; Chu, Yi Jun; Yung, Irene M. H.; Cheung, Catherine S. K.; Zheng, Lin; Lam, Judy S. Y.; Wong, Ka Tak; Sin, Winnie W. Y.; Choi, Kin Wing; Lee, Nelson

    2016-01-01

    Background We aimed to study the pathogenic roles of High-Mobility Group Box 1 (HMGB1) / Receptor-for-Advanced-Glycation-End-products (RAGE) signaling and pro-inflammatory cytokines in patients with active pulmonary tuberculosis (PTB). Methods A prospective study was conducted among non-HIV adults newly-diagnosed with active PTB at two acute-care hospitals (n = 80); age-and-sex matched asymptomatic individuals (tested for latent TB) were used for comparison (n = 45). Plasma concentrations of 8 cytokines/chemokines, HMGB1, soluble-RAGE, and transmembrane-RAGE expressed on monocytes/dendritic cells, were measured. Gene expression (mRNA) of HMGB1, RAGE, and inflammasome-NALP3 was quantified. Patients’ PBMCs were stimulated with recombinant-HMGB1 and MTB-antigen (lipoarabinomannan) for cytokine induction ex vivo. Results In active PTB, plasma IL-8/CXCL8 [median(IQR), 6.0(3.6–15.1) vs 3.6(3.6–3.6) pg/ml, P<0.001] and IL-6 were elevated, which significantly correlated with mycobacterial load, extent of lung consolidation (rs +0.509, P<0.001), severity-score (rs +0.317, P = 0.004), and fever and hospitalization durations (rs +0.407, P<0.001). IL-18 and sTNFR1 also increased. Plasma IL-8/CXCL8 (adjusted OR 1.12, 95%CI 1.02–1.23 per unit increase, P = 0.021) and HMGB1 (adjusted OR 1.42 per unit increase, 95%CI 1.08–1.87, P = 0.012) concentrations were independent predictors for respiratory failure, as well as for ICU admission/death. Gene expression of HMGB1, RAGE, and inflammasome-NALP3 were upregulated (1.2−2.8 fold). Transmembrane-RAGE was increased, whereas the decoy soluble-RAGE was significantly depleted. RAGE and HMGB1 gene expressions positively correlated with cytokine levels (IL-8/CXCL8, IL-6, sTNFR1) and clinico-/radiographical severity (e.g. extent of consolidation rs +0.240, P = 0.034). Ex vivo, recombinant-HMGB1 potentiated cytokine release (e.g. TNF-α) when combined with lipoarabinomannan. Conclusion In patients with active PTB, HMGB1/RAGE

  18. Mycobacterial Bacilli Are Metabolically Active during Chronic Tuberculosis in Murine Lungs: Insights from Genome-Wide Transcriptional Profiling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic tuberculosis represents a major health problem for one third of the world’s population today. A key question relevant to chronic tuberculosis is the physiological status of Mycobacterium tuberculosis during this important stage of infection. Previous work on chronic tuberculosis revealed t...

  19. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Infectious Diseases, Immune Disorders and Nutritional Deficiencies § 4.88c Ratings for inactive nonpulmonary... active tuberculosis 100 Thereafter: Rate residuals under the specific body system or systems...

  20. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Infectious Diseases, Immune Disorders and Nutritional Deficiencies § 4.88c Ratings for inactive nonpulmonary... active tuberculosis 100 Thereafter: Rate residuals under the specific body system or systems...

  1. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Infectious Diseases, Immune Disorders and Nutritional Deficiencies § 4.88c Ratings for inactive nonpulmonary... active tuberculosis 100 Thereafter: Rate residuals under the specific body system or systems...

  2. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Infectious Diseases, Immune Disorders and Nutritional Deficiencies § 4.88c Ratings for inactive nonpulmonary... active tuberculosis 100 Thereafter: Rate residuals under the specific body system or systems...

  3. Enzymatic Activities and DNA Substrate Specificity of Mycobacterium tuberculosis DNA Helicase XPB

    PubMed Central

    Balasingham, Seetha V.; Zegeye, Ephrem Debebe; Homberset, Håvard; Rossi, Marie L.; Laerdahl, Jon K.; Bohr, Vilhelm A.; Tønjum, Tone

    2012-01-01

    XPB, also known as ERCC3 and RAD25, is a 3′→5′ DNA repair helicase belonging to the superfamily 2 of helicases. XPB is an essential core subunit of the eukaryotic basal transcription factor complex TFIIH. It has two well-established functions: in the context of damaged DNA, XPB facilitates nucleotide excision repair by unwinding double stranded DNA (dsDNA) surrounding a DNA lesion; while in the context of actively transcribing genes, XPB facilitates initiation of RNA polymerase II transcription at gene promoters. Human and other eukaryotic XPB homologs are relatively well characterized compared to conserved homologs found in mycobacteria and archaea. However, more insight into the function of bacterial helicases is central to understanding the mechanism of DNA metabolism and pathogenesis in general. Here, we characterized Mycobacterium tuberculosis XPB (Mtb XPB), a 3′→5′ DNA helicase with DNA-dependent ATPase activity. Mtb XPB efficiently catalyzed DNA unwinding in the presence of significant excess of enzyme. The unwinding activity was fueled by ATP or dATP in the presence of Mg2+/Mn2+. Consistent with the 3′→5′ polarity of this bacterial XPB helicase, the enzyme required a DNA substrate with a 3′ overhang of 15 nucleotides or more. Although Mtb XPB efficiently unwound DNA model substrates with a 3′ DNA tail, it was not active on substrates containing a 3′ RNA tail. We also found that Mtb XPB efficiently catalyzed ATP-independent annealing of complementary DNA strands. These observations significantly enhance our understanding of the biological roles of Mtb XPB. PMID:22615856

  4. Tuberculosis (TB)

    MedlinePlus

    ... Skip Content Marketing Share this: Main Content Area Tuberculosis Research The New Challenge for TB Research NIAID ... HIV/AIDS Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis Research Agenda (PDF) TB Research at NIAID Research ...

