Sample records for suspected active tuberculosis

  1. Prevalence of pulmonary TB and spoligotype pattern of Mycobacterium tuberculosis among TB suspects in a rural community in Southwest Ethiopia

    PubMed Central

    2012-01-01

    Background In Ethiopia where there is no strong surveillance system and state of the art diagnostic facilities are limited, the real burden of tuberculosis (TB) is not well known. We conducted a community based survey to estimate the prevalence of pulmonary TB and spoligotype pattern of the Mycobacterium tuberculosis isolates in Southwest Ethiopia. Methods A total of 30040 adults in 10882 households were screened for pulmonary TB in Gilgel Gibe field research centre in Southwest Ethiopia. A total of 482 TB suspects were identified and smear microscopy and culture was done for 428 TB suspects. Counseling and testing for HIV/AIDS was done for all TB suspects. Spoligotyping was done to characterize the Mycobacterium tuberculosis isolates. Results Majority of the TB suspects were females (60.7%) and non-literates (83.6%). Using smear microscopy, a total of 5 new and 4 old cases of pulmonary TB cases were identified making the prevalence of TB 30 per 100,000. However, using the culture method, we identified 17 new cases with a prevalence of 76.1 per 100,000. There were 4.3 undiagnosed pulmonary TB cases for every TB case who was diagnosed through the passive case detection mechanism in the health facility. Eleven isolates (64.7%) belonged to the six previously known spoligotypes: T, Haarlem and Central-Asian (CAS). Six new spoligotype patterns of Mycobacterium tuberculosis, not present in the international database (SpolDB4) were identified. None of the rural residents was HIV infected and only 5 (5.5%) of the urban TB suspects were positive for HIV. Conclusion The prevalence of TB in the rural community of Southwest Ethiopia is low. There are large numbers of undiagnosed TB cases in the community. However, the number of sputum smear-positive cases was very low and therefore the risk of transmitting the infection to others may be limited. Active case finding through health extension workers in the community can improve the low case detection rate in Ethiopia. A large scale study on the genotyping of Mycobacterium tuberculosis in Ethiopia is crucial to understand transmission dynamics, identification of drug resistant strains and design preventive strategies. PMID:22414165

  2. Knowledge, Health Seeking Behavior and Perceived Stigma towards Tuberculosis among Tuberculosis Suspects in a Rural Community in Southwest Ethiopia

    Microsoft Academic Search

    Gemeda Abebe; Amare Deribew; Ludwig Apers; Kifle Woldemichael; Jaffer Shiffa; Markos Tesfaye; Alemseged Abdissa; Fetene Deribie; Chali Jira; Mesele Bezabih; Abraham Aseffa; Luc Duchateau; Robert Colebunders

    2010-01-01

    BackgroundPerceived stigma and lack of awareness could contribute to the late presentation and low detection rate of tuberculosis (TB). We conducted a study in rural southwest Ethiopia among TB suspects to assess knowledge about and stigma towards TB and their health seeking behavior.MethodsA community based cross sectional survey was conducted from February to March 2009 in the Gilgel Gibe field

  3. Factors influencing polymerase chain reaction outcomes in patients with clinically suspected ocular tuberculosis

    PubMed Central

    2014-01-01

    Background Polymerase chain reaction (PCR) assay can be a useful method for definitive diagnosis in paucibacillary infections such as ocular tuberculosis (TB). In this study, we have evaluated factors affecting PCR outcomes in patients with clinically suspected ocular TB. Patients with clinically suspected ocular TB were investigated by PCR of aqueous or vitreous samples. Three control groups were also tested: group 1 included culture-proven non-tuberculous endophthalmitis, group 2 culture-negative non-tuberculous endophthalmitis, and group 3 patients undergoing surgery for uncomplicated cataract. PCR targeted one or more of following targets: IS6110, MPB64, and protein b genes of Mycobacterium tuberculosis complex. Multiple regression analysis (5% level of significance) was done to evaluate the associations between positive PCR outcome and laterality of disease, tuberculin skin test (TST)/interferon-gamma release assay (IGRA), chest radiography, and type of sample (aqueous or vitreous). The main outcome measures were positive PCR by one or more gene targets, and factors influencing positive PCR outcomes. Results All 114 samples were tested for MPB64, 110 for protein b, and 88 for IS6110. MPB64 was positive in 70.2% (n?=?80) of tested samples, protein b in 40.0% (n?=?44), and IS6110 in only 9.1% (n?=?8). DNA sequencing of amplicons from four randomly chosen PCR reactions showed homology for M. tuberculosis complex. Of the 80 PCR-positive patients, 71 completed a full course of antitubercular therapy, of which 65 patients (91.5%) had complete resolution of inflammation at final follow-up. Among controls, 12.5% (3 out of 24) in group 1 and 18.7% (6 out of 32) in group 2 also tested positive by PCR. No PCR-positive outcome was observed in control group 3 (n?=?25). Multiple regression analysis revealed significant association of positive PCR outcome with bilateral presentation, but not with a positive TST/IGRA, chest radiography, or type of sample (aqueous/vitreous) used. Conclusions Careful selection of gene targets can yield high PCR positivity in clinically suspected ocular TB. Bilateral disease presentation but not any evidence of latent systemic TB influences PCR outcomes. False-positive results may be seen in ocular inflammation unrelated to ocular TB. PMID:24661354

  4. Antimicrobial Resistant Profile of Streptococcus Pneumoniae Isolated from Suspected Tuberculosis Patients in Ekpoma, Nigeria and its Environs

    Microsoft Academic Search

    2004-01-01

    Seven isolates of Streptococcus pneumoniae were isolated from sputum samples of suspected tuberculosis patients and characterized. Kirby- Bauer disc diffusion technique was adopted in susceptibility testing of isolates. Isolates showed the highest resistance of 85.7% to norfloxacin and ampicillin -cloxacillin, while the lowest resistance of 14. 3% was to caftaxidime and pefloxacin. The difference in resistance observed between norfloxacin and

  5. Knowledge, Health Seeking Behavior and Perceived Stigma towards Tuberculosis among Tuberculosis Suspects in a Rural Community in Southwest Ethiopia

    PubMed Central

    Abebe, Gemeda; Deribew, Amare; Apers, Ludwig; Woldemichael, Kifle; Shiffa, Jaffer; Tesfaye, Markos; Abdissa, Alemseged; Deribie, Fetene; Jira, Chali; Bezabih, Mesele; Aseffa, Abraham; Duchateau, Luc; Colebunders, Robert

    2010-01-01

    Background Perceived stigma and lack of awareness could contribute to the late presentation and low detection rate of tuberculosis (TB). We conducted a study in rural southwest Ethiopia among TB suspects to assess knowledge about and stigma towards TB and their health seeking behavior. Methods A community based cross sectional survey was conducted from February to March 2009 in the Gilgel Gibe field research area. Any person 15 years and above with cough for at least 2 weeks was considered a TB suspect and included in the study. Data were collected by trained personnel using a pretested structured questionnaire. Logistic regression analysis was done using SPSS 15.0 statistical software. Results Of the 476 pulmonary TB suspects, 395 (83.0%) had ever heard of TB; “evil eye” (50.4%) was the commonly mentioned cause of TB. Individuals who could read and write were more likely to be aware about TB [(crude OR?=?2.98, (95%CI: 1.25, 7.08)] and more likely to know that TB is caused by a microorganism [(adjusted OR?=?3.16, (95%CI: 1.77, 5.65)] than non-educated individuals. Males were more likely to know the cause of TB [(adjusted OR?=?1.92, (95%CI: 1.22, 3.03)] than females. 51.3% of TB suspects perceived that other people would consider them inferior if they had TB. High stigma towards TB was reported by 199(51.2%). 220 (46.2%) did not seek help for their illness. Individuals who had previous anti-TB treatment were more likely to have appropriate health seeking behavior [(adjusted OR?=?3.65, (95%CI: 1.89, 7.06)] than those who had not. Conclusion There was little knowledge about TB in the Gilgel Gibe field research area. We observed inappropriate health seeking behavior and stigma towards TB. TB control programs in Ethiopia should educate rural communities, particularly females and non-educated individuals, about the cause and the importance of early diagnosis and treatment of TB. PMID:20948963

  6. The Incremental Cost-Effectiveness of Engaging Private Practitioners to Refer Tuberculosis Suspects to DOTS Services in Jogjakarta, Indonesia

    PubMed Central

    Mahendradhata, Yodi; Probandari, Ari; Ahmad, Riris A.; Utarini, Adi; Trisnantoro, Laksono; Lindholm, Lars; van der Werf, Marieke J.; Kimerling, Michael; Boelaert, Marleen; Johns, Benjamin; Van der Stuyft, Patrick

    2010-01-01

    We aimed to evaluate the incremental cost-effectiveness of engaging private practitioners (PPs) to refer tuberculosis (TB) suspects to public health centers in Jogjakarta, Indonesia. Effectiveness was assessed for TB suspects notified between May 2004 and April 2005. Private practitioners referred 1,064 TB suspects, of which 57.5% failed to reach a health center. The smear-positive rate among patients reaching a health center was 61.8%. Two hundred eighty (280) out of a total of 1,306 (21.4%) new smear-positive cases were enrolled through the PPs strategy. The incremental cost-effectiveness ratio per smear-positive case successfully treated for the PPs strategy was US$351.66 (95% CI 322.84–601.33). On the basis of an acceptability curve using the National TB control program's willingness-to-pay threshold (US$448.61), we estimate the probability that the PPs strategy is cost-effective at 66.8%. The strategy of engaging PPs was incrementally cost-effective, although under specific conditions, most importantly a well-functioning public directly observed treatment, short-course (DOTS) program. PMID:20519613

  7. Prevalence of Non-Tuberculosis Mycobacterial Infections among Tuberculosis Suspects in Iran: Systematic Review and Meta-Analysis

    PubMed Central

    Nasiri, Mohammad Javad; Dabiri, Hossein; Darban-Sarokhalil, Davood; Hashemi Shahraki, Abdolrazagh

    2015-01-01

    Introduction The infections due to Non-Tuberculosis Mycobacteria (NTM) are becoming an important health problem in many countries in the world. Globally, an increase in NTM infections has been reported from many countries around the world. However, limited information is available about the prevalence of NTM infections in Iran. Material and Methods The data of the prevalence of NTM infections were collected from databases such as PubMed, Web of science, Cochrane Library, Embase, Scopus, Iranmedex, and Scientific Information Database. Comprehensive Meta-Analysis (V2.0, Biostat) software was used to analyze the data. Results The meta-analyses showed that the prevalence of NTM infections was 10.2% (95% confidence interval [95% CI] 6.3-15.9) among culture-positive cases of tuberculosis (TB) in Iran. The further stratified analyses indicated that the prevalence of NTM was higher in studies that were done after year 2000. Additionally, M. simiae (43.3% [95% CI 36.8-50.0]), M. intracellucar (27.3% [95% CI 0.7-95.5]) and M. fortuitum (22.7% [95% CI 16.1-30.9]) were the most prevalent NTM species, respectively. Discussion The relatively high prevalence of NTM infections (10.2%) among culture positive cases for TB underlines the need for greater enforcement of infection control strategies. Establishment of appropriate diagnostic criteria and management guidelines for NTM diseases and expanding the number and quality of regional reference laboratories may facilitate more accurate action for prevention and control of NTM infections in Iran. PMID:26052701

  8. Prevalence of Non-Tuberculous Mycobacterial Infections among Tuberculosis Suspects in Nigeria

    PubMed Central

    Aliyu, Gambo; El-Kamary, Samer S.; Abimiku, Alash’le; Brown, Clayton; Tracy, Kathleen; Hungerford, Laura; Blattner, William

    2013-01-01

    Background Nigeria is ranked in the top five countries for tuberculosis deaths worldwide. This study investigated the mycobacterial agents associated with presumptive clinical pulmonary tuberculosis (TB) in Nigeria and evaluated the pattern and frequency of mycobacterial infections over twelve calendar months period. Methods Sputum samples from 1,603 consecutive new cases with presumptive diagnosis of TB were collected from August 2010 to July 2011. All sputum samples were incubated for detection of mycobacterial growth and those with positive acid fast bacilli (AFB) growth were tested to detect mycobacterium tuberculosis (MTB) complex and characterized to differentiate between MTB complex species. Cultures suggestive of Non-tuberculous mycobacterial infections (NTM) were sub-cultured and characterized. Results Of the 1,603 patients screened, 444 (28%) culture-positive cases of pulmonary tuberculosis were identified. Of these, 375 (85%) were due to strains of MTB complex (354 cases of M. tuberculosis, 20 M. africanum and one case of M. bovis) and 69 (15%) were due to infection with NTM. In contrast to the MTB complex cases, the NTM cases were more likely to have been diagnosed during the calendar months of the Harmattan dust season (OR?=?2.34, 1.28–4.29; p?=?0.01), and aged older than 35 years (OR?=?2.77, 1.52–5.02, p?=?0.0007), but less likely to have AFB identified on their sputum smear (OR?=?0.06, 0.02–0.14, p<0.0001). Among those with NTM infection, cases 35 years or younger were more likely to have co-infection with HIV (3.76, 1.72–8.22; p?=?0.0009) compared to those older than 35 years. Interpretation The high proportion of younger patients with clinical pulmonary TB due to NTM and co-infection with HIV and the likely role of the seasonal dust exposure in the occurrence of the disease, present novel public health challenges for prevention and treatment. PMID:23671669

  9. 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

  10. 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 ? (IFN-?), interleukin 2 (IL-2), and tumor necrosis factor ? (TNF-?). Results.?Frequencies of CD4+ and CD8+ cells secreting IFN-?-only, TNF-?-only and dual IFN-?/TNF-? 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 ? (CD127) expression. The frequency of PPD-specific CD4+ TNF-?-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

  11. Isoxyl Activation Is Required for Bacteriostatic Activity against Mycobacterium tuberculosis

    Microsoft Academic Search

    Jana Kordulakova; Yves L. Janin; Avraham Liav; Nathalie Barilone; Tiago Dos Vultos; Jean Rauzier; Patrick J. Brennan; Brigitte Gicquel; Mary Jackson

    2007-01-01

    Isoxyl (ISO), a thiourea derivative that was successfully used for the clinical treatment of tuberculosis during the 1960s, is an inhibitor of the synthesis of oleic and mycolic acids in Mycobacterium tuberculosis. Its effect on oleic acid synthesis has been shown to be attributable to its inhibitory activity on the stearoyl- coenzyme A desaturase DesA3, but its enzymatic target(s) in

  12. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...false Effect of diagnosis of active tuberculosis. 3.374 Section 3.374 Pensions...374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service...department diagnosis of active pulmonary tuberculosis will be accepted unless a...

  13. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...false Effect of diagnosis of active tuberculosis. 3.374 Section 3.374 Pensions...374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service...department diagnosis of active pulmonary tuberculosis will be accepted unless a...

  14. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...false Effect of diagnosis of active tuberculosis. 3.374 Section 3.374 Pensions...374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service...department diagnosis of active pulmonary tuberculosis will be accepted unless a...

  15. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...false Effect of diagnosis of active tuberculosis. 3.374 Section 3.374 Pensions...374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service...department diagnosis of active pulmonary tuberculosis will be accepted unless a...

  16. Arginine Adjunctive Therapy in Active Tuberculosis

    PubMed Central

    Shafaat, Omid; Sofian, Masoomeh; Kahbazi, Manijeh

    2015-01-01

    Background. Dietary supplementation has been used as a mechanism to augment the immune system. Adjunctive therapy with L-arginine has the potential to improve outcomes in active tuberculosis. Methods. In a randomized clinical trial 63 participants with smear-positive pulmonary tuberculosis in Markazi Province of Iran were given arginine or placebo for 4 weeks in addition to conventional chemotherapy. The final treatment success, sputum conversion, weight gain, and clinical symptoms after one and two months were considered as primary outcomes and secondary outcomes were ESR, CRP, and Hg. Data were collected and analyzed with SPSS software (ver. 18). Results. Arginine supplementation reduced constitutional symptoms (P = 0.032) in patients with smear-positive TB at the end of the first month of treatment. Arginine treated patients had significantly increased BMI at the end of the first and second months of treatment (P = 0.032 and P = 0.04) and a reduced CRP at the end of the first month of treatment (P = 0.03) versus placebo group. Conclusion. Arginine is useful as an adjunctive therapy in patients with active tuberculosis, in which the effects are more likely mediated by the increased production of nitric oxide and improved constitutional symptoms and weight gain. This trial is registered with Clinical Trials Registry of Iran: IRCT201211179855N2. PMID:25734013

  17. Different screening strategies (single or dual) for the diagnosis of suspected latent tuberculosis: a cost effectiveness analysis

    Microsoft Academic Search

    Anil Pooran; Helen Booth; Robert F Miller; Geoff Scott; Motasim Badri; Jim F Huggett; Graham Rook; Alimuddin Zumla; Keertan Dheda

    2010-01-01

    BACKGROUND: Previous health economic studies recommend either a dual screening strategy [tuberculin skin test (TST) followed by interferon-?-release assay (IGRA)] or a single one [IGRA only] for latent tuberculosis infection (LTBI), the former largely based on claims that it is more cost-effective. We sought to examine that conclusion through the use of a model that accounts for the additional costs

  18. Does Neutralization of Gastric Aspirates from Children with Suspected Intrathoracic Tuberculosis Affect Mycobacterial Yields on MGIT Culture?

    PubMed Central

    Parashar, Deepak; Kabra, Sushil K.; Lodha, Rakesh; Singh, Varinder; Mukherjee, Aparna; Arya, Tina; Grewal, Harleen M. S.

    2013-01-01

    The microbiological confirmation of pulmonary tuberculosis in children relies on cultures of gastric aspirate (GA) specimens. Conventionally, GAs are neutralized to improve culture yields of mycobacteria. However, there are limited data to support this practice. To study the utility of neutralization of GAs with sodium bicarbonate in children with intrathoracic tuberculosis, a total of 116 children of either sex, aged 6 months to 14 years (median age, 120 months; interquartile range [IQR], 7 to 192 months), underwent gastric aspiration on 2 consecutive days. Gastric aspirates were divided into two aliquots, and only one aliquot was neutralized with 1% sodium bicarbonate. Both aliquots were processed for smear and culture examinations. Out of the 232 gastric aspirates, 12 (5.17%) were acid-fast bacilli (AFB) smear positive. There were no differences in smear positivity rates from samples with or without neutralization. The yield of Mycobacterium tuberculosis on a Bactec MGIT 960 culture system was significantly lower in the neutralized samples (16.3% [38/232]) than in the nonneutralized samples (21.5% [50/232]) (P = 0.023). There was no significant difference between the neutralized and the nonneutralized samples in time to detection using the MGIT 960 system (average, 24.6 days; IQR, 12 to 37 days) (P = 0.9). The contamination rates were significantly higher in the neutralized samples than in the nonneutralized samples (17.2% [40/232] versus 3.9% [9/232]) (P = 0.001). The agreement for positive mycobacterial culture between the two approaches was 66.5% (P = 0.001). Hence, we recommend that gastric aspirate samples not be neutralized with sodium bicarbonate prior to culture for M. tuberculosis. PMID:23536406

  19. Programmatic approaches to screening for active tuberculosis.

    PubMed

    Uplekar, M; Creswell, J; Ottmani, S-E; Weil, D; Sahu, S; Lönnroth, K

    2013-10-01

    Passive case finding, the detection of tuberculosis (TB) cases among persons presenting to health facilities with symptoms suggestive of TB, has remained the principal public health approach for TB diagnosis. While this approach, in combination with improved treatment, has led to substantial global progress, the overall epidemiological impact has been inadequate. Stagnating case notifications and sluggish decline in incidence prompt the pursuit of a more active approach to TB case detection. Screening among contacts of TB patients and people living with human immunodeficiency virus infection, long recommended, needs scaling up. Screening in other risk groups may also be considered, depending on the epidemiological situation. The World Health Organization (WHO) has recently produced recommendations on systematic screening for active TB, which set out principles and provide guidance on the prioritisation of risk groups for screening and choice of screening and diagnostic algorithms. With a view to help translate WHO recommendations into practice, this concluding article of the State of the Art series discusses programmatic approaches. Published literature is scanty. However, considerable field experience exists to draw important lessons. Cautioning against a hasty pursuit of active case finding, the article stresses that programmatic implementation of TB screening requires a systematic approach. Important considerations should include setting clear goals and objectives based on a thorough assessment of the situation; considering the place of TB screening in the overall approach to enhancing TB detection; identifying and prioritising risk groups; choosing appropriate screening and diagnostic algorithms; and pursuing setting-specific implementation strategies with engagement of relevant partners, due attention to ethical considerations and built-in monitoring and evaluation. PMID:24025375

  20. Indoleamides are active against drug-resistant Mycobacterium tuberculosis

    PubMed Central

    Lun, Shichun; Guo, Haidan; Onajole, Oluseye K.; Pieroni, Marco; Gunosewoyo, Hendra; Chen, Gang; Tipparaju, Suresh K.; Ammerman, Nicole C.; Kozikowski, Alan P.; Bishai, William R.

    2014-01-01

    Responsible for nearly two million deaths each year, the infectious disease tuberculosis remains a serious global health challenge. The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis confounds control efforts, and new drugs with novel molecular targets are desperately needed. Here we describe lead compounds, the indoleamides, with potent activity against both drug-susceptible and drug-resistant strains of M. tuberculosis by targeting the mycolic acid transporter MmpL3. We identify a single mutation in mmpL3 which confers high resistance to the indoleamide class while remaining susceptible to currently used first- and second-line tuberculosis drugs, indicating a lack of cross-resistance. Importantly, an indoleamide derivative exhibits dose-dependent anti-mycobacterial activity when orally administered to M. tuberculosis-infected mice. The bioavailability of the indoleamides, combined with their ability to kill tubercle bacilli, indicates great potential for translational developments of this structure class for the treatment of drug-resistant tuberculosis. PMID:24352433

  1. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...2011-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions...Diseases § 3.378 Changes from activity in pulmonary tuberculosis pension cases. A permanent and total...

  2. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...2013-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions...Diseases § 3.378 Changes from activity in pulmonary tuberculosis pension cases. A permanent and total...

  3. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...2014-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions...Diseases § 3.378 Changes from activity in pulmonary tuberculosis pension cases. A permanent and total...

  4. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...2012-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions...Diseases § 3.378 Changes from activity in pulmonary tuberculosis pension cases. A permanent and total...

  5. 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

  6. Clinical Predictors and Accuracy of Empiric Tuberculosis Treatment among Sputum Smear-Negative HIV-Infected Adult TB Suspects in Uganda

    PubMed Central

    Nakiyingi, Lydia; Bwanika, John Mark; Kirenga, Bruce; Nakanjako, Damalie; Katabira, Catherine; Lubega, Gloria; Sempa, Joseph; Nyesiga, Barnabas; Albert, Heidi; Manabe, Yukari C.

    2013-01-01

    Introduction The existing diagnostic algorithms for sputum smear-negative tuberculosis (TB) are complicated, time-consuming, and often difficult to implement. The decision to initiate TB treatment in resource-limited countries is often largely based on clinical predictors. We sought to determine the clinical predictors and accuracy of empiric TB treatment initiation in HIV-infected sputum smear-negative TB suspects using sputum culture as a reference standard. Setting Out-patient HIV-TB integrated urban clinic in Kampala, Uganda. Methods HIV-infected TB suspects were screened using sputum smear microscopy, and mycobacterial sputum liquid and solid cultures were performed. Smear results were made available to the clinician who made a clinical decision on empiric TB treatment initiation for sputum smear-negative patients. Clinic records were reviewed for patients whose sputum smears were negative to collect data on socio-demographics, TB symptomatology, chest X-ray findings, CD4 cell counts and TB treatment initiation. Results Of 253 smear-negative TB suspects, 56% (142/253) were females, median age 38 IQR (31–44) years, with a median CD4 cell count of 291 IQR (150–482) cells/mm3. Of the 85 (33.6%) smear-negative patients empirically initiated on TB treatment, 35.3% (n?=?30) were sputum culture positive compared to only 18 (10.7%) of the 168 untreated patients (p<0.001). Abnormal chest X-ray [aOR 10.18, 95% CI (3.14–33.00), p<0.001] and advanced HIV clinical stage [aOR 3.92, 95% CI (1.20–12.85), p?=?0.024] were significantly associated with empiric TB treatment initiation. The sensitivity and specificity of empiric TB treatment initiation in the diagnosis of TB in HIV-infected patients after negative smear microscopy was 62.5% and 73.7% respectively. Conclusion In resource-limited settings, clinically advanced HIV and abnormal chest X-ray significantly predict a clinical decision to empirically initiate TB treatment in smear-negative HIV-infected patients. Empiric TB treatment initiation correlates poorly with TB cultures. Affordable, accurate and rapid point-of-care diagnostics are needed in resource-limited settings to more accurately determine which HIV-infected TB suspects have smear-negative TB. PMID:24040151

  7. Impact of port of entry referrals on initiation of follow-up evaluations for immigrants with suspected tuberculosis: Illinois.

    PubMed

    Bell, Teal R; Molinari, NoelleAngelique M; Blumensaadt, Sena; Selent, Monica U; Arbisi, Michael; Shah, Neha; Christiansen, Demian; Philen, Rossanne; Puesta, Benjamin; Jones, Joshua; Lee, Deborah; Vang, Arnold; Cohen, Nicole J

    2013-08-01

    US-bound immigrants with suspected non-infectious TB are encouraged to be medically re-evaluated after arrival in the United States. We evaluated the Centers for Disease Control and Prevention's immigrant referral process, designed to facilitate timely post-arrival evaluations. Over 1,200 immigrants with suspected TB arriving during October 1, 2008-September 30, 2010 were identified. In 2011, differences in days to evaluation initiation were assessed by referral type using survival analysis and Cox proportional hazard models. Among those receiving any referral, median time to post-arrival evaluation was significantly lower compared with immigrants receiving no referral (16 vs. 69 days, respectively; p < 0.0001). After adjusting for the covariates, immigrants receiving any referral initiated follow-up at 4 times the rate (adjusted hazard ratio = 4.0; p < 0.0001) of those receiving no referral. Implementing a referral system at US ports of entry will improve timeliness and increase the proportion of immigrants initiating domestic evaluation. PMID:23393046

  8. Tuberculosis

    MedlinePLUS

    ... for Parents for Kids for Teens Teens Home Body Mind Sexual Health Food & Fitness Diseases & Conditions Infections Q&A School & Jobs Drugs & Alcohol Staying Safe Recipes En Español Making a ... Tuberculosis KidsHealth > Teens > Infections > Bacterial & Viral Infections > ...

  9. [Organization of active patient detection with tuberculosis by using computer technologies].

    PubMed

    Kucherov, A L; Il'icheva, E Iu

    1998-01-01

    The paper presents the authors' experience in introducing a new system for active detection of patients with tuberculosis by using the database (a computer-register of individuals aged above 15 years and a programme for rapid evaluatin of the individual risk for tuberculosis, which reduces the scope of fluorographic and other examinations of the population for tuberculosis. PMID:9691681

  10. Effect of Active Tuberculosis on Skin Prick Allergy Tests and Serum IgE Levels

    Microsoft Academic Search

    A Kutlu; E Bozkanat; B Bozkurt; R Gorur; O Taskapan

    ? Abstract Objective: Mycobacterium tuberculosis has been shown to suppress allergic airway disease driven by type 2 helper T cells in animal models. In this study, we investigated the effect of active tuberculosis on skin prick test (SPT) positivity and serum immunoglobulin (Ig) E levels of atopic patients with and without tuberculosis infection. Materials and methods: Seventeen atopic HIV-negative men

  11. Tuberculosis

    MedlinePLUS

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

  12. Macrophage activation and resistance to pulmonary tuberculosis.

    PubMed Central

    Lefford, M J

    1980-01-01

    Mice were vaccinated with 300 micrograms of BCG cell walls (BCG-CW) in oil-in-water emulsion intravenously or with a high or low dose of living BCG by inhalation (BCG-HD or BCG-LD, respectively). The consequences of vaccination were evaluated in terms of the growth of BCG in the lungs and spleen, lung and spleen weight, resistance to intravenous and airborne challenge with Listeria monocytogenes, airborne challenge with virulent Mycobacterium tuberculosis H37Rv, and transfer of adoptive immunity. BCG-CW and BCG-HD mice developed increased lung weight, which was associated with transiet, low-level resistance to airborne L. monocytogenes and initial resistance to airborne H37Rv. Only BCG-CW mice developed splenomegaly, which was accompanied by high resistance to intravenous challenge with L. monocytogenes. The initial resistance of BCG-CW mice to H37Rv was not sustained, whereas that of BCG-HD mice persisted. There was no initial resistance to H37Rv in BCG-LD mice, but immunity was generated later. Overall, BCG-HD mice were most resistant to H37Rv, and BCG-CW and BCG-LD mice were less but equally resistant. PMID:6772560

  13. 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

  14. Chromospheric activity in Delta Scuti stars - The suspected variable Tau Cygni

    NASA Technical Reports Server (NTRS)

    Fracassini, M.; Pasinetti Fracassini, L. E.; Mariani, A.; Pastori, L.; Teays, T. J.

    1991-01-01

    High-resolution IUE spectra of the suspected variable Tau Cyg were obtained to search for a possible variability of the Mg II h, k double-peaked emission. The observations, spanning an interval of about 6.3 h, have shown flux excursions within or just near 15 percent, a value suggested as the detection limit of actual variations with IUE spectra. A variability, difficult to explain, could be present in the ratios Fk2v/Fk2r. The emission fluxes seem to be higher than those of the Delta Scuti variables Rho Pup and Beta Cas. This comparison could give some insights on the possible role of the convection on the pulsational and chromospheric activities of Tau Cyg. A positive correlation between the total emission fluxes and the rotational velocities of these stars was found.

  15. Liquid vs Solid Culture Medium to Evaluate Proportion and Time to Change in Management of Suspects of Tuberculosis—A Pragmatic Randomized Trial in Secondary and Tertiary Health Care Units in Brazil

    PubMed Central

    Moreira, Adriana da Silva Rezende; Huf, Gisele; Vieira, Maria Armanda Monteiro da Silva; da Costa, Paulo Albuquerque; Aguiar, Fábio; Marsico, Anna Grazia; Fonseca, Leila de Souza; Ricks, Mônica; Oliveira, Martha Maria; Detjen, Anne; Fujiwara, Paula Isono; Squire, Stephen Bertel; Kritski, Afranio Lineu

    2015-01-01

    Background The use of liquid medium (MGIT960) for tuberculosis (TB) diagnosis was recommended by WHO in 2007. However, there has been no evaluation of its effectiveness on clinically important outcomes. Methods and Findings A pragmatic trial was carried out in a tertiary hospital and a secondary health care unit in Rio de Janeiro City, Brazil. Participants were 16 years or older, suspected of having TB. They were excluded if only cerebral spinal fluid or blood specimens were available for analysis. MGIT960 technique was compared with the Lowenstein-Jensen (LJ) method for laboratory diagnosis of active TB. Primary outcome was the proportion of patients who had their initial medical management changed within 2 months after randomisation. Secondary outcomes were: mean time for changing the procedure, patient satisfaction with the overall treatment and adverse events. Data were analysed by intention-to-treat. Between April 2008 and September 2011, 693 patients were enrolled (348 to MGIT, 345 to LJ). Smear and culture results were positive for 10% and 15.7% of participants, respectively. Patients in the MGIT arm had their initial medical management changed more frequently than those in the LJ group (10.1% MGIT vs 3.8% LJ, RR 2.67 95% CI 1.44–.96, p = 0.002, NNT 16, 95% CI 10–39). Mean time for changing the initial procedure was greater in LJ group at both sites: 20.0 and 29.6 days in MGIT group and 52.2 and 64.3 in LJ group (MD 33.5, 95% CI 30.6–36.4, p = 0.0001). No other important differences were observed. Conclusions This study suggests that opting for the MGIT960 system for TB diagnosis provides a promising case management model for improving the quality of care and control of TB. Trial Registration Controlled-Trials.com ISRCTN79888843 PMID:26046532

  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. 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 sensitivity and specificity levels for the immunodiagnosis of active TB. PMID:21966416

  18. Evaluation of Voice Disorders in Patients with Active Laryngeal Tuberculosis

    PubMed Central

    Lucena, Marcia Mendonça; da Silva, Fernanda dos Santos; da Costa, Ananda Dutra; Guimarães, Gabriela Rodrigues; Ruas, Ana Cristina Nunes; Braga, Frederico Pereira Bom; Braga, Mateus Pereira Bom; Reis, João Gustavo Corrêa; da Costa, Daniel César Silva; Palmeiro, Mariana Reuter; Rolla, Valéria Cavalcanti; Valete-Rosalino, Cláudia Maria

    2015-01-01

    Introduction Laryngeal tuberculosis (LTB) is the most frequent larynx granulomatous disease. In general there is lung involvement, but in an important proportion of cases you can find LTB without pulmonary disease. The lesions observed in LTB, such as ulceration and fibrosis, can interfere in the process of voice production. The involvement of the mucous lining of the vocal folds can change their flexibility and, consequently, change voice quality, and the main symptom is dysphonia present in almost 90% of cases. Objective To describe the anatomical characteristics and voice quality in LTB patients. Material and Method A descriptive cross-sectional study was conducted with 24 patients. Result The most frequently affected sites were vocal folds in 87.5% patients, vestibular folds in 66.7%, epiglottis in 41.7%, arytenoid in 50%, aryepiglottic folds in 33.3%, and interarytenoid region in 33.3% patients. We found 95.8% cases of dysphonia. The voice acoustic analysis showed 58.3% cases of Jitter alterations, 83.3% of Shimmer and 70.8% of GNE. Conclusion Voice disorders found in active laryngeal tuberculosis are similar to those reported after clinical healing of the disease, suggesting that sequelae and vocal adjustments may install during the active phase of the disease, negatively impacting the process of vocal quality reestablishment. PMID:26009888

  19. Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis.