  5. Tuberculosis (TB)

    MedlinePlus

    ... Skip Content Marketing Share this: Main Content Area Tuberculosis (TB) Overview In developed countries, such as the ... thought to be infected with TB bacteria, Mycobacterium tuberculosis ( Mtb ). TB is a chronic bacterial infection. It ...

  6. Structure-activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis

    PubMed Central

    Meissner, Anja; Boshoff, Helena I.; Vasan, Mahalakshmi; Duckworth, Benjamin P.; Barry, Clifton E.; Aldrich, Courtney C.

    2013-01-01

    A series of 2-aminothiazoles was synthesized based on a HTS scaffold from a whole-cell screen against Mycobacterium tuberculosis (Mtb). The SAR shows the central thiazole moiety and the 2-pyridyl moiety at C-4 of the thiazole are intolerant to modification. However, the N-2 position of the aminothiazole exhibits high flexibility and we successfully improved the antitubercular activity of the initial hit by more than 128-fold through introduction of substituted benzoyl groups at this position. N-(3-Chlorobenzoyl)-4-(2-pyridinyl)-1,3-thiazol-2-amine (55) emerged as one of the most promising analogues with a MIC of 0.024 μM or 0.008 μg/mL in 7H9 media and therapeutic index of nearly ~300. However, 55 is rapidly metabolized by human liver microsomes (t1/2 = 28 min) with metabolism occurring at the invariant aminothiazole moiety and Mtb develops spontaneous resistance with a high frequency of ~10−5. PMID:24075144

  7. Impact of Diabetes Mellitus on Treatment Outcomes of Patients with Active Tuberculosis

    PubMed Central

    Dooley, Kelly E.; Tang, Tania; Golub, Jonathan E.; Dorman, Susan E.; Cronin, Wendy

    2009-01-01

    Diabetes mellitus (DM) is an emerging chronic health condition of developed and developing countries. We conducted a retrospective cohort study of patients with active, culture-confirmed tuberculosis (TB) in Maryland to determine the impact of DM on TB treatment outcomes. Of 297 TB patients, 42 (14%) had DM. Patients with diabetes had 2.0 times higher odds of death than patients without diabetes (95% confidence interval [CI] 0.74–5.2, P = 0.18). Adjusting for human immunodeficiency virus (HIV), age, weight, and foreign birth, the odds of death were 6.5 times higher in patients with diabetes than patients without diabetes (95% CI 1.1–38.0, P = 0.039). In pulmonary TB patients, time to sputum culture conversion was longer in patients with diabetes than patients without diabetes (median 49 versus 39 days, P = 0.09). Two-month culture conversion proportions were similar (70% and 69%). Treatment failure occurred in 4.1% of patients without diabetes and 6.7% of patients with diabetes (P = 0.51). In conclusion, DM was a risk factor for death in Maryland TB patients. There was a trend toward increased time to culture conversion; two-month culture conversion proportions, however, were similar. PMID:19346391

  8. Elevated serum IL-35 and increased expression of IL-35-p35 or -EBI3 in CD4+CD25+ T cells in patients with active tuberculosis

    PubMed Central

    Kong, Bin; Liu, Gan-Bin; Zhang, Jun-Ai; Fu, Xiao-Xia; Xiang, Wen-Yu; Gao, Yu-Chi; Lu, Yuan-Bin; Wu, Xian-Jing; Qiu, Feng; Wang, Wan-Dang; Yi, Lai-Long; Zhong, Ji-Xin; Chen, Zheng W; Xu, Jun-Fa

    2016-01-01

    Despite the recent appreciation of interleukin 35 (IL-35) function in inflammatory diseases, little is known for IL-35 response in patients with active tuberculosis (ATB). In the current study, we demonstrated that ATB patients exhibited increases in serum IL-35 and in mRNA expression of both subunits of IL-35 (p35 and EBI3) in white blood cells and peripheral blood mononuclear cells. Consistently, anti-TB drug treatment led to reduction in serum IL-35 level and p35 or EBI3 expression. TB infection was associated with expression of p35 or EBI3 protein in CD4+ but not CD8+ T cells. Most p35+CD4+ T cells and EBI3+CD4+ T cells expressed Treg-associated marker CD25. Our findings may be important in understanding immune pathogenesis of TB. IL-35 in the blood may potentially serve as a biomarker for immune status and prognosis in TB. PMID:27158354

  9. Cardiovascular Disease and Cancer: Student Awareness Activities.

    ERIC Educational Resources Information Center

    Meyer, James H., Comp.

    Awareness activities pertaining to cancer and cardiovascular disease are presented as a supplement for high school science classes. The exercises can be used to enrich units of study dealing with the circulatory system, the cell, or human diseases. Eight activities deal with the following topics: (1) cardiovascular disease risk factors; (2)…

  10. Impacts of neglected tropical disease on incidence and progression of HIV/AIDS, tuberculosis, and malaria: scientific links.

    PubMed

    Simon, G G

    2016-01-01

    The neglected tropical diseases (NTDs) are the most common infections of humans in Sub-Saharan Africa. Virtually all of the population living below the World Bank poverty figure is affected by one or more NTDs. New evidence indicates a high degree of geographic overlap between the highest-prevalence NTDs (soil-transmitted helminths, schistosomiasis, onchocerciasis, lymphatic filariasis, and trachoma) and malaria and HIV, exhibiting a high degree of co-infection. Recent research suggests that NTDs can affect HIV and AIDS, tuberculosis (TB), and malaria disease progression. A combination of immunological, epidemiological, and clinical factors can contribute to these interactions and add to a worsening prognosis for people affected by HIV/AIDS, TB, and malaria. Together these results point to the impacts of the highest-prevalence NTDs on the health outcomes of malaria, HIV/AIDS, and TB and present new opportunities to design innovative public health interventions and strategies for these 'big three' diseases. This analysis describes the current findings of research and what research is still needed to strengthen the knowledge base of the impacts NTDs have on the big three. PMID:26594012

  11. U.S. College and University Student Health Screening Requirements for Tuberculosis and Vaccine-Preventable Diseases, 2012

    PubMed Central

    Jewett, A.; Bell, T; Cohen, NJ.; Buckley, K.; Leino, V.; Even, S.; Beavers, S.; Brown, C.; Marano, N.