    PubMed

    Kahnert, Antje; Seiler, Peter; Stein, Maik; Bandermann, Silke; Hahnke, Karin; Mollenkopf, Hans; Kaufmann, Stefan H E

    2006-03-01

    A potent Th1 immune response is critical to the control of tuberculosis. The impact of an additive Th2 response on the course of disease has so far been insufficiently characterized, despite increased morbidity after co-infection with Mycobacterium tuberculosis and Th2-eliciting helminths and possible involvement of Th2 polarization in reactivation of latent tuberculosis. Here, we describe the gene expression profile of murine bone marrow-derived macrophages alternatively activated by IL-4 in response to infection with M. tuberculosis. Comparison of transcriptional profiles of infected IL-4- and IFN-gamma-activated macrophages revealed delayed and partially diminished responses to intracellular bacteria in alternatively activated macrophages, characterized by reduced exposure to nitrosative stress and increased iron availability, respectively. Alternative activation of host macrophages correlated with elevated expression of the M. tuberculosis iron storage protein bacterioferritin as well as reduced expression of the mycobactin synthesis genes mbtI and mbtJ. The extracellular matrix-remodeling enzyme matrix metalloproteinase (MMP)-12 was induced in alternatively activated macrophages in vitro, and MMP-12-expressing macrophages were abundant at late, but not early, stages of tuberculosis in murine lungs. Our findings emphasize that alternative activation deprives macrophages of control mechanisms that limit mycobacterial growth in vivo, thus supporting intracellular persistence of M. tuberculosis. PMID:16479545

  20. Differential expression of CD57 in antigen-reactive CD4(+) T cells between active and latent tuberculosis infection.

    PubMed

    Lee, Ji Yeon; Jeong, Ina; Joh, Joon-Sung; Jung, Young Won; Sim, Soo Yeon; Choi, Boram; Jee, Hyeon-Gun; Lim, Dong-Gyun

    2015-07-01

    The development of diagnostic tests that predict the progression of latent tuberculosis infection to active disease is pivotal for the eradication of tuberculosis. As an initial step to achieve this goal, our study's aim was to identify biomarkers that differentiate active from latent tuberculosis infection. We compared active and latent tuberculosis infection groups in terms of the precursor frequency, functional subset differentiation, and senescence/exhaustion surface marker expression of antigen-specific CD4(+) T cells, which were defined as dividing cells upon their encountering with Mycobacterium (M.) tuberculosis antigens. Among several parameters shown to have statistically significant differences between the two groups, the frequency of CD57-expressing cells could differentiate effectively between active disease and latent infection. Our results suggest that the expression of CD57 in M. tuberculosis-reactive CD4(+) T cells could be a promising candidate biomarker with which to identify individuals with latent tuberculosis infection prone to progression to active disease. PMID:25931385

  1. Increased exhaled nitric oxide in active pulmonary tuberculosis due to inducible NO synthase upregulation in alveolar macrophages

    Microsoft Academic Search

    C.-H. Wang; C.-Y. Liu; H.-C. Lin; C.-T. Yu; K. F. Chung; H.-P. Kuo

    1998-01-01

    Nitric oxide (NO) plays an important role in resistance to Mycobacte- rium tuberculosis infection. Our aim was to determine whether inducible NO synthase (iNOS) expression and generation of reactive nitrogen intermediates (RNI) by alveo- lar macrophages (AM) are increased in patients infected with M. tuberculosis. NO levels in the exhaled air of 19 active pulmonary tuberculosis (TB) and 14 con-

  2. Identification and characterization of Mycobacterium tuberculosis antigens in urine of patients with active pulmonary tuberculosis: an innovative and alternative approach of antigen discovery of useful microbial molecules

    PubMed Central

    Kashino, S S; Pollock, N; Napolitano, D R; Rodrigues, V; Campos-Neto, A

    2008-01-01

    Despite the clear need to control tuberculosis, the diagnosis and prevention of this serious disease are poorly developed and have remained fundamentally unchanged for more than 50 years. Here, we introduce an innovative approach to directly identify Mycobacterium tuberculosis antigens produced in vivo in humans with tuberculosis. We combined reversed phase high performance liquid chromatography and mass spectrometry and categorize four distinct M. tuberculosis proteins produced presumably in lung lesions and excreted in the urine of patients with pulmonary tuberculosis. The genes (MT_1721, MT_1694, MT_2462 and MT_3444) coding for these proteins were cloned and the recombinant molecules were produced in Escherichia coli. The proteins were recognized by immunoglobulin G antibodies from tuberculosis patients but not from non-diseased subjects. In addition, the recombinant proteins were recognized strongly by peripheral blood mononuclear cells from healthy purified protein derivative of tuberculin-positive individuals and to a lesser extent from patients with tuberculosis. These molecules are the only proteins reported to date that are derived directly from bodily fluids of tuberculosis patients, therefore are interesting candidate antigens for the development of vaccine and/or antigen detection assay for accurate diagnosis of active tuberculosis. PMID:18460016

  3. ANALYSIS OF THE SPECTRA OF GENETIC ACTIVITY PRODUCED BY KNOWN OR SUSPECTED HUMAN CARCINOGENS

    EPA Science Inventory

    For 24 agents classified by the International Agency for Research on Cancer as known or suspected human carcinogens, we previously catalogued the qualitative genetic bioassay data available in the literature. In the present analysis, dose information, where available, was added t...

  4. Latent and Active Tuberculosis Infection Increase Immune Activation in Individuals Co-Infected with HIV????

    PubMed Central

    Sullivan, Zuri A.; Wong, Emily B.; Ndung'u, Thumbi; Kasprowicz, Victoria O.; Bishai, William R.

    2015-01-01

    In recent years, chronic immune activation and systemic inflammation have emerged as hallmarks of HIV disease progression and mortality. Several studies indicate that soluble inflammatory biomarkers (sCD14, IL-6, IL-8, CRP and hyaluronic acid), as well as surface markers of T-cell activation (CD38, HLA-DR) independently predict progression to AIDS and mortality in HIV-infected individuals. While co-infections have been shown to contribute to immune activation, the impact of latent tuberculosis infection (LTBI), which is widely endemic in the areas most affected by the global AIDS epidemic, has not been evaluated. We hypothesized that both active and latent states of Mycobacterium tuberculosis co-infection contribute to elevated immune activation as measured by these markers. In HIV-infected individuals with active, but not latent TB, we found elevated levels of soluble markers associated with monocyte activation. Interestingly, T-cell activation was elevated individuals with both latent and active TB. These results suggest that in the highly TB- and HIV-endemic settings of southern Africa, latent TB-associated T-cell activation may contribute to HIV disease progression and exacerbate the HIV epidemic. In addition, our findings indicate that aggressive campaigns to treat LTBI in HIV-infected individuals in high-burden countries will not only impact TB rates, but may also slow HIV progression. Significance Latent tuberculosis, which affects an estimated 1/3 of the world's population, has long been thought to be a relatively benign, quiescent state of M. tuberculosis infection. While HIV co-infection is known to exacerbate M. tuberculosis infection and increase the risk of developing active TB, little is known about the potential effect of latent TB infection on HIV disease. This study shows that HIV-infected individuals with both active and latent TB have elevated levels of inflammation and immune activation, biomarkers of HIV disease progression and elevated risk of mortality. These results suggest that, in the context of HIV, latent TB infection may be associated with increased risk of progression to AIDS and mortality. PMID:26114158

  5. [Primary and pulmonary tuberculosis].

    PubMed

    Toujani, S; Ben Salah, N; Cherif, J; Mjid, M; Ouahchy, Y; Zakhama, H; Daghfous, J; Beji, M; Mehiri-Ben Rhouma, N; Louzir, B

    2015-01-01

    Tuberculosis is a major public health problem worldwide. Indeed, a third of the world population is infected with Mycobacterium tuberculosis and more than 8 million new cases of tuberculosis each year. Pulmonary tuberculosis is the most common location. Its diagnosis is difficult and often established with a delay causing a spread of infection. The diagnosis of tuberculosis infection is mainly based on immunological tests represented by the tuberculin skin test and detection of gamma interferon, while the diagnosis of pulmonary tuberculosis is suspected on epidemiological context, lasting general and respiratory symptoms, contrasting usually with normal lung examination, and a chest radiography showing suggestive lesions. The radioclinical feature may be atypical in patients with extreme ages and in case of immunodeficiency. Confirmation of tuberculosis is bacteriological. Conventional bacteriological methods remain the reference. Innovative tests using the technique of molecular biology have improved the diagnosis of tuberculosis in terms of sensitivity and especially speed. However, those techniques are of limited use. PMID:25749628

  6. Mycobacterium tuberculosis Activates Human Macrophage Peroxisome Proliferator-Activated Receptor ? Linking Mannose Receptor Recognition to Regulation of Immune Responses

    PubMed Central

    Rajaram, Murugesan V. S.; Brooks, Michelle N.; Morris, Jessica D.; Torrelles, Jordi B.; Azad, Abul K.; Schlesinger, Larry S.

    2010-01-01

    Mycobacterium tuberculosis enhances its survival in macrophages by suppressing immune responses in part through its complex cell wall structures. Peroxisome proliferator-activated receptor ? (PPAR?), a nuclear receptor superfamily member, is a transcriptional factor that regulates inflammation and has high expression in alternatively activated alveolar macrophages and macrophage-derived foam cells, both cell types relevant to tuberculosis pathogenesis. In this study, we show that virulent M. tuberculosis and its cell wall mannose-capped lipoarabinomannan induce PPAR? expression through a macrophage mannose receptor-dependent pathway. When activated, PPAR? promotes IL-8 and cyclooxygenase 2 expression, a process modulated by a PPAR? agonist or antagonist. Upstream, MAPK-p38 mediates cytosolic phospholipase A2 activation, which is required for PPAR? ligand production. The induced IL-8 response mediated by mannose-capped lipoarabinomannan and the mannose receptor is independent of TLR2 and NF-?B activation. In contrast, the attenuated Mycobacterium bovis bacillus Calmette-Guérin induces less PPAR? and preferentially uses the NF-?B–mediated pathway to induce IL-8 production. Finally, PPAR? knockdown in human macrophages enhances TNF production and controls the intracellular growth of M. tuberculosis. These data identify a new molecular pathway that links engagement of the mannose receptor, an important pattern recognition receptor for M. tuberculosis, with PPAR? activation, which regulates the macrophage inflammatory response, thereby playing a role in tuberculosis pathogenesis. PMID:20554962

  7. Seroprevalence of toxoplasma-specific antibodies in patients suspected to have active toxoplasmosis: A cross-sectional survey

    PubMed Central

    Eskandarian, Abbas Ali; Jafarnezghad, Gholam-Abbas; Akbari, Mojtaba

    2014-01-01

    Background: The aim of this study was to investigate the presence and distribution of anti-toxoplasma-specific IgM and IgG tantibodies in patients suspected to have toxoplasmosis and investigate for any association between IgM and IgG antibodies and some toxoplasmosis risk factors as well. Materials and Methods: In a comparative cross-sectional study, 70 patients suspected to had active toxoplasmosis and 30 control volunteers, who gave informed consent, entered the study. In each group, patient age, sex, signs of appearance, education level, residency status (urban / rural), occupation, frequency of toxoplasma-specific IgG and IgM antibodies, abortion history, and some risk factors (Direct cat exposure, Occupational exposure to raw meat, and Raw vegetable consumption) were recorded. The enzyme-linked immunosorbent assay (ELISA) kits (EUROIMMUN®, United Kingdom) were used for the evaluation of anti-toxoplasma IgG and IgM antibodies according to the manufacturer's instructions. All analyses were done using SPSS-20. Results: The frequency of toxoplasma-specific IgG and IgM antibodies like: Direct cat exposures, Occupational exposure to raw meat, and Raw vegetable consumption were not statistically significant between the two groups (P > 0.05). The history of previous abortions in women in the toxoplasmosis-suspected group was significantly higher than that in the controls (31.4% versus 6.7%; P = 0.009). Conclusion: The frequency of specific IgM and IgG antibodies in toxoplasmosis suspected in the toxoplasmosis and control groups was not statistically significant. PMID:25538922

  8. [A case of gallbladder tuberculosis diagnosed by positive tuberculosis-polymerase chain reaction].

    PubMed

    Ryu, Mi Jin; Jeon, Tae Joo; Park, Ji Young; Choi, Yena; Baek, Seung Suk; Sinn, Dong Hyun; Oh, Tae Hoon; Kim, Jung Yeon

    2014-01-25

    Gallbladder tuberculosis is an extremely rare disease that is rarely reported in the literature. Arriving at the correct diagnosis of gallbladder tuberculosis is difficult, and it is usually made by histopathologic examination after cholecystectomy. However, due to the low sensitivity of acid-fast stain and culture result, diagnosing gallbladder tuberculosis is still demanding even after tissue acquisition. To overcome this problem, tuberculosis-polymerase chain reaction (TB-PCR) is performed on the resected specimen, which has high sensitivity and specificity. A 70-year-old female who had previously undergone total gastrectomy for advanced gastric cancer was admitted with right upper quadrant pain. Abdominal ultrasonography and computed tomography revealed acute cholecystitis without gallstones or sludge. She underwent cholecystectomy and the histopathologic finding of the specimen showed chronic active cholecystitis without gallstones or sludge. Because she was suspected to have pulmonary tuberculosis, TB-PCR was also performed on the resected gallbladder. TB-PCR showed positive reaction for Mycobacterium tuberculosis and we could diagnose it as gallbladder tuberculosis. Herein, we present a case of gallbladder tuberculosis diagnosed by TB-PCR from resected gallbladder. PMID:24463290

  9. 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

  10. In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis.

    PubMed

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

    2015-01-01

    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

  11. The structure-activity relationship of urea derivatives as anti-tuberculosis agents.

    PubMed

    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

    2011-09-15

    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 hydrolase enzymes. The inhibitors also showed potent inhibition of humans soluble epoxide hydrolase, but limited cytotoxicity suggesting that future studies must be towards increasing the selectivity of epoxide hydrolase inhibition towards the M. tuberculosis enzymes. PMID:21840723

  12. 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

  13. BTLA exhibits immune memory for ?? T cells in patients with active pulmonary tuberculosis

    PubMed Central

    Zeng, Jin-Cheng; Lin, Dong-Zi; Yi, Lai-Long; Liu, Gan-Bin; Zhang, Hui; Wang, Wan-Dang; Zhang, Jun-Ai; Wu, Xian-Jing; Xiang, Wen-Yu; Kong, Bin; Chen, Zheng W; Wang, Cong-Yi; Xu, Jun-Fa

    2014-01-01

    Despite past extensive studies, the role of B and T lymphocyte attenuator (BTLA) in ?? T cells in patients with active pulmonary tuberculosis (ATB) remains poorly understood. Here we demonstrate that BTLA expression on ?? T cells is decreased in patients with M. tuberculosis (Mtb) infection. Particularly, BTLA expression levels are likely critical for ?? T cells to manifest and maintain an active central memory phenotype with high capacity for secretion of IFN-? and perforin, which are important for immune memory against TB infection. BTLAhigh ?? T cells also exhibited higher capacity in response to Mtb peptide stimulation. In contrast to the role of BTLA played for negative regulation of immune responses, our data in the current studies suggest that BTLA expression on ?? T cells is likely associated with protective immune memory against Mtb infection in the setting of patients with active pulmonary tuberculosis. This previous unappreciated role for BTLA may have implications for prevention and treatment of patients with Mtb infection. PMID:25360214

  14. Synthesis and inhibitory activity of thymidine analogues targeting Mycobacterium tuberculosis thymidine monophosphate kinase

    Microsoft Academic Search

    Sara Van Poecke; Hélène Munier-Lehmann; Olivier Helynck; Matheus Froeyen; Serge Van Calenbergh

    We report on Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) inhibitory activities of a series of new 3?- and 5?-modified thymidine analogues including ?- and ?-derivatives. In addition, several analogues were synthesized in which the 4-oxygen was replaced by a more lipophilic sulfur atom to probe the influence of this modification on TMPKmt inhibitory activity. Several compounds showed an inhibitory potency

  15. 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

  16. Activity against drug resistant-tuberculosis strains of plants used in Mexican traditional medicine to treat tuberculosis and other respiratory diseases.

    PubMed

    Camacho-Corona, María Del Rayo; Ramírez-Cabrera, Mónica A; Santiago, Omar González-; Garza-González, Elvira; Palacios, Isidoro de Paz; Luna-Herrera, Julieta

    2008-01-01

    Tuberculosis (TB) kills about 3 million people per year worldwide. Furthermore, TB is an infectious disease associated with HIV patients, and there is a rise in multidrug-resistant TB (MDR-TB) cases around the world. There is a need for new anti-TB agents. The study evaluated the antimycobacterial activity of nine plants used in Mexican traditional medicine to treat tuberculosis and other respiratory diseases. Nasturtium officinale showed the best activity (MIC = 100 microg/mL) against the sensitive Mycobacterium tuberculosis. The following plants were active also but at 200 microg/mL: Citrus sinensis, Citrus aurantifolia, Foeniculum vulgare, Larrea tridentata, Musa acuminata and Olea europaea. Contrary to the above data, activity against drug-resistant variants of M. tuberculosis was more evident, e.g. N. officinale was the most potent (MIC < or = 100 microg/mL) against the four mono-resistant variants tested; F. vulgare and O. europaea were active against all the resistant variants (MICs < or = 100 microg/mL). The most susceptible variant was the isoniazid resistant, being inhibited by C. aurantifolia, C. sinensis and O. europaea (MIC = 25 microg/mL). These data point to the importance of biological testing of extracts against drug-resistant M. tuberculosis isolates, and the bioguided assay of these extracts for the identification of lead compounds against MDR-TB isolates. PMID:17726732

  17. Circulating B-Lymphocytes as Potential Biomarkers of Tuberculosis Infection Activity

    PubMed Central

    Sebina, Ismail; Biraro, Irene A.; Dockrell, Hazel M.; Elliott, Alison M.; Cose, Stephen

    2014-01-01

    Accurate biomarkers of Mycobacterium tuberculosis infection activity would significantly improve early diagnosis, treatment and management of M. tuberculosis infection. We hypothesised that circulating B-lymphocytes may be useful biomarkers of tuberculosis (TB) infection status in highly TB-endemic settings. Ex-vivo and in-vitro mycobacteria-specific B-cell ELISPOT assays were used to examine the plasmablast (PB) and memory B-cell (MBC) responses in the peripheral blood of adult, healthy, community controls (n?=?151) and of active TB patients (n?=?48) living in Uganda. Frequencies of mycobacteria-specific PBs were markedly higher in active TB patients compared to healthy controls, and, conversely, MBCs were markedly higher in the healthy controls compared to active TB patients. In addition, the community controls with evidence of latent TB infection had higher peripheral blood PB and MBC responses than those without evidence of TB infection. These data demonstrate that peripheral blood B-cell responses are differentially modulated during latent and active M. tuberculosis infection, and suggest that the PB to MBC ratio may be a useful biomarker of TB infection activity. PMID:25192196

  18. Pentacyclic Nitrofurans with In Vivo Efficacy and Activity against Nonreplicating Mycobacterium tuberculosis

    PubMed Central

    Scherman, Michael S.; Woolhiser, Lisa K.; Madhura, Dora B.; Maddox, Marcus M.; Singh, Aman P.; Lee, Robin B.; Hurdle, Julian G.; McNeil, Michael R.; Lenaerts, Anne J.; Meibohm, Bernd; Lee, Richard E.

    2014-01-01

    The reductively activated nitroaromatic class of antimicrobials, which include nitroimidazole and the more metabolically labile nitrofuran antitubercular agents, have demonstrated some potential for development as therapeutics against dormant TB bacilli. In previous studies, the pharmacokinetic properties of nitrofuranyl isoxazolines were improved by incorporation of the outer ring elements of the antitubercular nitroimidazole OPC-67683. This successfully increased stability of the resulting pentacyclic nitrofuran lead compound Lee1106 (referred to herein as 9a). In the current study, we report the synthesis and antimicrobial properties of 9a and panel of 9a analogs, which were developed to increase oral bioavailability. These hybrid nitrofurans remained potent inhibitors of Mycobacterium tuberculosis with favorable selectivity indices (>150) and a narrow spectrum of activity. In vivo, the pentacyclic nitrofuran compounds showed long half-lives and high volumes of distribution. Based on pharmacokinetic testing and lack of toxicity in vivo, 9a remained the series lead. 9a exerted a lengthy post antibiotic effect and was highly active against nonreplicating M. tuberculosis grown under hypoxia. 9a showed a low potential for cross resistance to current antitubercular agents, and a mechanism of activation distinct from pre-clinical tuberculosis candidates PA-824 and OPC-67683. Together these studies show that 9a is a nanomolar inhibitor of actively growing as well as nonreplicating M. tuberculosis. PMID:24505329

  19. In Vitro and In Vivo Activities of Three Oxazolidinones against Nonreplicating Mycobacterium tuberculosis

    PubMed Central

    Zhang, Ming; Sala, Claudia; Dhar, Neeraj; Vocat, Anthony; Sambandamurthy, Vasan K; Sharma, Sreevalli; Marriner, Gwendolyn; Balasubramanian, V.

    2014-01-01

    Oxazolidinones represent a new class of antituberculosis drugs that exert their function by inhibiting protein synthesis. Here, we compared the activities of three oxazolidinones, linezolid, PNU-100480, and AZD5847, against latent tuberculosis using a simple model employing the streptomycin-starved Mycobacterium tuberculosis strain 18b. The in vitro drug susceptibility results showed that the three oxazolidinones had a bacteriostatic effect against actively growing bacilli but potent bactericidal activity against nonreplicating cells. In the murine model of latent infection with M. tuberculosis 18b, the efficacy of the three compounds varied greatly. Indeed, AZD5847 or its prodrug exhibited no activity or only modest activity, respectively, after 2 months of treatment, whereas both linezolid and PNU-100480 were effective against latent bacilli in mice and showed promising outcomes in combination therapy with rifampin. Moreover, the potency of PNU-100480 was significantly greater than that of linezolid, making it an attractive drug candidate in the development of new combination therapies for latent tuberculosis. PMID:24663022

  20. 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-?) and interferon gamma (IFN-?) levels was observed with treatments, with 125I-DPA-713 SPECT correlating best with tissue TNF-? levels (? = 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

  1. Intracellular activity of tedizolid phosphate and ACH-702 versus Mycobacterium tuberculosis infected macrophages

    PubMed Central

    2014-01-01

    Background Due to the emergency of multidrug-resistant strains of Mycobacterium tuberculosis, is necessary the evaluation of new compounds. Findings Tedizolid, a novel oxazolidinone, and ACH-702, a new isothiazoloquinolone, were tested against M. tuberculosis infected THP-1 macrophages. These two compounds significantly decreased the number of intracellular mycobacteria at 0.25X, 1X, 4X and 16X the MIC value. The drugs were tested either in nanoparticules or in free solution. Conclusion Tedizolid and ACH-702 have a good intracellular killing activity comparable to that of rifampin or moxifloxacin. PMID:24708819

  2. Mycobacterium tuberculosis Rv2185c contributes to nuclear factor-?B activation.

    PubMed

    Zhang, Huan; Ouyang, Haiping; Wang, Dang; Shi, Junwei; Ouyang, Chao; Chen, Huanchun; Xiao, Shaobo; Fang, Liurong

    2015-08-01

    Tuberculosis caused by Mycobacterium tuberculosis has a detrimental impact on public health worldwide, especially in developing countries. The nuclear factor-?B (NF-?B) signaling pathway is reportedly involved in the innate immune response against M. tuberculosis infections. We screened the secreted proteins, membrane proteins, and lipoproteins of the M. tuberculosis H37Rv strain using luciferase activity assays. The Rv2185c protein exhibited the potential to activate NF-?B in HeLa and A549 cells. Overexpression of Rv2185c-induced I?B? degradation and nuclear translocation of NF-?B; it also induced NF-?B-dependent inflammatory factors, including interleukin (IL)-6, IL-8, IL-1? and tumor necrosis factor (TNF)-?. The intact binding site for the NF-?B element is required for the activation of Rv2185c-induced IL-6 and IL-8 gene expression. NF-?B activation and NF-?B-regulated genes encoding TNF-? and TNF-related apoptosis-inducing ligand have also been shown to be involved in Rv2185c-induced apoptosis. PMID:25771181

  3. Lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis

    Microsoft Academic Search

    Mekonnen Kurabachew; Stephen H. J. Lu; Philipp Krastel; Esther K. Schmitt; Bangalore L. Suresh; Anne Goh; John E. Knox; Ngai Ling Ma; Jan Jiricek; David Beer; Michael Cynamon; Frank Petersen; Veronique Dartois; Thomas Keller; Thomas Dick; Vasan K. Sambandamurthy

    2008-01-01

    Objectives: The aim of this study was to determine the in vitro activity of lipiarmycin against drug- resistant strains of Mycobacterium tuberculosis (MTB) and to establish the resistance mechanism of MTB against lipiarmycin using genetic approaches. Methods: MIC values were measured against a panel of drug-resistant strains of MTB using the broth microdilution method. Spontaneous lipiarmycin-resistant mutants of MTB were

  4. Activity of Scottish plant, lichen and fungal endophyte extracts against Mycobacterium aurum and Mycobacterium tuberculosis.

    PubMed

    Gordien, Andréa Y; Gray, Alexander I; Ingleby, Kevin; Franzblau, Scott G; Seidel, Véronique

    2010-05-01

    With tuberculosis the leading bacterial killer worldwide and other mycobacterial diseases on the increase, the search for new antimycobacterial agents is timely. In this study, extracts from plants, lichens and fungal endophytes of Scottish provenance were screened for activity against Mycobacterium aurum and M. tuberculosis H(37)Rv. The best activity against M. aurum was observed for extracts of Juniperus communis roots and Cladonia arbuscula (MIC = 4 microg/mL), and a fungal endophyte isolated from Vaccinium myrtillus (MIC = 8 microg/mL). The best activity against M. tuberculosis was observed for extracts of C. arbuscula, Empetrum nigrum, J. communis roots, Calluna vulgaris aerial parts, Myrica gale roots and stems (93 to 99% inhibition at 100 microg/mL). Potent antitubercular activity (90 to 96% inhibition at 100 microg/mL) was also observed for the ethanol extracts of Xerocomus badius, Chalciporus piperatus, Suillus luteus and of endophytes isolated from C. vulgaris, E. nigrum, Vaccinium vitis-idaea and V. myrtillus. The results obtained this study provide, in part, some scientific basis for the traditional use of some of the selected plants in the treatment of tuberculosis. They also indicate that fungal endophytes recovered from Scottish plants are a source of antimycobacterial agents worthy of further investigation. PMID:19827032

  5. Risk Factors for Developing Active Tuberculosis After the Treatment of Latent Tuberculosis in Adults Infected With Human Immunodeficiency Virus

    PubMed Central

    Amoakwa, Kojo; Martinson, Neil A.; Moulton, Lawrence H.; Barnes, Grace L.; Msandiwa, Reginah; Chaisson, Richard E.

    2015-01-01

    Tuberculosis is the leading cause of death among adults infected with human immunodeficiency virus (HIV), and rates of tuberculosis remain high even after preventive therapy. Among 908 HIV-infected adults in a trial of preventive treatment, we found self-reported alcohol consumption, low baseline CD4 count, high baseline viral load, and tuberculin skin test size >15 mm as independent risk factors for incident tuberculosis.

  6. Activity of 7-methyljuglone derivatives against Mycobacterium tuberculosis and as subversive substrates for mycothiol disulfide reductase

    Microsoft Academic Search

    Anita Mahapatra; Sannah P. N. Mativandlela; B. Binneman; P. B. Fourie; Chris J. Hamilton; J. J. M. Meyer; F. van der Kooy; Peter Houghton; Namrita Lall

    2007-01-01

    The naphthoquinone 7-methyljuglone (5-hydroxy-7-methyl-1,4-naphthoquinone) has previously been isolated and identified as an active component of root extracts of Euclea natalensis which displays antitubercular activity. Herein, a series of synthetic and plant-derived naphthoquinone derivates of the 7-methyljuglone scaffold have been prepared and evaluated for antibacterial activity against Mycobacterium tuberculosis. Several of these compounds have been shown to operate as subversive substrates

  7. 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

  8. 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

  9. A Promoter Mutation Causes Differential Nitrate Reductase Activity of Mycobacterium tuberculosis and Mycobacterium bovis

    PubMed Central

    Stermann, Marion; Sedlacek, Ludwig; Maass, Silvia; Bange, Franz-Christoph

    2004-01-01

    The recent publication of the genome sequence of Mycobacterium bovis showed >99.95% identity to M. tuberculosis. No genes unique to M. bovis were found. Instead numerous single-nucleotide polymorphisms (SNPs) were identified. This has led to the hypothesis that differential gene expression due to SNPs might explain the differences between the human and bovine tubercle bacilli. One phenotypic distinction between M. tuberculosis and M. bovis is nitrate reduction, which not only is an essential diagnostic tool but also contributes to mycobacterial pathogenesis. We previously showed that narGHJI encodes a nitrate reductase in both M. tuberculosis and M. bovis and that NarGHJI-mediated nitrate reductase activity was substantially higher in the human tubercle bacillus. In the present study we used a genetic approach to demonstrate that an SNP within the promoter of the nitrate reductase gene cluster narGHJI is responsible for the different nitrate reductase activity of M. tuberculosis and M. bovis. This is the first example of an SNP that leads to differential gene expression between the human and bovine tubercle bacilli. PMID:15090527

  10. A promoter mutation causes differential nitrate reductase activity of Mycobacterium tuberculosis and Mycobacterium bovis.

    PubMed

    Stermann, Marion; Sedlacek, Ludwig; Maass, Silvia; Bange, Franz-Christoph

    2004-05-01

    The recent publication of the genome sequence of Mycobacterium bovis showed >99.95% identity to M. tuberculosis. No genes unique to M. bovis were found. Instead numerous single-nucleotide polymorphisms (SNPs) were identified. This has led to the hypothesis that differential gene expression due to SNPs might explain the differences between the human and bovine tubercle bacilli. One phenotypic distinction between M. tuberculosis and M. bovis is nitrate reduction, which not only is an essential diagnostic tool but also contributes to mycobacterial pathogenesis. We previously showed that narGHJI encodes a nitrate reductase in both M. tuberculosis and M. bovis and that NarGHJI-mediated nitrate reductase activity was substantially higher in the human tubercle bacillus. In the present study we used a genetic approach to demonstrate that an SNP within the promoter of the nitrate reductase gene cluster narGHJI is responsible for the different nitrate reductase activity of M. tuberculosis and M. bovis. This is the first example of an SNP that leads to differential gene expression between the human and bovine tubercle bacilli. PMID:15090527

  11. Glycolipids of Mycobacterium tuberculosis Strain H37Rv Are Potential Serological Markers for Diagnosis of Active Tuberculosis

    Microsoft Academic Search

    R. P. Tiwari; Dileep Tiwari; Sanjay K. Garg; Ramesh Chandra; Prakash S. Bisen

    2005-01-01

    A simple and cost-effective diagnostic tool (TB Screen Test) for the screening of patients with pulmonary and extrapulmonary tuberculosis and for differentiation of those individuals from individuals without tuberculosis, other common infections, and healthy controls has been developed. The serological responses of purified mycobacterial glycolipid antigens were examined by a liposome agglutination assay. The assay was able to detect very

  12. Mycobacterium tuberculosis 6 kDa early secreted antigenic target stimulates activation of J774 macrophages

    Microsoft Academic Search

    Gyanesh Singh; Balwan Singh; Vladimir Trajkovic; Pawan Sharma

    2005-01-01

    The influence of the 6kDa early-secreted antigenic target (ESAT-6) of Mycobacterium tuberculosis on macrophage activation was investigated using J774 macrophage cell line. While without effect if applied alone, ESAT-6 in a dose-dependent manner enhanced nitric oxide (NO) release by IFN-?-stimulated J774 cells. However, it completely failed to modulate NO production in J774 cells activated with E. coli lipopolysaccharide. The effect

  13. Activity of diclofenac used alone and in combination with streptomycin against Mycobacterium tuberculosis in mice

    Microsoft Academic Search

    Noton Kumar Dutta; Kaushiki Mazumdar; Sujata G. Dastidar; Jae-Hak Park

    2007-01-01

    The non-steroidal anti-inflammatory drug diclofenac (DCL) shows noteworthy in vitro and in vivo antimycobacterial activity. The aim of this study was to ascertain whether DCL used in combination with the first-line antitubercular antibiotic streptomycin (STM) synergistically augments its efficacy in vitro as well as in a murine tuberculosis infection model. In vitro minimum inhibitory concentrations (MICs) and synergistic activities of

  14. Rapid testing for nitrate reductase activity of Mycobacterium tuberculosis grown in an automated culture system.

    PubMed

    Meyer, A; Sedlacek, L; Bange, F-C

    2003-07-01

    In order to reduce the time to detection of nitrate reductase activity, which is arguably the most widely used phenotypic trait to differentiate between Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium bovis BCG, the following study was conducted using cultures grown in an automated system. Automated culture systems, which are typically based on liquid medium, have greatly reduced the time-to-recovery of mycobacteria. Yet subsequent testing of isolates for nitrate reductase activity may take several weeks, because culture on solid media is required. Presented here is a procedure to obtain a final result within 24 h for nitrate reductase activity of cultures grown in an automated culture system. Using this procedure, Mycobacterium tuberculosis was rapidly differentiated from Mycobacterium bovis and Mycobacterium bovis BCG. PMID:12827528

  15. Identifying a Theft Suspect

    NSDL National Science Digital Library

    This page was authored by the CATALST Group at the University of Minnesota, based on an activity developed by Roxy Peck at California Polytechnic State University that is based on an original idea by Tom Short, John Carroll University, and Iddo Gal, University of Haifa, Israel.

    This model-eliciting activity (MEA) challenges students to develop a model for predicting the characteristics of a person who has committed a crime. Students work with real data on shoe length, height, and gender to develop the model. Students write a report to the crime victim that identifies a suspect and justifies their decision. The activity sets the stage for students to learn about regression models, and reinforces their understanding of central tendency and variability. It is suggested that this activity be used prior to a formal introduction to linear relationships.

  16. Plants and fungal products with activity against tuberculosis.

    PubMed

    De Souza, Marcus Vinicius Nora

    2005-08-15

    Tuberculosis (TB) is becoming an ever more serious worldwide problem. This contagious disease kills four people every minute somewhere in the world and accounts for more than 2 million deaths per year. Due to the rapid spread of TB strains resistant to all the major anti-TB drugs on the market, and the association of TB with human immunodeficiency virus (HIV) infection in AIDS, we urgently need to develop new drugs to fight against TB. In this context, due to the importance of nature in the development of new drugs, the aim of the present review is to highlight a series of new and promising anti-TB agents derived from plants and fungi discovered between 2001 and 2005. PMID:16113939

  17. 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

  18. Improved control of tuberculosis and activation of macrophages in mice lacking protein kinase R.

    PubMed

    Wu, Kangyun; Koo, Jovanka; Jiang, Xiuju; Chen, Ran; Cohen, Stanley N; Nathan, Carl

    2012-01-01

    Host factors that microbial pathogens exploit for their propagation are potential targets for therapeuic countermeasures. No host enzyme has been identified whose genetic absence benefits the intact mammalian host in vivo during infection with Mycobacterium tuberculosis (Mtb), the leading cause of death from bacterial infection. Here, we report that the dsRNA-dependent protein kinase (PKR) is such an enzyme. PKR-deficient mice contained fewer viable Mtb and showed less pulmonary pathology than wild type mice. We identified two potential mechanisms for the protective effect of PKR deficiency: increased apoptosis of macrophages in response to Mtb and enhanced activation of macrophages in response to IFN-gamma. The restraining effect of PKR on macrophage activation was explained by its mediation of a previously unrecognized ability of IFN-gamma to induce low levels of the macrophage deactivating factor interleukin 10 (IL10). These observations suggest that PKR inhibitors may prove useful as an adjunctive treatment for tuberculosis. PMID:22359543

  19. Nitric Oxide Generated from Isoniazid Activation by KatG: Source of Nitric Oxide and Activity against Mycobacterium tuberculosis

    PubMed Central

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

    2004-01-01

    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 (N?) 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 N? provided protection against the antimycobacterial activity of INH in bacterial culture. No significant increases in mycobacterial protein nitration were detected, suggesting that N? 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

  20. Mycobacterium tuberculosis Catalase and Peroxidase Activities and Resistance to Oxidative Killing in Human Monocytes In Vitro

    Microsoft Academic Search

    CLAUDIA MANCA; SIMON PAUL; CLIFTON E. BARRY; VICTORIA H. FREEDMAN; GILLA KAPLAN

    1999-01-01

    Mycobacterium tuberculosis has a relatively high resistance to killing by hydrogen peroxide and organic peroxides. Resistance may be mediated by mycobacterial catalase-peroxidase (KatG) and possibly by alkyl hydroperoxide reductase (AhpC). To determine the interrelationship between sensitivity to H2O2, catalase and peroxidase activities, and bacillary growth rates measured both intracellularly in human monocytes and in culture medium, we examined one laboratory

  1. Diterpenes Synthesized from the Natural Serrulatane Leubethanol and Their in Vitro Activities against Mycobacterium tuberculosis.