    2016-01-01

    Objective Colleges are at risk for communicable disease outbreaks because of the high degree of person-to-person interactions and relatively crowded dormitory settings. This report describes the U.S. college student health screening requirements among U.S. resident and international students for tuberculosis (TB) and vaccine-preventable diseases (VPD) as it relates to the American College Health Association (ACHA) Guidelines. Methods/Participants In April 2012, U.S. college health administrators (N=2858) were sent online surveys to assess their respective school’s TB screening and immunization requirements. Results Surveys were completed by 308 (11%) schools. Most schools were aware of the ACHA immunization (78%) and TB screening (76%) guidelines. Schools reported having policies related to immunization screening (80.4%), immunization compliance (93%), TB screening (55%), and TB compliance (87%). Conclusion Most colleges were following ACHA guidelines. However, there are opportunities for improvement to fully utilize the recommendations and prevent outbreaks of communicable diseases among students in colleges. PMID:26730492

  12. Preventing the Establishment of a Wildlife Disease Reservoir: A Case Study of Bovine Tuberculosis in Wild Deer in Minnesota, USA

    PubMed Central

    Carstensen, Michelle; DonCarlos, Michael W.

    2011-01-01

    Bovine tuberculosis (bTB) has been found in 12 cattle operations and 27 free-ranging white-tailed deer (Odocoileus virginianus) in northwestern Minnesota, following the state's most recent outbreak of the disease in 2005 in the northwest part of the state. Both deer and cattle have the same strain of bTB. The Minnesota Board of Animal Health has been leading efforts to eradicate the disease in Minnesota's cattle, which have included the depopulation of all infected herds, a cattle buy-out program, and mandatory fencing of stored feeds. The Minnesota Department of Natural Resources began surveillance efforts in free-ranging white-tailed deer in fall 2005. All bTB-infected deer have been found within a 16 km2 area in direct association with infected cattle farms. Aggressive efforts to reduce deer densities through liberalized hunting and sharpshooting have resulted in a 55% decline in deer densities. Also, recreational feeding of wild deer has been banned. Disease prevalence in deer has decreased from 1.2% in 2005 to an undetectable level in 2010. PMID:21647335

  13. 9 CFR 311.2 - Tuberculosis.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Tuberculosis. 311.2 Section 311.2... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.2 Tuberculosis. The... pathogenesis of tuberculosis in swine, cattle, sheep, goats, and equines. (a) Carcasses condemned. The...

  14. 9 CFR 311.2 - Tuberculosis.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Tuberculosis. 311.2 Section 311.2... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.2 Tuberculosis. The... pathogenesis of tuberculosis in swine, cattle, sheep, goats, and equines. (a) Carcasses condemned. The...

  15. Tuberculosis Facts - You Can Prevent TB

    MedlinePlus

    Tuberculosis (TB) Facts You Can Prevent TB What is TB? “TB” is short for a disease called tuberculosis. TB is spread through the air from one ... Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination TB Facts: You Can Prevent TB What ...

  16. 9 CFR 311.2 - Tuberculosis.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 2 2014-01-01 2014-01-01 false Tuberculosis. 311.2 Section 311.2... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.2 Tuberculosis. The... pathogenesis of tuberculosis in swine, cattle, sheep, goats, and equines. (a) Carcasses condemned. The...

  17. 9 CFR 311.2 - Tuberculosis.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 2 2013-01-01 2013-01-01 false Tuberculosis. 311.2 Section 311.2... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.2 Tuberculosis. The... pathogenesis of tuberculosis in swine, cattle, sheep, goats, and equines. (a) Carcasses condemned. The...

  18. Tuberculosis Facts - TB Can Be Treated

    MedlinePlus

    Tuberculosis (TB) Facts TB Can Be Treated What is TB? “TB” is short for a disease called tuberculosis. TB is spread through the air from one ... Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination Page 1 of 2 TB Facts: TB ...

  19. Bovine Tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tuberculosis (TB) in animals and humans may result from exposure to bacilli within the Mycobacterium tuberculosis complex (i.e., M. tuberculosis, M. bovis, M. africanum, M. pinnipedii, M. microti, M. caprae, or M. canetti). Mycobacterium bovis is the species most often isolated from tuberculous catt...

  20. Tuberculosis: From an incurable scourge to a curable disease - journey over a millennium

    PubMed Central

    Sharma, Surendra K.; Mohan, Alladi

    2013-01-01

    Globally, tuberculosis (TB) still remains a major public health problem. India is a high TB burden country contributing to 26 per cent of global TB burden. During 1944-1980, TB became treatable and short-course chemotherapy emerged as the standard of care. When TB elimination seemed possible in the early 1980s, global human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS) pandemic resulted in a resurgence of TB. Widespread occurrence of multidrug-resistant and extensively drug-resistant TB (M/XDR-TB) is threatening to destabilize TB control globally. Atypical clinical presentation still poses a challenge. Disseminated, miliary and cryptic TB are being increasingly recognized. Availability of newer imaging modalities has allowed more efficient localization of lesions and use of image guided procedures has facilitated definitive diagnosis of extrapulmonary TB. Introduction of liquid culture, rapid drug-susceptibility testing (DST), molecular diagnostic methods has helped in rapid detection, speciation and DST profiling of Mycobacterium tuberculosis isolates. While treatment of TB and HIV-TB co-infection has become simpler, efforts are on to shorten the treatment duration. However, drug toxicities and drug-drug interactions still constitute a significant challenge. Recently, there has been better understanding of anti-TB drug-induced hepatotoxicity and its frequent confounding by viral hepatitis, especially, in resource-constrained settings; and immune reconstitution inflammatory syndrome (IRIS) in HIV-TB. Quest for newer biomarkers for predicting a durable cure, relapse, discovery/repurposing of newer anti-TB drugs, development of newer vaccines continues to achieve the goal of eliminating TB altogether by 2050. PMID:23640554

  1. Baeyer-Villiger Monooxygenases EthA and MymA Are Required for Activation of Replicating and Non-replicating Mycobacterium tuberculosis Inhibitors.

    PubMed

    Grant, Sarah Schmidt; Wellington, Samantha; Kawate, Tomohiko; Desjardins, Christopher A; Silvis, Melanie R; Wivagg, Carl; Thompson, Matthew; Gordon, Katherine; Kazyanskaya, Edward; Nietupski, Raymond; Haseley, Nathan; Iwase, Noriaki; Earl, Ashlee M; Fitzgerald, Michael; Hung, Deborah T

    2016-06-23

    Successful treatment of Mycobacterium tuberculosis infection typically requires a complex regimen administered over at least 6 months. Interestingly, many of the antibiotics used to treat M. tuberculosis are prodrugs that require intracellular activation. Here, we describe three small molecules, active against both replicating and non-replicating M. tuberculosis, that require activation by Baeyer-Villiger monooxygenases (BVMOs). Two molecules require BVMO EthA (Rv3854c) for activation and the third molecule requires the BVMO MymA (Rv3083). While EthA is known to activate the antitubercular drug ethionamide, this is the first description of MymA as an activating enzyme of a prodrug. Furthermore, we found that MymA also plays a role in activating ethionamide, with loss of MymA function resulting in ethionamide-resistant M. tuberculosis. These findings suggest overlap in function and specificity of the BVMOs in M. tuberculosis. PMID:27321573

  2. Update on cutaneous tuberculosis*

    PubMed Central

    Dias, Maria Fernanda Reis Gavazzoni; Bernardes Filho, Fred; Quaresma, Maria Victória; do Nascimento, Leninha Valério; Nery, José Augusto da Costa; Azulay, David Rubem

    2014-01-01

    Tuberculosis continues to draw special attention from health care professionals and society in general. Cutaneous tuberculosis is an infection caused by M. tuberculosis complex, M. bovis and bacillus Calmette-Guérin. Depending on individual immunity, environmental factors and the type of inoculum, it may present varied clinical and evolutionary aspects. Patients with HIV and those using immunobiological drugs are more prone to infection, which is a great concern in centers where the disease is considered endemic. This paper aims to review the current situation of cutaneous tuberculosis in light of this new scenario, highlighting the emergence of new and more specific methods of diagnosis, and the molecular and cellular mechanisms that regulate the parasite-host interaction. PMID:25387498

  3. IL-10 Dependent Suppression of Type 1, Type 2 and Type 17 Cytokines in Active Pulmonary Tuberculosis

    PubMed Central

    Kumar, Nathella Pavan; Gopinath, Venugopal; Sridhar, Rathinam; Hanna, Luke E.; Banurekha, Vaithilingam V.; Jawahar, Mohideen S.; Nutman, Thomas B.; Babu, Subash

    2013-01-01

    Background Although Type 1 cytokine responses are considered protective in pulmonary tuberculosis (PTB), their role as well as those of Type 2, 17 and immunoregulatory cytokines in tuberculous lymphadenitis (TBL) and latent tuberculosis (LTB) have not been well studied. Aim and Methods To identify cytokine responses associated with pulmonary tuberculosis (TB), TB lymphadenitits and latent TB, we examined mycobacterial antigen-specific immune responses of PTB, TBL and LTB individuals. More specifically, we examined ESAT-6 and CFP-10 induced Type 1, Type 2 and Type 17 cytokine production and their regulation using multiplex ELISA. Results PTB individuals exhibited a significantly lower baseline as well as antigen-specific production of Type 1 (IFNγ, TNFα and IL-2); Type 2 (IL-4) and Type 17 (IL-17A and IL-17F) cytokines in comparison to both TBL and LTB individuals. TBL individuals exhibited significantly lower antigen-specific IFNγ responses alone in comparison to LTB individuals. Although, IL-10 levels were not significantly higher, neutralization of IL-10 during antigen stimulation resulted in significantly enhanced production of IFNγ, IL-4 and IL-17A in PTB individuals, indicating that IL-10 mediates (at least partially) the suppression of cytokine responses in PTB. Conclusion Pulmonary TB is characterized by an IL-10 dependent antigen-specific suppression of Type 1, Type 2 and Type 17 cytokines, reflecting an important association of these cytokines in the pathogenesis of active TB. PMID:23544075

  4. The condensing activities of the Mycobacterium tuberculosis type II fatty acid synthase are differentially regulated by phosphorylation.

    PubMed

    Molle, Virginie; Brown, Alistair K; Besra, Gurdyal S; Cozzone, Alain J; Kremer, Laurent

    2006-10-01

    Phosphorylation of proteins by Ser/Thr protein kinases (STPKs) has recently become of major physiological importance because of its possible involvement in virulence of bacterial pathogens. Although Mycobacterium tuberculosis has eleven STPKs, the nature and function of the substrates of these enzymes remain largely unknown. In this work, we have identified for the first time STPK substrates in M. tuberculosis forming part of the type II fatty acid synthase (FAS-II) system involved in mycolic acid biosynthesis: the malonyl-CoA::AcpM transacylase mtFabD, and the beta-ketoacyl AcpM synthases KasA and KasB. All three enzymes were phosphorylated in vitro by different kinases, suggesting a complex network of interactions between STPKs and these substrates. In addition, both KasA and KasB were efficiently phosphorylated in M. bovis BCG each at different sites and could be dephosphorylated by the M. tuberculosis Ser/Thr phosphatase PstP. Enzymatic studies revealed that, whereas phosphorylation decreases the activity of KasA in the elongation process of long chain fatty acids synthesis, this modification enhances that of KasB. Such a differential effect of phosphorylation may represent an unusual mechanism of FAS-II system regulation, allowing pathogenic mycobacteria to produce full-length mycolates, which are required for adaptation and intracellular survival in macrophages. PMID:16873379

  5. An Update on Global Tuberculosis (TB)

    PubMed Central

    Talip, Balkis A.; Sleator, Roy D.; Lowery, Colm J.; Dooley, James S.G.; Snelling, William J.