    PubMed

    Escarcena, Ricardo; Perez-Meseguer, Jonathan; Del Olmo, Esther; Alanis-Garza, Blanca; Garza-González, Elvira; Salazar-Aranda, Ricardo; Waksman de Torres, Noemí

    2015-01-01

    Seventeen new derivatives of the natural diterpene leubethanol, including some potential pro-drugs, with changes in the functionality of the aliphatic chain or modifications of aromatic ring and the phenolic group, were synthesized and tested in vitro by the MABA technique for their activity against the H37Rv strain of Mycobacterium tuberculosis. Some compounds showed antimycobacterial selectivity indices higher than leubethanol. PMID:25905603

  2. In vitro and in vivo Activities of a New Lead Compound I2906 against Mycobacterium tuberculosis

    Microsoft Academic Search

    Jingning Lu; Jun Yue; Jing Wu; Rusong Luo; Zhidong Hu; Jianrong Li; Yun Bai; Zhijiao Tang; Qiaoyang Xian; Xuelian Zhang; Honghai Wang

    2010-01-01

    Background: Due to the long duration of treatment and the emergence of multidrug-resistant strains, new antitubercular agents are urgently needed. I2906, as a novel lead, was screened and tested for efficacy in vitro and in vivo. Methods:To determine the efficacy of I2906,the minimum inhibitory concentrations against Mycobacterium tuberculosis and cytotoxicity were tested, and its in vivo activities were assessed by

  3. Strong Antibody Responses to Mycobacterium tuberculosis PE-PGRS62 Protein Are Associated with Latent and Active Tuberculosis

    Microsoft Academic Search

    Kah Wee Koh; Shu E Soh; Geok Teng Seah

    2009-01-01

    Mycobacterium tuberculosis has a unique family of PE-PGRS proteins with conserved N-terminal domains (PE) containing site-specific proline-glutamine residues and polymorphic GC-rich repetitive sequences (PGRS). Tuberculosis (TB) patients produce antibodies against some such proteins, but it is not clear whether these responses correlate with disease. Clinical groups with different mycobacterium exposure were studied for their seroreactivity to PE-PGRS17 and PE-PGRS62 proteins

  4. Bactericidal activities of commonly used antiseptics against multidrug-resistant mycobacterium tuberculosis.

    PubMed

    Rikimaru, T; Kondo, M; Kajimura, K; Hashimoto, K; Oyamada, K; Sagawa, K; Tanoue, S; Oizumi, K

    2002-01-01

    Seventeen clinical isolates of Mycobacterium tuberculosis were selected in order to study the bactericidal activities against drug-resistant M. tuberculosis. The effects of different antiseptics against multidrug-resistant M. tuberculosis (MDR-TB) were examined. Each of the test strains was cultured on the surface of an agar slant containing Löwenstein-Jensen medium. 0.05 ml of the bacillary suspension was poured into a test tube, and 0.45 ml of various antiseptics was added. After the bacilli had been exposed to the antiseptic solution with 2% human serum for various periods of incubation time, the antiseptic was inactivated by addition of 0.45 ml neutralizer, a mixture containing 10% Tween 80, 3% soybean lecithin and 0.5% sodium thiosulfate. As the results, povidone-iodine (PVP-I) at a concentration of 0.2% killed 99.9% or more of all strains tested within 30 s. All of the strains tested with PVP-I were killed almost completely within 60 s. There was no difference in bactericidal activities of PVP-I between standard strain H37Rv and MDR-TB. 99.9% or more of all strains tested were killed after exposure to 1.0% cresol for 60 s. In the case of cresol however, the exposure time of 30 s was not enough to get satisfactory effects. 2.0% glutaraldehyde needed 5 min to kill 99.99% or more of the bacilli tested, and 0.2% alkyldiaminoethylglycine hydrochloride required 60 min to do so. The results of bactericidal activities of common antiseptics against MDR-TB were similar to those against H37Rv. We conclude that the commercially available PVP-I product is a useful antiseptic against MDR-TB similar to other M. tuberculosis. PMID:12011515

  5. Structure, Activity, and Inhibition of the Carboxyltransferase ?-Subunit of Acetyl Coenzyme A Carboxylase (AccD6) from Mycobacterium tuberculosis

    PubMed Central

    Reddy, Manchi C. M.; Breda, Ardala; Bruning, John B.; Sherekar, Mukul; Valluru, Spandana; Thurman, Cory; Ehrenfeld, Hannah

    2014-01-01

    In Mycobacterium tuberculosis, the carboxylation of acetyl coenzyme A (acetyl-CoA) to produce malonyl-CoA, a building block in long-chain fatty acid biosynthesis, is catalyzed by two enzymes working sequentially: a biotin carboxylase (AccA) and a carboxyltransferase (AccD). While the exact roles of the three different biotin carboxylases (AccA1 to -3) and the six carboxyltransferases (AccD1 to -6) in M. tuberculosis are still not clear, AccD6 in complex with AccA3 can synthesize malonyl-CoA from acetyl-CoA. A series of 10 herbicides that target plant acetyl-CoA carboxylases (ACC) were tested for inhibition of AccD6 and for whole-cell activity against M. tuberculosis. From the tested herbicides, haloxyfop, an arylophenoxypropionate, showed in vitro inhibition of M. tuberculosis AccD6, with a 50% inhibitory concentration (IC50) of 21.4 ± 1 ?M. Here, we report the crystal structures of M. tuberculosis AccD6 in the apo form (3.0 ?) and in complex with haloxyfop-R (2.3 ?). The structure of M. tuberculosis AccD6 in complex with haloxyfop-R shows two molecules of the inhibitor bound on each AccD6 subunit. These results indicate the potential for developing novel therapeutics for tuberculosis based on herbicides with low human toxicity. PMID:25092705

  6. Structure, activity, and inhibition of the Carboxyltransferase ?-subunit of acetyl coenzyme A carboxylase (AccD6) from Mycobacterium tuberculosis.

    PubMed

    Reddy, Manchi C M; Breda, Ardala; Bruning, John B; Sherekar, Mukul; Valluru, Spandana; Thurman, Cory; Ehrenfeld, Hannah; Sacchettini, James C

    2014-10-01

    In Mycobacterium tuberculosis, the carboxylation of acetyl coenzyme A (acetyl-CoA) to produce malonyl-CoA, a building block in long-chain fatty acid biosynthesis, is catalyzed by two enzymes working sequentially: a biotin carboxylase (AccA) and a carboxyltransferase (AccD). While the exact roles of the three different biotin carboxylases (AccA1 to -3) and the six carboxyltransferases (AccD1 to -6) in M. tuberculosis are still not clear, AccD6 in complex with AccA3 can synthesize malonyl-CoA from acetyl-CoA. A series of 10 herbicides that target plant acetyl-CoA carboxylases (ACC) were tested for inhibition of AccD6 and for whole-cell activity against M. tuberculosis. From the tested herbicides, haloxyfop, an arylophenoxypropionate, showed in vitro inhibition of M. tuberculosis AccD6, with a 50% inhibitory concentration (IC50) of 21.4 ± 1 ?M. Here, we report the crystal structures of M. tuberculosis AccD6 in the apo form (3.0 Å) and in complex with haloxyfop-R (2.3 Å). The structure of M. tuberculosis AccD6 in complex with haloxyfop-R shows two molecules of the inhibitor bound on each AccD6 subunit. These results indicate the potential for developing novel therapeutics for tuberculosis based on herbicides with low human toxicity. PMID:25092705

  7. Bovine tuberculosis: immune responses in the peripheral blood and at the site of active disease

    PubMed Central

    Rhodes, S G; Buddle, B M; Hewinson, R G; Vordermeier, H M

    2000-01-01

    This report describes a comparison of immune responses in the peripheral blood and at the site of active disease in cattle 20 weeks after experimental infection with Mycobacterium bovis. Lymphocyte proliferation, and the production of interferon-? (IFN-?) and interleukin (IL)-2 were measured in response to tuberculin and a number of mycobacterial antigens, including ESAT-6, MPB64, MPB70, MPB83, hsp 16.1, hsp 65, hsp 70 and the 38 000 MW lipoprotein antigen. The level of transforming growth factor-? (TGF-?) was measured following stimulation of cells with tuberculin. Our results suggest little difference in the responses of peripheral blood and lymph node cells to most of the antigens used. However, tuberculin purified protein derivative (PPD) and ESAT-6 elicited stronger responses in the peripheral blood compared with lymph node cells. Investigation of the responding T-cell subpopulations in the peripheral blood showed that both CD4+ and, to a lesser extent, ?? T-cell receptor-positive (TCR+) T cells contributed to these responses. This is the first report to compare peripheral and local immune responses in bovine tuberculosis. Unlike cases of human tuberculosis where immune activity at the site of disease and anergy in the peripheral blood have been reported, our results suggest that for bovine tuberculosis immune responses occurring in the peripheral blood reflect those at the site of disease. PMID:10692036

  8. Direct inhibitors of InhA are active against Mycobacterium tuberculosis.

    PubMed

    Manjunatha, Ujjini H; S Rao, Srinivasa P; Kondreddi, Ravinder Reddy; Noble, Christian G; Camacho, Luis R; Tan, Bee H; Ng, Seow H; Ng, Pearly Shuyi; Ma, Ng L; Lakshminarayana, Suresh B; Herve, Maxime; Barnes, Susan W; 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 multidrug-resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase InhA is one of the few clinically validated targets in tuberculosis drug discovery. 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 (reduced form of nicotinamide adenine dinucleotide)-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 Mycobacterium tuberculosis infection. 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

  9. 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

  10. Activities of drug combinations against Mycobacterium tuberculosis grown in aerobic and hypoxic acidic conditions.

    PubMed

    Piccaro, Giovanni; Giannoni, Federico; Filippini, Perla; Mustazzolu, Alessandro; Fattorini, Lanfranco

    2013-03-01

    Mycobacterium tuberculosis is exposed to hypoxia and acidity within granulomatous lesions. In this study, an acidic culture model of M. tuberculosis was used to test drug activity against aerobic 5-day-old (A5) and hypoxic 5-, 12-, and 19-day-old (H5, H12, and H19, respectively) bacilli after 7, 14, and 21 days of exposure. In A cultures, CFU and pH rapidly increased, while in H cultures growth stopped and pH increased slightly. Ten drugs were tested: rifampin (R), isoniazid (I), pyrazinamide (Z), ethambutol (E), moxifloxacin (MX), amikacin (AK), metronidazole (MZ), nitazoxanide (NZ), niclosamide (NC), and PA-824 (PA). Rifampin was the most active against A5, H5, H12, and H19 bacilli. Moxifloxacin and AK efficiently killed A5 and H5 cells, I was active mostly against A5 cells, Z was most active against H12 and H19 cells, and E showed low activity. Among nitrocompounds, NZ, NC, and PA were effective against A5, H5, H12, and H19 cells, while MZ was active against H12 and H19 cells. To kill all A and H cells, A5- and H5-active agents R, MX, and AK were used in combination with MZ, NZ, NC, or PA, in comparison with R-I-Z-E, currently used for human therapy. Mycobacterial viability was determined by CFU and a sensitive test in broth (day to positivity, MGIT 960 system). As shown by lack of regrowth in MGIT, the most potent combination was R-MX-AK-PA, which killed all A5, H5, H12, and H19 cells in 14 days. These observations demonstrate the sterilizing effect of drug combinations against cells of different M. tuberculosis stages grown in aerobic and hypoxic acidic conditions. PMID:23295931

  11. Challenges of Loss to Follow-up in Tuberculosis Research

    Microsoft Academic Search

    Thomas N. Nissen; Michala V. Rose; Godfather Kimaro; Ib C. Bygbjerg; Sayoki G. Mfinanga; Pernille Ravn

    2012-01-01

    BackgroundIn studies evaluating methods for diagnosing tuberculosis (TB), follow-up to verify the presence or absence of active TB is crucial and high dropout rates may significantly affect the validity of the results. In a study assessing the diagnostic performance of the QuantiFERON®-TB Gold In-Tube test in TB suspect children in Tanzania, factors influencing patient adherence to attend follow-up examinations and

  12. SILA-421 activity in vitro against rifampicin-susceptible and rifampicin-resistant Mycobacterium tuberculosis, and in vivo in a murine tuberculosis model.

    PubMed

    de Knegt, Gerjo J; Bakker-Woudenberg, Irma A J M; van Soolingen, Dick; Aarnoutse, Rob; Boeree, Martin J; de Steenwinkel, Jurriaan E M

    2015-07-01

    Due to the emergence of multidrug-resistant and extensively drug-resistant tuberculosis (TB), there is an urgent need for new TB drugs or for compounds that improve the efficacy of currently used drugs. In this study, time-kill kinetics of SILA-421 as a single drug and in combination with isoniazid (INH), rifampicin (RIF), moxifloxacin (MXF) or amikacin (AMK) against Mycobacterium tuberculosis were assessed. Therapeutic efficacy in vivo in a mouse TB model was also studied. Further in vitro analysis was performed with a RIF-susceptible and RIF-resistant strains of M. tuberculosis. When used as a single drug, SILA-421 in vitro showed concentration-dependent and time-dependent bactericidal activity. SILA-421 also enhanced the activity of INH and RIF, resulting in synergy in the case of INH. Emergence of INH resistance following exposure to INH can be prevented by the addition SILA-421. SILA-421 had no additional value in combination with MXF or AMK. Furthermore, SILA-421 enhanced the activity of RIF towards a RIF-resistant strain and resulted in complete elimination of RIF-resistant mycobacteria. Unfortunately, in mice with TB induced by a Beijing genotype strain, addition of SILA-421 to an isoniazid-rifampicin-pyrazinamide regimen for 13 weeks did not result in enhanced therapeutic efficacy. PMID:25951996

  13. [Tuberculosis treatment].

    PubMed

    Ben Amar, J; Dhahri, B; Aouina, H; Azzabi, S; Baccar, M A; El Gharbi, L; Bouacha, H

    2015-01-01

    The aim of this article is to give practicing physicians a practical approach to the treatment of latent and active tuberculosis. Most patients follow TB standard treatment recommended by WHO that depend on category of patient. It is a combination of four essential tuberculosis drugs of the first group: isoniazid, rifampicin, pyrazinamid and ethambutol; in some cases streptomycin can replace ethambutol. This initial phase of intensive treatment is followed by a consolidation phase. Drugs should be administered in the morning on an empty stomach one hour before meals. Treatment of latent tuberculosis (TB) infection is an important component of TB control programs. Preventive treatment can reduce the risk of developing active TB. PMID:25434510

  14. Ursolic Acid Activates Intracellular Killing Effect of Macrophages During Mycobacterium tuberculosis Infection.

    PubMed

    Podder, Biswajit; Jang, Woong Sik; Nam, Kung-Woo; Lee, Byung-Eui; Song, Ho-Yeon

    2015-05-28

    Tuberculosis is one of the most threatening infectious diseases to public health all over the world, for which Mycobacterium tuberculosis (MTB) is the etiological agent of pathogenesis. Ursolic acid (UA) has immunomodulatory function and exhibits antimycobacterial activity. However, the intracellular killing effect of UA has yet to be elucidated. The aim of this study was to evaluate the intracellular killing effect of UA during mycobacterial infection. The intracellular killing activity of UA was evaluated in the macrophage cell line THP-1 by the MGIT 960 system as well as by CFU count. The production of reactive oxygen species (ROS) and the level of nitric oxide (NO) were measured using DCF-DA and Griess reagent, respectively. Phagocytosis was observed by a fluorescence-based staining method, and the colony forming units were enumerated on 7H11 agar medium following infection. In addition, MRP8 mRNA expression was measured by qRT-PCR. UA significantly decreased the number of intracellular Mycobacterium through generation of ROS and NO. In addition, it profoundly activated the phagocytosis process of THP-1 cells during MTB-infection. Furthermore, our data demonstrated that UA activated the phagocytosis process in human monocyte cells through MRP8 induction. These data suggest that UA firmly contributes to the intracellular killing effect of macrophages during mycobacterial infection. PMID:25406534

  15. Non-transpeptidase binding arylthioether ?-lactams active against Mycobacterium tuberculosis and Moraxella catarrhalis.

    PubMed

    Beck, Tim N; Lloyd, Dina; Kuskovsky, Rostislav; Minah, Jeanette; Arora, Kriti; Plotkin, Balbina J; Green, Jacalyn M; Boshoff, Helena I; Barry, Clifton; Deschamps, Jeffrey; Konaklieva, Monika I

    2015-02-01

    The prevalence of drug resistance in both clinical and community settings as a consequence of alterations of biosynthetic pathways, enzymes or cell wall architecture is a persistent threat to human health. We have designed, synthesized, and tested a novel class of non-transpeptidase, ?-lactamase resistant monocyclic ?-lactams that carry an arylthio group at C4. These thioethers exhibit inhibitory and cidal activity against serine ?-lactamase producing Mycobacterium tuberculosis wild type strain (Mtb) and multiple (n=8) ?-lactamase producing Moraxella catarrhalis clinical isolates. PMID:25549898

  16. Identification and structure-activity relationship study of carvacrol derivatives as Mycobacterium tuberculosis chorismate mutase inhibitors.

    PubMed

    Alokam, Reshma; Jeankumar, Variam Ullas; Sridevi, Jonnalagadda Padma; Matikonda, Siddharth Sai; Peddi, Santosh; Alvala, Mallika; Yogeeswari, Perumal; Sriram, Dharmarajan

    2014-08-01

    In the present study, we identified carvacrol, a major phenolic component of oregano oil as a novel small molecule inhibitor of Mycobacterium tuberculosis (MTB) chorismate mutase (CM) enzyme with IC50 of 1.06 ± 0.4 µM. Virtual screening of the BITS-Pilani in-house database using the crystal structure of the MTB CM bound transition state intermediate (PDB: 2FP2) as framework identified carvacrol as a potential lead. Further various carvacrol derivatives were evaluated in vitro for their ability to inhibit MTB CM enzyme, whole cell MTB and cytotoxicity as steps toward the derivation of structure-activity relationships (SAR) and lead optimization. PMID:24090423

  17. 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

  18. Mycobacterium tuberculosis dormancy-associated antigen of Rv2660c induces stronger immune response in latent Mycobacterium tuberculosis infection than that in active tuberculosis in a Chinese population.

    PubMed

    He, H; Yang, H; Deng, Y

    2015-06-01

    One-third of the world's human population is latently infected with Mycobacterium tuberculosis (M. tb), and adult tuberculosis (TB) is largely caused by the resuscitation of latent M. tb. Rv2660c, an M. tb dormancy-related antigen, is preferentially expressed during latent infection. Identification and characterization of Rv2660c are crucial to understanding host-pathogen interactions and to develop drug target and vaccine candidates. In this study, T-cell and antibody immune responses against recombinant Rv2660c protein were respectively investigated in latent M. tb infection (LTBI) cases, pulmonary tuberculosis (PTB) patients, and healthy individuals (HI). After stimulation with recombinant Rv2660c protein, stronger cellular responses were induced in LTBI cases compared with those in PTB patients or in HI. Meanwhile, Rv2660c stimulated higher levels of IgG, IgG1, and IgG2a antibody titers in LTBI cases compared with those in PTB patients. The results showed that Rv2660c is able to elicit prominent cellular immune responses and strong humoral immunity in a Chinese LTBI population, suggesting that Rv2660c is a potential target to develop new vaccines and drugs to control LTBI. PMID:25652607

  19. 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

  20. Synthesis, anti-tuberculosis activity, and 3D-QSAR study of 4-(adamantan-1-yl)-2-substituted quinolines

    Microsoft Academic Search

    Amit Nayyar; Vikramdeep Monga; Alpeshkumar Malde; Evans Coutinho; Rahul Jain

    2007-01-01

    Structural optimization of the previously identified 4-(adamantan-1-yl)-2-quinolinecarbohydrazide (AQCH, MIC=6.25?g\\/mL, 99% inhibition, Mycobacterium tuberculosis H37Rv) has led to two series of 4-(adamantan-1-yl)-2-substituted quinolines (Series 1–2). All new derivatives were evaluated in vitro for antimycobacterial activities against drug-sensitive M. tuberculosis H37Rv strain. Several 4-adamantan-1-yl-quinoline-2-carboxylic acid N?-alkylhydrazides (Series 1) described herein showed promising inhibitory activity. In particular, analogs 7, 9, 20, and 21

  1. Monocyte signal transduction receptors in active and latent tuberculosis.

    PubMed

    Druszczynska, Magdalena; Wlodarczyk, Marcin; Janiszewska-Drobinska, Beata; Kielnierowski, Grzegorz; Zawadzka, Joanna; Kowalewicz-Kulbat, Magdalena; Fol, Marek; Szpakowski, Piotr; Rudnicka, Karolina; Chmiela, Magdalena; Rudnicka, Wieslawa

    2013-01-01

    The mechanisms that promote either resistance or susceptibility to TB disease remain insufficiently understood. Our aim was to compare the expression of cell signaling transduction receptors, CD14, TLR2, CD206, and ?2 integrin LFA-1 on monocytes from patients with active TB or nonmycobacterial lung disease and healthy individuals with M.tb latency and uninfected controls to explain the background of the differences between clinical and subclinical forms of M.tb infection. A simultaneous increase in the expression of the membrane bound mCD14 receptor and LFA-1 integrin in patients with active TB may be considered a prodrome of breaking immune control by M.tb bacilli in subjects with the latent TB and absence of clinical symptoms. PMID:23401703

  2. Diagnosing active inflammation in the SAPHO syndrome using 18 FDG-PET\\/CT in suspected metastatic vertebral bone tumors

    Microsoft Academic Search

    Kentaro Inoue; Tatsuo Yamaguchi; Hiroshi Ozawa; Ken Okada; Yasuyuki Taki; Ryoi Goto; Shigeo Kinomura; Tomohiro Kaneta; Hiroshi Fukuda

    2007-01-01

    The vertebral spine is frequently affected by the SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome.\\u000a We report the collective imaging findings of hybrid F-18 fluorodeoxyglucose-positron emission tomography\\/computed tomography\\u000a (18FDG-PET\\/CT), as well as bone scans and magnetic resonance imaging, in a patient who had suspected metastatic vertebral bone\\u000a tumors. 18FDG-PET\\/CT can be utilized to exclude metastatic vertebral tumors, as well

  3. 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-?) release in active TB patients. Herein, we explored whether the MTB antigen-stimulated TNF-? release would be useful for monitoring responses to anti-TB treatment. Methods We compared unstimulated (TNF-?Nil), MTB antigen-stimulated (TNF-?Ag), and MTB antigen-stimulated minus unstimulated TNF-? levels (TNF-?Ag-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-?Ag and TNF-?Ag-Nil levels decreased significantly after treatment in patients with active TB. In addition, TNF-?Nil, TNF-?Ag, and TNF-?Ag-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-? response may be a potential adjunctive marker for monitoring treatment response in active TB patients.

  4. 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.

  5. Isoniazid’s Bactericidal Activity Ceases because of the Emergence of Resistance, Not Depletion of Mycobacterium tuberculosis in the Log Phase of Growth

    Microsoft Academic Search

    Tawanda Gumbo; Arnold Louie; Weiguo Liu; David Brown

    2007-01-01

    Background. It is believed that the cessation of isoniazid's early bactericidal activity during the initial phase of antituberculosis therapy is due to the depletion of Mycobacterium tuberculosis in the exponential phase of growth. We examined the veracity of this cornerstone belief. Methods. We used an in vitro infection model in which M. tuberculosis was exposed to isoniazid concentration- time profiles

  6. Pulmonary Tuberculoma and Miliary Tuberculosis in Silicosis

    PubMed Central

    Verma, Sanjeev Kumar; Karmakar, Saurabh

    2013-01-01

    Tuberculosis is a disease with protean manifestations. We present a case which was initially suspected as bronchogenic carcinoma with lymphangitic carcinomatosis, based on radiological appearance but later diagnosed as pulmonary tuberculoma with military tuberculosis and silicosis after thoracotomy and open lung biopsy. The patient was treated successfully with Antituberculosis Therapy (ATT). Rarity of presentation in form of pulmonary tuberculoma co-existing with histological features of miliary tuberculosis and silicosis, led us to report this case. PMID:23543249

  7. Detection of mRNA Transcripts and Active Transcription in Persistent Mycobacterium tuberculosis Induced by Exposure to Rifampin or Pyrazinamide

    Microsoft Academic Search

    YANMIN HU; JOSEPH A. MANGAN; JASVIR DHILLON; KATH M. SOLE; DENIS A. MITCHISON; PHILIP D. BUTCHER; ANTHONY R. M. COATES

    2000-01-01

    Mycobacterium tuberculosis can persist in an altered physiological state for many years after initial infection, and it may reactivate to cause active disease. An analogous persistent state, possibly consisting of several different subpopulations of bacteria, may arise during chemotherapy; this state is thought to be responsible for the prolonged period required for effective chemotherapy. Using two models of drug-induced persistence,

  8. ATP-dependent motor activity of the transcription termination factor Rho from Mycobacterium tuberculosis.

    PubMed

    D'Heygère, François; Schwartz, Annie; Coste, Franck; Castaing, Bertrand; Boudvillain, Marc

    2015-07-13

    The bacterial transcription termination factor Rho-a ring-shaped molecular motor displaying directional, ATP-dependent RNA helicase/translocase activity-is an interesting therapeutic target. Recently, Rho from Mycobacterium tuberculosis (MtbRho) has been proposed to operate by a mechanism uncoupled from molecular motor action, suggesting that the manner used by Rho to dissociate transcriptional complexes is not conserved throughout the bacterial kingdom. Here, however, we demonstrate that MtbRho is a bona fide molecular motor and directional helicase which requires a catalytic site competent for ATP hydrolysis to disrupt RNA duplexes or transcription elongation complexes. Moreover, we show that idiosyncratic features of the MtbRho enzyme are conferred by a large, hydrophilic insertion in its N-terminal 'RNA binding' domain and by a non-canonical R-loop residue in its C-terminal 'motor' domain. We also show that the 'motor' domain of MtbRho has a low apparent affinity for the Rho inhibitor bicyclomycin, thereby contributing to explain why M. tuberculosis is resistant to this drug. Overall, our findings support that, in spite of adjustments of the Rho motor to specific traits of its hosting bacterium, the basic principles of Rho action are conserved across species and could thus constitute pertinent screening criteria in high-throughput searches of new Rho inhibitors. PMID:25999346

  9. Bactericidal Activity and Mechanism of Action of AZD5847, a Novel Oxazolidinone for Treatment of Tuberculosis

    PubMed Central

    Balasubramanian, V.; Solapure, S.; Iyer, H.; Ghosh, A.; Sharma, S.; Kaur, P.; Deepthi, R.; Subbulakshmi, V.; Ramya, V.; Ramachandran, V.; Balganesh, M.; Wright, L.; Melnick, D.; Butler, S. L.

    2014-01-01

    Treatment of tuberculosis (TB) is impaired by the long duration and complexity of therapy and the rising incidence of drug resistance. There is an urgent need for new agents with improved efficacy, safety, and compatibility with combination chemotherapies. Oxazolidinones offer a potential new class of TB drugs, and linezolid—the only currently approved oxazolidinone—has proven highly effective against extensively drug-resistant (XDR) TB in experimental trials. However, widespread use of linezolid is prohibited by its significant toxicities. AZD5847, a novel oxazolidinone, demonstrates improved in vitro bactericidal activity against both extracellular and intracellular M. tuberculosis compared to that of linezolid. Killing kinetics in broth media and in macrophages indicate that the rate and extent of kill obtained with AZD5847 are superior to those obtained with linezolid. Moreover, the efficacy of AZD5847 was additive when tested along with a variety of conventional TB agents, indicating that AZD5847 may function well in combination therapies. AZD5847 appears to function similarly to linezolid through impairment of the mycobacterial 50S ribosomal subunit. Future studies should be undertaken to further characterize the pharmacodynamics and pharmacokinetics of AZD5847 in both in vitro and animal models as well is in human clinical trials. PMID:24189255

  10. 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-?-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

  11. Chlorinated Coumarins from the Polypore Mushroom, Fomitopsis officinalis, and their Activity Against Mycobacterium tuberculosis

    PubMed Central

    Hwang, Chang Hwa; Jaki, Birgit U.; Klein, Larry L.; Lankin, David C.; McAlpine, James B.; Napolitano, José G.; Fryling, Nicole A.; Franzblau, Scott G.; Cho, Sang Hyun; Stamets, Paul E.; Wang, Yuehong; Pauli, Guido F.

    2013-01-01

    An EtOH extract of the polypore mushroom, Fomitopsis officinalis afforded two new naturally occurring chlorinated coumarins which were identified as the previously synthesized compounds, 6-chloro-4-phenyl-2H-chromen-2-one (1) and ethyl 6-chloro-2-oxo-4-phenyl-2H-chromen-3-carboxylate (2). The structures of the two isolates were deduced ab initio by spectroscopic methods and confirmed by chemical synthesis. In addition, an analogue of each was synthesized as of 7-chloro-4-phenyl-2H-chromen-2-one (3) and ethyl 7-chloro-2-oxo-4-phenyl-2H-chromen-3-carboxylate (4). All four compounds were characterized physicochemically, and their antimicrobial activity profiles revealed a narrow spectrum of activity with lowest MICs against the Mycobacterium tuberculosis complex. PMID:24087924

  12. Mining large-scale response networks reveals ‘topmost activities’ in Mycobacterium tuberculosis infection

    PubMed Central

    Sambarey, Awanti; Prashanthi, Karyala; Chandra, Nagasuma

    2013-01-01

    Mycobacterium tuberculosis owes its high pathogenic potential to its ability to evade host immune responses and thrive inside the macrophage. The outcome of infection is largely determined by the cellular response comprising a multitude of molecular events. The complexity and inter-relatedness in the processes makes it essential to adopt systems approaches to study them. In this work, we construct a comprehensive network of infection-related processes in a human macrophage comprising 1888 proteins and 14,016 interactions. We then compute response networks based on available gene expression profiles corresponding to states of health, disease and drug treatment. We use a novel formulation for mining response networks that has led to identifying highest activities in the cell. Highest activity paths provide mechanistic insights into pathogenesis and response to treatment. The approach used here serves as a generic framework for mining dynamic changes in genome-scale protein interaction networks. PMID:23892477

  13. Genome-Wide Expression Profiling Identifies Type 1 Interferon Response Pathways in Active Tuberculosis

    PubMed Central

    Ottenhoff, Tom H. M.; Zhang, Mingzi M.; Wong, Hazel E. E.; Sahiratmadja, Edhyana; Khor, Chiea Chuen; Alisjahbana, Bachti; van Crevel, Reinout; Marzuki, Sangkot; Seielstad, Mark; van de Vosse, Esther; Hibberd, Martin L.

    2012-01-01

    Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains the leading cause of mortality from a single infectious agent. Each year around 9 million individuals newly develop active TB disease, and over 2 billion individuals are latently infected with M.tb worldwide, thus being at risk of developing TB reactivation disease later in life. The underlying mechanisms and pathways of protection against TB in humans, as well as the dynamics of the host response to M.tb infection, are incompletely understood. We carried out whole-genome expression profiling on a cohort of TB patients longitudinally sampled along 3 time-points: during active infection, during treatment, and after completion of curative treatment. We identified molecular signatures involving the upregulation of type-1 interferon (?/?) mediated signaling and chronic inflammation during active TB disease in an Indonesian population, in line with results from two recent studies in ethnically and epidemiologically different populations in Europe and South Africa. Expression profiles were captured in neutrophil-depleted blood samples, indicating a major contribution of lymphocytes and myeloid cells. Expression of type-1 interferon (?/?) genes mediated was also upregulated in the lungs of M.tb infected mice and in infected human macrophages. In patients, the regulated gene expression-signature normalized during treatment, including the type-1 interferon mediated signaling and a concurrent opposite regulation of interferon-gamma. Further analysis revealed IL15RA, UBE2L6 and GBP4 as molecules involved in the type-I interferon response in all three experimental models. Our data is highly suggestive that the innate immune type-I interferon signaling cascade could be used as a quantitative tool for monitoring active TB disease, and provide evidence that components of the patient’s blood gene expression signature bear similarities to the pulmonary and macrophage response to mycobacterial infection. PMID:23029268

  14. 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

  15. Expanding the epidemiologic profile: risk factors for active tuberculosis in people immigrating to Ontario

    Microsoft Academic Search

    Wendy L. Wobeser; Lilian Yuan; Monika Naus; Paul Corey; Jeff Edelson; Neil Heywood; D. Linn Holness

    Background: Many people immigrating to Canada come from countries with a high burden of tuberculosis. The aim of this study was to develop a detailed epi- demiologic profile of foreign-born people with tuberculosis living in Ontario. Methods: In this population-based case-control study, cases of tuberculosis diag- nosed in 1994-1995 were identified from the database of the Ontario Re- portable Disease

  16. 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

  17. New Classes of Alanine Racemase Inhibitors Identified by High-Throughput Screening Show Antimicrobial Activity against Mycobacterium tuberculosis

    PubMed Central

    Anthony, Karen G.; Strych, Ulrich; Yeung, Kacheong R.; Shoen, Carolyn S.; Perez, Oriana; Krause, Kurt L.; Cynamon, Michael H.; Aristoff, Paul A.; Koski, Raymond A.

    2011-01-01

    Background In an effort to discover new drugs to treat tuberculosis (TB) we chose alanine racemase as the target of our drug discovery efforts. In Mycobacterium tuberculosis, the causative agent of TB, alanine racemase plays an essential role in cell wall synthesis as it racemizes L-alanine into D-alanine, a key building block in the biosynthesis of peptidoglycan. Good antimicrobial effects have been achieved by inhibition of this enzyme with suicide substrates, but the clinical utility of this class of inhibitors is limited due to their lack of target specificity and toxicity. Therefore, inhibitors that are not substrate analogs and that act through different mechanisms of enzyme inhibition are necessary for therapeutic development for this drug target. Methodology/Principal Findings To obtain non-substrate alanine racemase inhibitors, we developed a high-throughput screening platform and screened 53,000 small molecule compounds for enzyme-specific inhibitors. We examined the ‘hits’ for structural novelty, antimicrobial activity against M. tuberculosis, general cellular cytotoxicity, and mechanism of enzyme inhibition. We identified seventeen novel non-substrate alanine racemase inhibitors that are structurally different than any currently known enzyme inhibitors. Seven of these are active against M. tuberculosis and minimally cytotoxic against mammalian cells. Conclusions/Significance This study highlights the feasibility of obtaining novel alanine racemase inhibitor lead compounds by high-throughput screening for development of new anti-TB agents. PMID:21637807

  18. 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-?) 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-? 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-?), IFN-?, monokine induced by IFN-? (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-?, IFN-?, 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

  19. IQG-607 abrogates the synthesis of mycolic acids and displays intracellular activity against Mycobacterium tuberculosis in infected macrophages.

    PubMed

    Rodrigues-Junior, Valnês S; dos Santos Junior, André A; Villela, Anne D; Belardinelli, Juan M; Morbidoni, Héctor R; Basso, Luiz A; Campos, Maria M; Santos, Diógenes S

    2014-01-01

    In this work, the antitubercular activity of a pentacyano(isoniazid)ferrate(II) compound (IQG-607) was investigated using a macrophage model of Mycobacterium tuberculosis infection. Importantly, treatment of M.-tuberculosis-infected macrophages with IQG-607 significantly diminished the number of CFU compared with the untreated control group. The antitubercular activity of IQG-607 was similar to that observed for the positive control drugs isoniazid and rifampicin. Nevertheless, higher concentrations of IQG-607 produced a significantly greater reduction in bacterial load compared with the same concentrations of isoniazid. Analysis of the mechanism of action of IQG-607 revealed that the biosynthesis of mycolic acids was blocked. The promising activity of IQG-607 in infected macrophages and the experimental determination of its mechanism of action may help in further studies aimed at the development of a new antimycobacterial agent. PMID:24139881

  20. 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

  1. Contribution of efflux activity to isoniazid resistance in the Mycobacterium tuberculosis complex

    Microsoft Academic Search

    Liliana Rodrigues; Diana Machado; Isabel Couto; Leonard Amaral; Miguel Viveiros

    2012-01-01

    Resistance to isoniazid (INH), one of the main drugs used in tuberculosis (TB) therapy, is mostly due to chromosomal mutations in target genes. However, approximately 20-30% of INH resistant Mycobacterium tuberculosis isolates do not have mutations in any of the genes associated with INH resistance. This sug- gests that other mechanism(s) may be involved, namely efflux pump systems capable of

  2. Synergistic effect of muramyl dipeptide with heat shock protein 70 from Mycobacterium tuberculosis on immune activation.