    2013-01-01

    Tuberculosis globally results in almost 2 million human deaths annually, with 1 in 4 deaths from tuberculosis being human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)-related. Primarily a pathogen of the respiratory system, aerobic Mycobacterium tuberculosis complex (MTBC) infects the lungs via the inhalation of infected aerosol droplets generated by people with pulmonary disease through coughing. This review focuses on M. tuberculosis transmission, epidemiology, detection methods and technologies. PMID:24847176

  6. Activity of phosphino palladium(II) and platinum(II) complexes against HIV-1 and Mycobacterium tuberculosis.

    PubMed

    Gama, Ntombenhle H; Elkhadir, Afag Y F; Gordhan, Bhavna G; Kana, Bavesh D; Darkwa, James; Meyer, Debra

    2016-08-01

    Treatment of human immunodeficiency virus (HIV) is currently complicated by increased prevalence of co-infection with Mycobacterium tuberculosis. The development of drug candidates that offer the simultaneous management of HIV and tuberculosis (TB) would be of great benefit in the holistic treatment of HIV/AIDS, especially in sub-Saharan Africa which has the highest global prevalence of HIV-TB coinfection. Bis(diphenylphosphino)-2-pyridylpalladium(II) chloride (1), bis(diphenylphosphino)-2-pyridylplatinum(II) chloride (2), bis(diphenylphosphino)-2-ethylpyridylpalladium(II) chloride (3) and bis(diphenylphosphino)-2-ethylpyridylplatinum(II) (4) were investigated for the inhibition of HIV-1 through interactions with the viral protease. The complexes were subsequently assessed for biological potency against Mycobacterium tuberculosis H37Rv by determining the minimal inhibitory concentration (MIC) using broth microdilution. Complex (3) showed the most significant and competitive inhibition of HIV-1 protease (p = 0.014 at 100 µM). Further studies on its in vitro effects on whole virus showed reduced viral infectivity by over 80 % at 63 µM (p < 0.05). In addition, the complex inhibited the growth of Mycobacterium tuberculosis at an MIC of 5 µM and was non-toxic to host cells at all active concentrations (assessed by tetrazolium dye and real time cell electronic sensing). In vitro evidence is provided here for the possibility of utilizing a single metal-based compound for the treatment of HIV/AIDS and TB. PMID:27246555

  7. Whole genome sequencing of Mycobacterium tuberculosis reveals slow growth and low mutation rates during latent infections in humans.

    PubMed

    Colangeli, Roberto; Arcus, Vic L; Cursons, Ray T; Ruthe, Ali; Karalus, Noel; Coley, Kathy; Manning, Shannon D; Kim, Soyeon; Marchiano, Emily; Alland, David

    2014-01-01

    Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5 X 10(-10) mutations/bp/generation for recently transmitted tuberculosis and 7.3 X 10(-11) mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u 20 hr mutation rate attributable to the remaining latent period was 1.6 × 10(-11) mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest

  8. Whole Genome Sequencing of Mycobacterium tuberculosis Reveals Slow Growth and Low Mutation Rates during Latent Infections in Humans

    PubMed Central

    Colangeli, Roberto; Arcus, Vic L.; Cursons, Ray T.; Ruthe, Ali; Karalus, Noel; Coley, Kathy; Manning, Shannon D.; Kim, Soyeon; Marchiano, Emily; Alland, David

    2014-01-01

    Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5X10−10 mutations/bp/generation for recently transmitted tuberculosis and 7.3X10−11 mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u20hr mutation rate attributable to the remaining latent period was 1.6×10−11 mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest

  9. Immunometabolism in Tuberculosis

    PubMed Central

    Shi, Lanbo; Eugenin, Eliseo A.; Subbian, Selvakumar

    2016-01-01

    Immunometabolism, the study of the relationship between bioenergetic pathways and specific functions of immune cells, has recently gained increasing appreciation. In response to infection, activation of the host innate and adaptive immune cells is accompanied by a switch in the bioenergetic pathway from oxidative phosphorylation to glycolysis, a metabolic remodeling known as the Warburg effect, which is required for the production of antimicrobial and pro-inflammatory effector molecules. In this review, we summarize the current understanding of the Warburg effect and discuss its association with the expression of host immune responses in tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb). We also discuss potential mechanisms underlying the Warburg effect with a focus on the expression and regulation of hypoxia-inducible factor 1 alpha (HIF-1α), the regulatory subunit of HIF-1, a major transcription regulator involved in cellular stress adaptation processes, including energy metabolism and antimicrobial responses. We also propose a novel hypothesis that Mtb perturbs the Warburg effect of immune cells to facilitate its survival and persistence in the host. A better understanding of the dynamics of metabolic states of immune cells and their specific functions during TB pathogenesis can lead to the development of immunotherapies capable of promoting Mtb clearance and reducing Mtb persistence and the emergence of drug resistant strains. PMID:27148269

  10. Immunometabolism in Tuberculosis.

    PubMed

    Shi, Lanbo; Eugenin, Eliseo A; Subbian, Selvakumar

    2016-01-01

    Immunometabolism, the study of the relationship between bioenergetic pathways and specific functions of immune cells, has recently gained increasing appreciation. In response to infection, activation of the host innate and adaptive immune cells is accompanied by a switch in the bioenergetic pathway from oxidative phosphorylation to glycolysis, a metabolic remodeling known as the Warburg effect, which is required for the production of antimicrobial and pro-inflammatory effector molecules. In this review, we summarize the current understanding of the Warburg effect and discuss its association with the expression of host immune responses in tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb). We also discuss potential mechanisms underlying the Warburg effect with a focus on the expression and regulation of hypoxia-inducible factor 1 alpha (HIF-1α), the regulatory subunit of HIF-1, a major transcription regulator involved in cellular stress adaptation processes, including energy metabolism and antimicrobial responses. We also propose a novel hypothesis that Mtb perturbs the Warburg effect of immune cells to facilitate its survival and persistence in the host. A better understanding of the dynamics of metabolic states of immune cells and their specific functions during TB pathogenesis can lead to the development of immunotherapies capable of promoting Mtb clearance and reducing Mtb persistence and the emergence of drug resistant strains. PMID:27148269

  11. The Singapore Tuberculosis Elimination Programme: the first five years.

    PubMed Central

    Chee, Cynthia B. E.; James, Lyn

    2003-01-01

    The Singapore Tuberculosis Elimination Programme (STEP) was launched in 1997 because the incidence of the disease had remained between 49 and 56 per 100,000 resident population for the preceding 10 years. STEP involves the following key interventions: directly observed therapy (DOT) in public primary health care clinics; monitoring of treatment progress and outcome for all cases by means of a National Treatment Surveillance Registry; and preventive therapy for recently infected close contacts of infectious tuberculosis cases. Among other activities are the revamping of the National Tuberculosis Notification Registry, the discontinuation of BCG revaccination for schoolchildren, the tightening up of defaulter tracing, and the education of the medical community and the public. Future plans include an outreach programme for specific groups of patients who are unable to attend their nearest public primary care clinics for DOT, the detention of infectious recalcitrant defaulters for treatment under the Infectious Diseases Act, the molecular fingerprinting of tuberculosis isolates, and targeted screening of high-risk groups. The incidence of tuberculosis fell from 57 per 100,000 population in 1998 to 48 per 100,000 in 1999 and continued to decline to 44 per 100,000 in 2001. With political will and commitment and the support of the medical community and the public it is hoped that STEP will achieve further progress towards the elimination of tuberculosis in Singapore. PMID:12764518

  12. Discrimination between active and latent tuberculosis based on ratio of antigen-specific to mitogen-induced IP-10 production.

    PubMed

    Jeong, Yun Hee; Hur, Yun-Gyoung; Lee, Hyejon; Kim, Sunghyun; Cho, Jang-Eun; Chang, Jun; Shin, Sung Jae; Lee, Hyeyoung; Kang, Young Ae; Cho, Sang-Nae; Ha, Sang-Jun

    2015-02-01

    Mycobacterium tuberculosis is the major causative agent of tuberculosis (TB). The gamma interferon (IFN-γ) release assay (IGRA) has been widely used to diagnose TB by testing cell-mediated immune responses but has no capacity for distinguishing between active TB and latent TB infection (LTBI). This study aims to identify a parameter that will help to discriminate active TB and LTBI. Whole-blood samples from 33 active TB patients, 20 individuals with LTBI, and 26 non-TB controls were applied to the commercial IFN-γ release assay, QuantiFERON-TB Gold In-Tube, and plasma samples were analyzed for interleukin-2 (IL-2), IL-6, IL-8, IL-10, IL-13, tumor necrosis factor-alpha (TNF-α), IFN-γ, monokine induced by IFN-γ (MIG), interferon gamma inducible protein 10 (IP-10), interferon-inducible T cell alpha chemoattractant (I-TAC), and monocyte chemoattractant protein 1 (MCP-1) by using a commercial cytometric bead array. The Mycobacterium tuberculosis antigen-specific production of most of the assayed cytokines and chemokines was higher in the active TB than in the LTBI group. The mitogen-induced responses were lower in the active TB than in the LTBI group. When the ratio of TB-specific to mitogen-induced responses was calculated, IL-2, IL-6, IL-10, IL-13, TNF-α, IFN-γ, MIG, and IP-10 were more useful in discriminating active TB from LTBI. In particular, most patients showed higher IP-10 production to Mycobacterium tuberculosis antigens than to mitogen at the individual level, and the ratio for IP-10 was the strongest indicator of active infection versus LTBI with 93.9% sensitivity and 90% specificity. In conclusion, the ratio of the TB-specific to the mitogen-induced IP-10 responses showed the most promising accuracy for discriminating active TB versus LTBI and should be further studied to determine whether it can serve as a biomarker that might help clinicians administer appropriate treatments. PMID:25428147

  13. Mycobacterium tuberculosis PPE protein Rv0256c induces strong B cell response in tuberculosis patients.

    PubMed

    Abraham, Philip Raj; Latha, Gaddam Suman; Valluri, Vijaya Lakshmi; Mukhopadhyay, Sangita

    2014-03-01

    Tuberculosis (TB) is one of the most important diseases of humans and major public health problem worldwide. Early and accurate diagnosis of TB is necessary for the treatment, prevention, and control of TB. Therefore, it is important to identify suitable antigens that can differentiate active tuberculosis patients from BCG-vaccinated individuals. In the present study, we have used Rv0256c (PPE2) protein of Mycobacterium tuberculosis to screen the sera of infected patients belonging to different clinical TB presentations, and BCG-vaccinated clinically healthy individuals by enzyme immunoassay. Our results demonstrated that Rv0256c displayed stronger and specific immunoreactivity against the sera obtained from clinically active tuberculosis patients compared to PPD and ESAT-6 and could differentiate the TB-patients from the BCG-vaccinated controls. Importantly, Rv0256c was also found to detect even the extrapulmonary and smear-negative pulmonary cases which often are tedious and difficult to detect using conventional diagnostic methods. This study suggests that Rv0256c can be used as a potential marker for the serodiagnosis of tuberculosis patients. PMID:23827809

  14. Summary of CDC consultation to address social determinants of health for prevention of disparities in HIV/AIDS, viral hepatitis, sexually transmitted diseases, and tuberculosis. December 9-10, 2008.