    PubMed

    Kim, Tae-Hyoun; Park, Jong-Hwan; Park, Yeong-Min; Ryu, Seung-Wook; Shin, Sung Jae; Park, Jae-Hak; Kim, Dong-Jae

    2015-01-01

    Heat shock protein 70 from Mycobacterium tuberculosis (Mtb Hsp70) has been known to modulate immune response including dendritic cell activation. Muramyl dipeptide (MDP) is an immunoreactive derivative of peptidoglycan from all Gram-negative and Gram-positive bacteria and recognized to be responsible for function of Freund's complete adjuvant. In this study, we evaluated effect of MDP on in vitro activation of bone marrow derived dendritic cells (BMDCs) and in vivo production of cytokines and chemokines induced by Mtb Hsp70. MDP treatment with Mtb Hsp70 dramatically increased production of IL-6, IL-12p40 and TNF-? in BMDCs compared with Mtb Hsp70 alone whereas these effects were abolished in Nod2-deficient BMDCs. Phosphorylation of I?B-? and ERK and impairment of phagocytosis, which is an indicator of DC maturation were enhanced by MDP co-treatment with Mtb hsp70 in BMDCs. In addition, ability of Mtb Hsp70-stimulated BMDCs to induce IFN-? productions of T cells was increased by MDP co-treatment. Finally, intraperitoneal injection of MDP with Mtb Hsp70 dramatically increased production of IL-6, CXCL-1 and CCL2 in serum compared with Mtb hsp70 injection. Our study showed the synergistic effects of MDP with Mtb Hsp70 on DCs and in vivo immune activation. The use of MDP with Mtb Hsp70 to induce immune activation may provide an effective strategy for vaccination to treat cancer and protect against pathogens. PMID:25446399

  3. Evaluation of the detection of Mycobacterium tuberculosis with metabolic activity in culture-negative human clinical samples.

    PubMed

    Cubero, N; Esteban, J; Palenque, E; Rosell, A; Garcia, M J

    2013-03-01

    Mycobacterium tuberculosis is assumed to remain in a quiescent state during latent infection, being unable to grow in culture. The aim of this study was to evaluate the detection of viable but non-cultivable bacilli with metabolic activity in human clinical samples using a procedure that is independent of the immunological status of the patient. The study was performed on 66 human clinical samples, from patients subjected to routine diagnosis to rule out a mycobacterial infection. Specimens from pulmonary and extra-pulmonary origins were verified to contain human DNA before testing for M. tuberculosis DNA, rRNA and transient RNA by real-time quantitative PCR. Clinical records of 55 patients were also reviewed. We were able to detect viable but non-cultivable bacilli with a metabolic activity in both pulmonary and extra-pulmonary samples. Mycobacterium tuberculosis RNA was detected in the majority of culture-positive samples whereas it was detected in one-third of culture-negative samples, 20% of them showed metabolic activity. Amplifications of the ftsZ gene and particularly of the main promoter of the ribosomal operon rrnA, namely PCL1, seem to be good targets to detect active bacilli putatively involved in latent infection. Moreover, this last target would provide information on the basal metabolic activity of the bacilli detected. PMID:22360423

  4. Immune Thrombocytopenia in Tuberculosis: Causal or Coincidental?

    PubMed Central

    Srividya, Gopalakrishnan; Nikhila, Gopalakrishna Pillai Syamala; Kaushik, Adusumilli Venkatakrishna; Jayachandran, Kuppusamy

    2014-01-01

    Immune thrombocytopenia is a relatively rare hematological manifestation in tuberculosis. We report two cases of immune thrombocytopemia, one in sputum positive pulmonary tuberculosis and the other in miliary tuberculosis. Antituberculous drugs and immunosuppressive therapy corrected the thrombocytopenia in both patients. Our case reports stress that tuberculosis should be considered during the evaluation of immune thrombocytopenia, and also highlights the safety of immunosuppressive therapy during active tuberculosis along with antituberculous drugs. PMID:25191056

  5. Biochemical Characterization of Quinolinic Acid Phosphoribosyltransferase from Mycobacterium tuberculosis H37Rv and Inhibition of Its Activity by Pyrazinamide

    PubMed Central

    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

  6. Identification of a small molecule with activity against drug-resistant and persistent tuberculosis.

    PubMed

    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; Johnson, Kai; Mikusova, Katarina; Besra, Gurdyal S; Fütterer, Klaus; Robbins, Scott H; Barnes, S Whitney; Walker, John R; Jacobs, William R; Schultz, Peter G

    2013-07-01

    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-?-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

  7. Selective targeting of the conserved active site cysteine of Mycobacterium tuberculosis methionine aminopeptidase with electrophilic reagents.

    PubMed

    Reddi, Ravikumar; Arya, Tarun; Kishor, Chandan; Gumpena, Rajesh; Ganji, Roopa J; Bhukya, Supriya; Addlagatta, Anthony

    2014-09-01

    Methionine aminopeptidases (MetAPs) cleave initiator methionine from ~ 70% of the newly synthesized proteins in every living cell, and specific inhibition or knockdown of this function is detrimental. MetAPs are metalloenzymes, and are broadly classified into two subtypes, type I and type II. Bacteria contain only type I MetAPs, and the active site of these enzymes contains a conserved cysteine. By contrast, in type II enzymes the analogous position is occupied by a conserved glycine. Here, we report the reactivity of the active site cysteine in a type I MetAP, MetAP1c, of Mycobacterium tuberculosis (MtMetAP1c) towards highly selective cysteine-specific reagents. The authenticity of selective modification of Cys105 of MtMetAP1c was established by using site-directed mutagenesis and crystal structure determination of covalent and noncovalent complexes. On the basis of these observations, we propose that metal ions in the active site assist in the covalent modification of Cys105 by orienting the reagents appropriately for a successful reaction. These studies establish, for the first time, that the conserved cysteine of type I MetAPs can be targeted for selective inhibition, and we believe that this chemistry can be exploited for further drug discovery efforts regarding microbial MetAPs. PMID:24841365

  8. Reverse Translation in Tuberculosis: Neutrophils Provide Clues for Understanding Development of Active Disease

    PubMed Central

    Dorhoi, Anca; Iannaccone, Marco; Maertzdorf, Jeroen; Nouailles, Geraldine; Weiner, January; Kaufmann, Stefan H. E.

    2014-01-01

    Tuberculosis (TB) is a major health issue globally. Although typically the disease can be cured by chemotherapy in all age groups, and prevented in part in newborn by vaccination, general consensus exists that development of novel intervention measures requires better understanding of disease mechanisms. Human TB is characterized by polarity between host resistance as seen in 2 billion individuals with latent TB infection and susceptibility occurring in 9 million individuals who develop active TB disease every year. Experimental animal models often do not reflect this polarity adequately, calling for a reverse translational approach. Gene expression profiling has allowed identification of biomarkers that discriminate between latent infection and active disease. Functional analysis of most relevant markers in experimental animal models can help to better understand mechanisms driving disease progression. We have embarked on in-depth characterization of candidate markers of pathology and protection hereby harnessing mouse mutants with defined gene deficiencies. Analysis of mutants deficient in miR-223 expression and CXCL5 production allowed elucidation of relevant pathogenic mechanisms. Intriguingly, these deficiencies were linked to aberrant neutrophil activities. Our findings point to a detrimental potential of neutrophils in TB. Reciprocally, measures that control neutrophils should be leveraged for amelioration of TB in adjunct to chemotherapy. PMID:24550920

  9. Granulocytic myeloid derived suppressor cells expansion during active pulmonary tuberculosis is associated with high nitric oxide plasma level.

    PubMed

    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

  10. 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

  11. 9 CFR 77.17 - Interstate movement of cattle and bison that are exposed, reactors, or suspects, or from herds...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... false Interstate movement of cattle and bison that are exposed, reactors, or suspects...ANIMAL PRODUCTS TUBERCULOSIS Cattle and Bison § 77.17 Interstate movement of cattle and bison that are exposed, reactors, or...

  12. 9 CFR 77.17 - Interstate movement of cattle and bison that are exposed, reactors, or suspects, or from herds...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... false Interstate movement of cattle and bison that are exposed, reactors, or suspects...ANIMAL PRODUCTS TUBERCULOSIS Cattle and Bison § 77.17 Interstate movement of cattle and bison that are exposed, reactors, or...

  13. 9 CFR 77.17 - Interstate movement of cattle and bison that are exposed, reactors, or suspects, or from herds...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... false Interstate movement of cattle and bison that are exposed, reactors, or suspects...ANIMAL PRODUCTS TUBERCULOSIS Cattle and Bison § 77.17 Interstate movement of cattle and bison that are exposed, reactors, or...

  14. 9 CFR 77.17 - Interstate movement of cattle and bison that are exposed, reactors, or suspects, or from herds...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... false Interstate movement of cattle and bison that are exposed, reactors, or suspects...ANIMAL PRODUCTS TUBERCULOSIS Cattle and Bison § 77.17 Interstate movement of cattle and bison that are exposed, reactors, or...

  15. Low-Income Parents' Warmth and Parent-Child Activities for Children with Disabilities, Suspected Delays and Biological Risks

    ERIC Educational Resources Information Center

    Eshbaugh, Elaine M.; Peterson, Carla A.; Wall, Shavaun; Carta, Judith J.; Luze, Gayle; Swanson, Mark; Jeon, Hyun-Joo

    2011-01-01

    Warm and responsive parenting is optimal for child development, but this style of parenting may be difficult for some parents to achieve. This study examines how parents' observed warmth and their reported frequency of parent-child activities were related to children's classifications as having biological risks or a range of disability indicators.…

  16. Anti-HIV natural product (+)-calanolide A is active against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis

    Microsoft Academic Search

    Ze-Qi Xu; William W Barrow; William J Suling; Louise Westbrook; Esther Barrow; Yuh-Meei Lin; Michael T Flavin

    2004-01-01

    Naturally occurring anti-HIV-1 agent (+)-calanolide A was found to be active against all of the strains of Mycobacterium tuberculosis tested, including those resistant to the standard antitubercular drugs. Efficacy evaluations in macrophages revealed that (+)-calanolide A significantly inhibited intracellular replication of M. tuberculosis H37Rv at concentrations below the MIC observed in vitro. Preliminary mechanistic studies indicated that (+)-calanolide A rapidly

  17. The Effects of HIV on the Sensitivity of a Whole Blood IFN-gamma Release Assay in Zambian Adults with Active Tuberculosis

    Microsoft Academic Search

    Edward Raby; Maureen Moyo; Akash Devendra; Joseph Banda; Petra de Haas; Helen Ayles; Peter Godfrey-Faussett; Madhukar Pai

    2008-01-01

    BackgroundInterferon gamma release assays (IGRA) are replacing the tuberculin skin test (TST) as a diagnostic tool for Mycobacterium tuberculosis infection. However research into the test's performance in the high HIV-TB burden setting is scarce. This study aimed to define the sensitivity of an IGRA, QuantiFERON-TB® Gold In-Tube (QGIT), in adult Zambian patients with active smear-positive tuberculosis. Secondary outcomes focussed on

  18. Analysis of microRNA expression profiling identifies miR155 and miR155* as potential diagnostic markers for active tuberculosis: a preliminary study

    Microsoft Academic Search

    Jing Wu; Chanyi Lu; Ni Diao; Shu Zhang; Sen Wang; Feifei Wang; Yan Gao; Jiazhen Chen; Lingyun Shao; Jingning Lu; Xuelian Zhang; Xinhua Weng; Honghai Wang; Wenhong Zhang; Yuxian Huang

    To explore biologic behaviors and disease relevance of microRNAs (miRNAs) in the development of active tuberculosis (ATB), we investigated the expression profile of Mycobacterium tuberculosis (MTB) purified protein derivative (PPD)–induced miRNAs to determine the specific miRNAs involved in the pathogenesis of ATB. The expression profile of miRNA under PPD challenge was first measured using microarray analysis in peripheral blood mononuclear

  19. Fumarate Reductase Activity Maintains an Energized Membrane in Anaerobic Mycobacterium tuberculosis

    Microsoft Academic Search

    Shinya Watanabe; Michael Zimmermann; Michael B. Goodwin; Uwe Sauer; Clifton E. Barry; Helena I. Boshoff

    2011-01-01

    Oxygen depletion of Mycobacterium tuberculosis engages the DosR regulon that coordinates an overall down-regulation of metabolism while up-regulating specific genes involved in respiration and central metabolism. We have developed a chemostat model of M. tuberculosis where growth rate was a function of dissolved oxygen concentration to analyze metabolic adaptation to hypoxia. A drop in dissolved oxygen concentration from 50 mmHg

  20. Increased specific T cell cytokine responses in patients with active pulmonary tuberculosis from Central Africa

    Microsoft Academic Search

    Stefan Winkler; Magdalena Necek; Heidi Winkler; Ayola A. Adegnika; Thomas Perkmann; Michael Ramharter; Peter G. Kremsner

    2005-01-01

    An understanding of T cell responses that are crucial for control of Mycobacterium tuberculosis (MTB) has major implications for the development of immune-based interventions. We studied the frequency of purified protein derivative (PPD)-specific CD3+ cells expressing interleukin-2 (IL)-2, gamma interferon (IFN)-?, tumor necrosis factor (TNF)-? and IL-10 in HIV-negative pulmonary tuberculosis patients (TB, n=30) as well as in healthy individuals

  1. Limited Activity of Clofazimine as a Single Drug in a Mouse Model of Tuberculosis Exhibiting Caseous Necrotic Granulomas

    PubMed Central

    Irwin, Scott M.; Gruppo, Veronica; Brooks, Elizabeth; Gilliland, Janet; Scherman, Michael; Reichlen, Matthew J.; Leistikow, Rachel; Kramnik, Igor; Nuermberger, Eric L.; Voskuil, Martin I.

    2014-01-01

    New drugs and drugs with a novel mechanism of action are desperately needed to shorten the duration of tuberculosis treatment, to prevent the emergence of drug resistance, and to treat multiple-drug-resistant strains of Mycobacterium tuberculosis. Recently, there has been renewed interest in clofazimine (CFZ). In this study, we utilized the C3HeB/FeJ mouse model, possessing highly organized, hypoxic pulmonary granulomas with caseous necrosis, to evaluate CFZ monotherapy in comparison to results with BALB/c mice, which form only multifocal, coalescing cellular aggregates devoid of caseous necrosis. While CFZ treatment was highly effective in BALB/c mice, its activity was attenuated in the lungs of C3HeB/FeJ mice. This lack of efficacy was directly related to the pathological progression of disease in these mice, since administration of CFZ prior to the formation of hypoxic, necrotic granulomas reconstituted bactericidal activity in this mouse strain. These results support the continued use of mouse models of tuberculosis infection which exhibit a granulomatous response in the lungs that more closely resembles the pathology found in human disease. PMID:24798275

  2. Unique transcriptome signature of Mycobacterium tuberculosis in pulmonary tuberculosis.

    PubMed

    Rachman, Helmy; Strong, Michael; Ulrichs, Timo; Grode, Leander; Schuchhardt, Johannes; Mollenkopf, Hans; Kosmiadi, George A; Eisenberg, David; Kaufmann, Stefan H E

    2006-02-01

    Although tuberculosis remains a substantial global threat, the mechanisms that enable mycobacterial persistence and replication within the human host are ill defined. This study represents the first genome-wide expression analysis of Mycobacterium tuberculosis from clinical lung samples, which has enabled the identification of M. tuberculosis genes actively expressed during pulmonary tuberculosis. To obtain optimal information from our DNA array analyses, we analyzed the differentially expressed genes within the context of computationally inferred protein networks. Protein networks were constructed using functional linkages established by the Rosetta stone, phylogenetic profile, conserved gene neighbor, and operon computational methods. This combined approach revealed that during pulmonary tuberculosis, M. tuberculosis actively transcribes a number of genes involved in active fortification and evasion from host defense systems. These genes may provide targets for novel intervention strategies. PMID:16428773

  3. 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...

  4. Active phagocytosis of Mycobacterium tuberculosis (H37Ra) by T lymphocytes (Jurkat cells).

    PubMed

    Zhang, Min; Zhu, Qi; Shi, Ming; Liu, Yang; Ma, Lei; Yang, Yining; Feng, Dongyun; Dai, Wen; Zhang, Lin; Kang, Tao; Chen, Ping; He, Ying; Liu, Tingting; Zhao, Qing; Wang, Wenjing; Zhi, Jin; Feng, Guodong; Zhao, Gang

    2015-08-01

    This study aimed to co-culture Jurkat T lymphocytes with inactivated Mycobacterium tuberculosis (Mtb H37Ra), explore whether T lymphocytes could phagocytose H37Ra cells, and determine the underlying mechanism. Jurkat T lymphocytes were co-cultured with H37Ra cells, and confocal laser scanning microscopy, electron microscopy, and flow cytometry techniques were used to identify phagocytosis and elucidate its mechanism. After Jurkat T lymphocytes phagocytosed H37Ra cells, the cell body became larger, with abundant cytoplasm, the portion of the nucleus closest to the bacterium deformed, long and short pseudopodia were extended, and the folds of the cell membrane formed depressions that created phagocytic vesicles surrounding the bacterium. The macropinocytosis inhibitor amiloride and the cytoskeletal inhibitor cytochalasin D were found to inhibit phagocytic efficacy; serum complements might enhance phagocytosis through opsonization. Jurkat T lymphocytes could actively phagocytose inactivated Mtb via the macropinocytotic mechanism. Actin remodeling played an important role in the macropinocytotic process. Serum complements may regulate phagocytosis. PMID:26005110

  5. Primary hypoadrenalism assessed by the 1 microg ACTH test in hospitalized patients with active pulmonary tuberculosis.