    PubMed

    Sharpe, Tanya Telfair; Harrison, Kathleen McDavid; Dean, Hazel D

    2010-01-01

    In December 2008, the Centers for Disease Control and Prevention (CDC) convened a meeting of national public health partners to identify priorities for addressing social determinants of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), viral hepatitis, sexually transmitted diseases (STDs), and tuberculosis (TB). The consultants were divided into four working groups: (1) public health policy, (2) data systems, (3) agency partnerships and prevention capacity building, and (4) prevention research and evaluation. Groups focused on identifying top priorities; describing activities, methods, and metrics to implement priorities; and identifying partnerships and resources required to implement priorities. The meeting resulted in priorities for public health policy, improving data collection methods, enhancing existing and expanding future partnerships, and improving selection criteria and evaluation of evidence-based interventions. CDC is developing a national communications plan to guide and inspire action for keeping social determinants of HIV/AIDS, viral hepatitis, STDs, and TB in the forefront of public health activities. PMID:20626189

  15. Standardization of natural mycolic acid antigen composition and production for use in biomarker antibody detection to diagnose active tuberculosis.

    PubMed

    Ndlandla, F L; Ejoh, V; Stoltz, A C; Naicker, B; Cromarty, A D; van Wyngaardt, S; Khati, M; Rotherham, L S; Lemmer, Y; Niebuhr, J; Baumeister, C R; Al Dulayymi, J R; Swai, H; Baird, M S; Verschoor, J A

    2016-08-01

    Mycobacterium tuberculosis, the causative agent of tuberculosis, is characterized by the abundance of species specific, antigenic cell wall lipids called mycolic acids. These wax-like molecules all share an identical, amphiphilic mycolic motif, but have different functional groups in a long hydrophobic hydrocarbon mero-chain that divide them into three main classes: alpha-, keto- and methoxy-mycolic acids. Whereas alpha-mycolic acids constitutively maintain an abundance of around 50%, the ratio of methoxy- to keto-mycolic acid types may vary depending on, among other things, the growth stage of M. tuberculosis. In human patients, antibodies to mycolic acids have shown potential as diagnostic serum biomarkers for active TB. Variations in mycolic acid composition affect the antigenic properties and can potentially compromise the precision of detection of anti-mycolic acids antibodies in patient sera to natural mixtures. We demonstrate this here with combinations of synthetic mycolic acid antigens, tested against TB patient and control sera. Combinations of methoxy- and α-mycolic acids are more antigenic than combinations of keto- and α-mycolic acids, showing the former to give a more sensitive test for TB biomarker antibodies. Natural mixtures of mycolic acids isolated from mature cultures of M. tuberculosis H37Rv give the same sensitivity as that with synthetic methoxy- and α-mycolic acids in combination, in a surface plasmon resonance inhibition biosensor test. To ensure that the antigenic activity of isolates of natural mycolic acids is reproducible, we cultured M. tuberculosis H37Rv on Middlebrook 7H10 solid agar plates to stationary growth phase in a standardized, optimal way. The proportions of mycolic acid classes in various batches of the isolates prepared from these cultures were compared to a commercially available natural mycolic acid isolate. LC-MS/MS and NMR data for quantitation of mycolic acids class compositions show that the variation in batches

  16. On Modelling Minimal Disease Activity

    PubMed Central

    Jackson, Christopher H.; Su, Li; Gladman, Dafna D.

    2016-01-01

    Objective To explore methods for statistical modelling of minimal disease activity (MDA) based on data from intermittent clinic visits. Methods The analysis was based on a 2‐state model. Comparisons were made between analyses based on “complete case” data from visits at which MDA status was known, and the use of hidden model methodology that incorporated information from visits at which only some MDA defining criteria could be established. Analyses were based on an observational psoriatic arthritis cohort. Results With data from 856 patients and 7,024 clinic visits, analysis was based on virtually all visits, although only 62.6% provided enough information to determine MDA status. Estimated mean times for an episode of MDA varied from 4.18 years to 3.10 years, with smaller estimates derived from the hidden 2‐state model analysis. Over a 10‐year period, the estimated expected times spent in MDA episodes of longer than 1 year was 3.90 to 4.22, and the probability of having such an MDA episode was estimated to be 0.85 to 0.91, with longer times and greater probabilities seen with the hidden 2‐state model analysis. Conclusion A 2‐state model provides a useful framework for the analysis of MDA. Use of data from visits at which MDA status can not be determined provide more precision, and notable differences are seen in estimated quantities related to MDA episodes based on complete case and hidden 2‐state model analyses. The possibility of bias, as well as loss of precision, should be recognized when complete case analyses are used. PMID:26315478

  17. [Clinical and immunological features of concomitant HIV/tuberculosis infection and HIV infection without tuberculosis].

    PubMed

    Khaertynova, I M; Valiev, R Sh; Tsibul'kin, A P; Valiev, N R; Khamzina, R V; Lazarenko, O G; Romanenko, S E

    2009-01-01

    The clinical and hematological manifestations and functional state of the immune system were comparatively evaluated in patients with concomitant HIV/tuberculosis (TB) infection (n = 84) and in those with HIV infection without tuberculosis (n = 106). The course of concomitant HIV-TB infection was ascertained to differ from HIV monoinfection in a diversity of additional exposures that aggravated the patients' general condition. These included: the parameters of a long proceeding inflammatory process, which were accompanied by the signs of the infection-toxic syndrome, inflammatory changes in the hemogram, by a sharp stimulation of the nonspecific link of immunity. So the comparative analysis of the trend in HIV infection in combination with active tuberculosis and HIV monoinfection revealed a prompter progression of the disease in the former case. PMID:19642574

  18. Gamma Interferon Assays Used in the Diagnosis of Tuberculosis

    PubMed Central

    2015-01-01

    Tuberculosis (TB) is an ancient disease that has infected humans for thousands of years. However, despite diagnostic tests that detect the disease and effective therapy, there are still millions of people worldwide who are infected with TB. The first TB test used to detect infected patients was a skin test that identifies individuals actively infected with TB. This test used a mix of proteins from culture filtrates of the bacteria Mycobacterium tuberculosis. Recently, two new diagnostic tests have been introduced; these two new tests can detect TB infection in patients by challenging peripheral blood cells with specific TB proteins. These assays measure the cellular immune response to these proteins. This minireview evaluates the new assays and compares them to the use of the TB skin test. The use of these new assays may have some advantages in detecting individuals with active tuberculosis. However, there is still a role for the use of the skin test, especially in young patients. PMID:26018533

  19. Catalase-peroxidase (Mycobacterium tuberculosis KatG) catalysis and isoniazid activation.

    PubMed

    Chouchane, S; Lippai, I; Magliozzo, R S

    2000-08-15

    Resonance Raman spectra of native, overexpressed M. tuberculosis catalase-peroxidase (KatG), the enzyme responsible for activation of the antituberculosis antibiotic isoniazid (isonicotinic acid hydrazide), have confirmed that the heme iron in the resting (ferric) enzyme is high-spin five-coordinate. Difference Raman spectra did not reveal a change in coordination number upon binding of isoniazid to KatG. Stopped-flow spectrophotometric studies of the reaction of KatG with stoichiometric equivalents or small excesses of hydrogen peroxide revealed only the optical spectrum of the ferric enzyme with no hypervalent iron intermediates detected. Large excesses of hydrogen peroxide generated oxyferrous KatG, which was unstable and rapidly decayed to the ferric enzyme. Formation of a pseudo-stable intermediate sharing optical characteristics with the porphyrin pi-cation radical-ferryl iron species (Compound I) of horseradish peroxidase was observed upon reaction of KatG with excess 3-chloroperoxybenzoic acid, peroxyacetic acid, or tert-butylhydroperoxide (apparent second-order rate constants of 3.1 x 10(4), 1.2 x 10(4), and 25 M(-1) s(-1), respectively). Identification of the intermediate as KatG Compound I was confirmed using low-temperature electron paramagnetic resonance spectroscopy. Isoniazid, as well as ascorbate and potassium ferrocyanide, reduced KatG Compound I to the ferric enzyme without detectable formation of Compound II in stopped-flow measurements. This result differed from the reaction of horseradish peroxidase Compound I with isoniazid, during which Compound II was stably generated. These results demonstrate important mechanistic differences between a bacterial catalase-peroxidase and the homologous plant peroxidases and yeast cytochrome c peroxidase, in its reactions with peroxides as well as substrates. PMID:10933818

  20. Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents.

    PubMed

    Tiwari, Rohit; Moraski, Garrett C; Krchňák, Viktor; Miller, Patricia A; Colon-Martinez, Mariangelli; Herrero, Eliza; Oliver, Allen G; Miller, Marvin J

    2013-03-01

    The development of multidrug resistant (MDR) and extensively drug resistant (XDR) forms of tuberculosis (TB) has stimulated research efforts globally to expand the new drug pipeline. Nitroaromatic compounds, including 1,3-benzothiazin-4-ones (BTZs) and related agents, are a promising new class for the treatment of TB. Research has shown that the nitroso intermediates of BTZs that are generated in vivo cause suicide inhibition of decaprenylphosphoryl-β-D-ribose 2' oxidase (DprE1), which is responsible for cell wall arabinogalactan biosynthesis. We have designed and synthesized novel anti-TB agents inspired from BTZs and other nitroaromatic compounds. Computational studies indicated that the unsubstituted aromatic carbons of BTZ043 and related nitroaromatic compounds are the most electron-deficient and might be prone to nucleophilic attack. Our chemical studies on BTZ043 and the additional nitroaromatic compounds synthesized by us and others confirmed the postulated reactivity. The results indicate that nucleophiles such as thiolates, cyanide, and hydride induce nonenzymatic reduction of the nitro groups present in these compounds to the corresponding nitroso intermediates by addition at the unsubstituted electron-deficient aromatic carbon present in these compounds. Furthermore, we demonstrate here that these compounds are good candidates for the classical von Richter reaction. These chemical studies offer an alternate hypothesis for the mechanism of action of nitroaromatic anti-TB agents, in that the cysteine thiol(ate) or a hydride source at the active site of DprE1 may trigger the reduction of the nitro groups in a manner similar to the von Richter reaction to the nitroso intermediates, to initiate the inhibition of DprE1. PMID:23402278

  1. On Combining Multiple-Instance Learning and Active Learning for Computer-Aided Detection of Tuberculosis.

    PubMed

    Melendez, Jaime; van Ginneken, Bram; Maduskar, Pragnya; Philipsen, Rick H H M; Ayles, Helen; Sanchez, Clara I

    2016-04-01

    The major advantage of multiple-instance learning (MIL) applied to a computer-aided detection (CAD) system is that it allows optimizing the latter with case-level labels instead of accurate lesion outlines as traditionally required for a supervised approach. As shown in previous work, a MIL-based CAD system can perform comparably to its supervised counterpart considering complex tasks such as chest radiograph scoring in tuberculosis (TB) detection. However, despite this remarkable achievement, the uncertainty inherent to MIL can lead to a less satisfactory outcome if analysis at lower levels (e.g., regions or pixels) is needed. This issue may seriously compromise the applicability of MIL to tasks related to quantification or grading, or detection of highly localized lesions. In this paper, we propose to reduce uncertainty by embedding a MIL classifier within an active learning (AL) framework. To minimize the labeling effort, we develop a novel instance selection mechanism that exploits the MIL problem definition through one-class classification. We adapt this mechanism to provide meaningful regions instead of individual instances for expert labeling, which is a more appropriate strategy given the ap