    PubMed

    Kaplan, F J; Levitt, N S; Soule, S G

    2000-09-01

    Primary hypoadrenalism, assessed by 250 microg ACTH stimulation, is uncommon in patients with active pulmonary tuberculosis (PTB). Since 1 microg ACTH produces an equivalent +30 min cortisol response to 250 microg in control subjects, the 250 microg dose is supraphysiological and may lack sensitivity for the diagnosis of hypoadrenalism. Furthermore, the impact of coexistent HIV infection on the prevalence of primary hypoadrenalism in PTB is uncertain. We thus determined the cortisol response to an intravenous bolus of 1 microg ACTH in 21 controls, 18 HIV-positive (BMI 19.5+/-0.9 kg/m(2), albumin 24+/-1.4 g/l, CD4 count 192+/-47/mm(3)) and 22 HIV-negative (BMI 19.3+/-0.8 kg/m(2), albumin 29+/-1 g/l, CD4 count 652+/-76/mm(3)) patients with active PTB. The mean basal cortisol was greater in patients than in controls (559 vs. 373 nmol/l, p=0. 0009). The mean cortisol after 1 microg ACTH stimulation did not, however, differ significantly when comparing either patients and controls or patients who were HIV-positive and -negative (p>0.05). Using the minimum +30 min cortisol derived from the 21 controls as a marker of normal adrenal function (414 nmol/l), a single patient was classified as hypoadrenal. In conclusion, primary hypoadrenalism, as assessed by the 1 microg ACTH test, is uncommon in a cohort of ill, hospitalized patients with active PTB, irrespective of HIV status. PMID:10984555

  6. Oral Vaccination with Heat Inactivated Mycobacterium bovis Activates the Complement System to Protect against Tuberculosis

    PubMed Central

    Garrido, Joseba M.; Aranaz, Alicia; Sevilla, Iker; Villar, Margarita; Boadella, Mariana; Galindo, Ruth C.; Pérez de la Lastra, José M.; Moreno-Cid, Juan A.; Fernández de Mera, Isabel G.; Alberdi, Pilar; Santos, Gracia; Ballesteros, Cristina; Lyashchenko, Konstantin P.; Minguijón, Esmeralda; Romero, Beatriz; de Juan, Lucía; Domínguez, Lucas; Juste, Ramón; Gortazar, Christian

    2014-01-01

    Tuberculosis (TB) remains a pandemic affecting billions of people worldwide, thus stressing the need for new vaccines. Defining the correlates of vaccine protection is essential to achieve this goal. In this study, we used the wild boar model for mycobacterial infection and TB to characterize the protective mechanisms elicited by a new heat inactivated Mycobacterium bovis vaccine (IV). Oral vaccination with the IV resulted in significantly lower culture and lesion scores, particularly in the thorax, suggesting that the IV might provide a novel vaccine for TB control with special impact on the prevention of pulmonary disease, which is one of the limitations of current vaccines. Oral vaccination with the IV induced an adaptive antibody response and activation of the innate immune response including the complement component C3 and inflammasome. Mycobacterial DNA/RNA was not involved in inflammasome activation but increased C3 production by a still unknown mechanism. The results also suggested a protective mechanism mediated by the activation of IFN-? producing CD8+ T cells by MHC I antigen presenting dendritic cells (DCs) in response to vaccination with the IV, without a clear role for Th1 CD4+ T cells. These results support a role for DCs in triggering the immune response to the IV through a mechanism similar to the phagocyte response to PAMPs with a central role for C3 in protection against mycobacterial infection. Higher C3 levels may allow increased opsonophagocytosis and effective bacterial clearance, while interfering with CR3-mediated opsonic and nonopsonic phagocytosis of mycobacteria, a process that could be enhanced by specific antibodies against mycobacterial proteins induced by vaccination with the IV. These results suggest that the IV acts through novel mechanisms to protect against TB in wild boar. PMID:24842853

  7. Does trauma team activation associate with the time to CT scan for those suspected of serious head injuries?

    PubMed Central

    2013-01-01

    Background Traumatic brain injury (TBI) constitutes the leading cause of posttraumatic mortality. Practically, the major interventions required to treat TBI predicate expedited transfer to CT after excluding other immediately life-threatening conditions. At our center, trauma responses variably consist of either full trauma activation (FTA) including an attending trauma surgeon or a non-trauma team response (NTTR). We sought to explore whether FTAs expedited the time to CT head (TTCTH). Methods Retrospective review of augmented demographics of 88 serious head injuries identified from a Regional Trauma Registry within one year at a level I trauma center. The inclusion criteria consisted of a diagnosis of head injury recorded as intubated or GCS?activations involving attending trauma surgeons were quicker at transferring serious head injury patients to CT. Patients with FTA were younger and more seriously injured. Discerning the reasons for delays to CT should be used to refine protocols aimed at minimizing unnecessary delays and enhancing workforce efficiency and clinical outcome. PMID:24245486

  8. Synthesis, anti-tuberculosis activity, and 3D-QSAR study of 4-(adamantan-1-yl)-2-substituted quinolines.

    PubMed

    Nayyar, Amit; Monga, Vikramdeep; Malde, Alpeshkumar; Coutinho, Evans; Jain, Rahul

    2007-01-15

    Structural optimization of the previously identified 4-(adamantan-1-yl)-2-quinolinecarbohydrazide (AQCH, MIC=6.25 microg/mL, 99% inhibition, Mycobacterium tuberculosis H37Rv) has led to two series of 4-(adamantan-1-yl)-2-substituted quinolines (Series 1-2). All new derivatives were evaluated in vitro for antimycobacterial activities against drug-sensitive M. tuberculosis H37Rv strain. Several 4-adamantan-1-yl-quinoline-2-carboxylic acid N'-alkylhydrazides (Series 1) described herein showed promising inhibitory activity. In particular, analogs 7, 9, 20, and 21 displayed MIC of 3.125 microg/mL. Further investigation of AQCH by its reaction with various aliphatic, aromatic, and heteroaromatic aldehydes led to the synthesis of 4-adamantan-1-yl-quinoline-2-carboxylic acid alkylidene hydrazides (Series 2). Analogs 42-44 and 48 have produced promising antimycobacterial activities (99% inhibition) at 3.125 microg/mL against drug-sensitive M. tuberculosis H37Rv strain. The most potent analog 35 of the series produced 99% inhibition at 1.00 microg/mL against drug-sensitive strain, and MIC of 3.125 microg/mL against isoniazid-resistant TB strain. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by three methods-comparative molecular field analysis (CoMFA), CoMFA with inclusion of a hydropathy field (HINT), and comparative molecular similarity indices analysis (CoMSIA). Several statistically significant CoMFA, CoMFA with HINT, and CoMSIA models were generated. Prediction of the activity of a test set of molecules was the best for the CoMFA model generated with database alignment. Based on the CoMFA contours, we have tried to explain the structure-activity relationships of the compounds reported herein. PMID:17107805

  9. Synthesis, tuberculosis inhibitory activity, and SAR study of N-substituted-phenyl-1,2,3-triazole derivatives

    Microsoft Academic Search

    Marilia S. Costa; Núbia Boechat; Érica A. Rangel; Fernando de C. da Silva; Alessandra M. T. de Souza; Carlos R. Rodrigues; Helena C. Castro; Ivan N. Junior; Maria Cristina S. Lourenço; Solange M. S. V. Wardell; Vitor F. Ferreira

    2006-01-01

    The aim of this work was to describe the synthesis, the in vitro anti-Mycobacterium tuberculosis profile, and the structure–activity relationship (SAR) study of new N-substituted-phenyl-1,2,3-triazole-4-carbaldehydes (3a–l). The reactions of aromatic amine hydrochlorides with diazomalonaldehyde (1) produced several N-substituted-phenyl-1,2,3-triazole-4-carbaldehydes (3a–l) in moderate-to-good yields. In order to investigate the influence of the difluoromethylene group on the anti-Mycobacterium activity of these compounds, fluorination

  10. Costs and Consequences of Using Interferon-? Release Assays for the Diagnosis of Active Tuberculosis in India

    PubMed Central

    Little, Kristen M.; Pai, Madhukar; Dowdy, David W.

    2015-01-01

    Background There is growing concern that interferon-? release assays (IGRAs) are being used off-label for the diagnosis of active tuberculosis (TB) disease in many high-burden settings, including India, where the background prevalence of latent TB infection is high. We analyzed the costs and consequences of using IGRAs for the diagnosis of active TB in India from the perspective of the Indian TB control sector. Methods and Findings We constructed a decision analytic model to estimate the incremental cost and effectiveness of IGRAs for the diagnosis of active TB in India. We compared a reference scenario of clinical examination and non-microbiological tests against scenarios in which clinical diagnosis was augmented by the addition of either sputum smear microscopy, IGRA, or Xpert MTB/RIF. We examined costs (in 2013 US dollars) and consequences from the perspective of the Indian healthcare sector. Relative to sputum smear microscopy, use of IGRA for active TB resulted in 23,700 (95% uncertainty range, UR: 3,800 – 38,300) additional true-positive diagnoses, but at the expense of 315,700 (95% UR: 118,300 – 388,400) additional false-positive diagnoses and an incremental cost of US$49.3 million (95% UR: $34.9 – $58.0 million) (2.9 billion Indian Rupees). Relative to Xpert MTB/RIF (including the cost of treatment for drug resistant TB), use of IGRA led to 400 additional TB cases treated (95% UR: [-8,000] – 16,200), 370,600 (95% UR: 252,200 – 441,700) more false-positive diagnoses, 70,400 (95% UR: [-7,900] – 247,200) fewer disability-adjusted life years averted, and US$14.6 million (95%UR: [-$7.2] – $28.7 million) (854 million Indian Rupees) in additional costs. Conclusion Using IGRAs for diagnosis of active TB in a setting like India results in tremendous overtreatment of people without TB, and substantial incremental cost with little gain in health. These results support the policies by WHO and Standards for TB Care in India, which discourage the use of IGRAs for the diagnosis of active TB in India and similar settings. PMID:25918999

  11. Tuberculosis among the homeless at a temporary shelter in London: report of a chest x ray screening programme

    Microsoft Academic Search

    D Kumar; K M Citron; J Leese; J M Watson

    1995-01-01

    STUDY OBJECTIVE--To estimate the prevalence of active pulmonary tuberculosis in a homeless population in London and to assess whether those with suspected disease could be integrated into the existing health care system for further follow up and treatment. DESIGN--Voluntary screening programme based on a questionnaire survey and chest x ray. SETTING AND CASES--Screening programmes were set up over the Christmas

  12. 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 Sar?ta?; Alper, Emrah; Dall?, Ay?e; Ünsal, Belk?s

    2015-01-01

    Background Tumor necrosis factor (TNF)-? 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-? 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

  13. Immunological activity of a 38-kilodalton protein purified from Mycobacterium tuberculosis.

    PubMed Central

    Young, D; Kent, L; Rees, A; Lamb, J; Ivanyi, J

    1986-01-01

    A 38-kilodalton (kDa) protein antigen from Mycobacterium tuberculosis was purified by monoclonal antibody TB71-based affinity chromatography. This molecule carries two nonoverlapping epitopes recognized by monoclonal antibodies TB71 and TB72, which are expressed substantially more strongly by M. tuberculosis than by Mycobacterium bovis. However, cross-reactive determinants between these two species were revealed on the 38-kDa protein by a rabbit anti-BCG serum. An immunoradiometric assay based on the TB71 and TB72 antibody pair specifically determined 38-kDa-antigen concentrations in mycobacterial extracts. Antibodies in sera from tuberculosis patients estimated by binding to 38-kDa-antigen-coated microtiter plates were positively correlated with TB72 competing titers. Unlike antibodies, T-cell proliferative responses to the 38-kDa protein were expressed equally by 60% of tuberculosis patients and healthy BCG-vaccinated subjects. Similarly, delayed-type hypersensitivity skin reactions were elicited in both M. tuberculosis- and M. bovis-sensitized guinea pigs. The results suggest the immunodominance of the species-specific B-cell and cross-reactive T-cell stimulatory epitopes. Images PMID:2428751

  14. Flourensia cernua: Hexane Extracts a Very Active Mycobactericidal Fraction from an Inactive Leaf Decoction against Pansensitive and Panresistant Mycobacterium tuberculosis

    PubMed Central

    Molina-Salinas, Gloria María; Peña-Rodríguez, Luis Manuel; Mata-Cárdenas, Benito David; Escalante-Erosa, Fabiola; González-Hernández, Silvia; Torres de la Cruz, Víctor Manuel; Martínez-Rodríguez, Herminia Guadalupe; Said-Fernández, Salvador

    2011-01-01

    The efficacy of decoction in extracting mycobactericidal compounds from Flourensia cernua (Hojasé) leaves and fractionation with solvents having ascending polarity was compared with that of (i) ethanol extraction by still maceration, extraction with a Soxhlet device, shake-assisted maceration, or ultrasound-assisted maceration, followed by fractionation with n-hexane, ethyl acetate, and n-butanol; (ii) sequential extraction with n-hexane, ethyl acetate, and n-butanol, by still maceration, using a Soxhlet device, shake-assisted maceration, or ultrasound-assisted maceration. The in vitro mycobactericidal activity of each preparation was measured against drug-sensitive (SMtb) and drug-resistant (RMtb) Mycobacterium tuberculosis strains. The results of which were expressed as absolute mycobactericidal activity (AMA). These data were normalized to the ?AMA of the decoction fraction set. Although decoction was inactive, the anti-RMtb normalized ?AMA (NAMA) of its fractions was comparable with the anti-RMtb NAMA of the still maceration extracts and significantly higher than the anti-SMtb and anti-RMtb NAMAs of every other ethanol extract and serial extract and fraction. Hexane extracted, from decoction, material having 55.17% and 92.62% of antituberculosis activity against SMtb and RMtb, respectively. Although the mycobactericidal activity of decoction is undetectable; its efficacy in extracting F. cernua active metabolites against M. tuberculosis is substantially greater than almost all pharmacognostic methods. PMID:21584254

  15. Diagnostic value of T-SPOT.TB interferon-? release assays for active tuberculosis

    PubMed Central

    YAN, LIPING; XIAO, HEPING; HAN, MIN; ZHANG, QING

    2015-01-01

    The aim of the present study was to evaluate the diagnostic value of interferon-? release assays for the detection of active tuberculosis (ATB) in patients previously vaccinated with Bacillus Calmette-Guérin (BCG). In total, 540 patients underwent the T-SPOT.TB test, including 295 patients with active pulmonary TB (PTB), 52 patients with active extrapulmonary TB (EPTB), 11 individuals with inactive TB and 182 non-TB cases. Simultaneously, 186 patients with ATB, including PTB and EPTB cases, and 125 non-TB patients underwent tuberculin skin tests (TST). Associations between the sensitivity of the T-SPOT.TB assays and lung lesion severity, positive smear grade, disease site and the duration of anti-TB treatment were evaluated. The sensitivity and specificity values of the T-SPOT.TB assay for diagnosing ATB were 76.66 and 76.37%, respectively, and the positive rate in the inactive TB test results was significantly lower (23.63%; P<0.001). The diagnostic sensitivity was higher in the PTB cases when compared with the EPTB cases (P=0.01). Furthermore, the diagnostic sensitivity of the ATB cases undergoing anti-TB treatment was significantly lower when compared with the cases not undergoing treatment (P=0.002), and the sensitivity gradually decreased with the treatment duration (P=0.01). In addition, a statistically significant difference was identified in the specificity between the T-SPOT.TB assay and the TST (76.37 vs. 51.15%; P<0.001), whereas the sensitivity values did not differ significantly (76.66 vs. 75.56%). Therefore, the results indicated that the T-SPOT.TB assay is a promising diagnostic test for active PTB in a BCG-vaccinated population, and should replace the TST. As the administration of anti-TB treatment resulted in a lower sensitivity to the diagnostic test, the T-SPOT.TB assay may also be suitable for the assessment of treatment outcomes. PMID:26170960

  16. Antimycobacterial and anti-inflammatory activities of substituted chalcones focusing on an anti-tuberculosis dual treatment approach.

    PubMed

    Ventura, Thatiana Lopes Biá; Calixto, Sanderson Dias; de Azevedo Abrahim-Vieira, Bárbara; de Souza, Alessandra Mendonça Teles; Mello, Marcos Vinícius Palmeira; Rodrigues, Carlos Rangel; Soter de Mariz E Miranda, Leandro; Alves de Souza, Rodrigo Octavio Mendonça; Leal, Ivana Correa Ramos; Lasunskaia, Elena B; Muzitano, Michelle Frazão

    2015-01-01

    Tuberculosis (TB) remains a serious public health problem aggravated by the emergence of M. tuberculosis (Mtb) strains resistant to multiple drugs (MDR). Delay in TB treatment, common in the MDR-TB cases, can lead to deleterious life-threatening inflammation in susceptible hyper-reactive individuals, encouraging the discovery of new anti-Mtb drugs and the use of adjunctive therapy based on anti-inflammatory interventions. In this study, a series of forty synthetic chalcones was evaluated in vitro for their anti-inflammatory and antimycobacterial properties and in silico for pharmacokinetic parameters. Seven compounds strongly inhibited NO and PGE2 production by LPS-stimulated macrophages through the specific inhibition of iNOS and COX-2 expression, respectively, with compounds 4 and 5 standing out in this respect. Four of the seven most active compounds were able to inhibit production of TNF-? and IL-1?. Chalcones that were not toxic to cultured macrophages were tested for antimycobacterial activity. Eight compounds were able to inhibit growth of the M. bovis BCG and Mtb H37Rv strains in bacterial cultures and in infected macrophages. Four of them, including compounds 4 and 5, were active against a hypervirulent clinical Mtb isolate as well. In silico analysis of ADMET properties showed that the evaluated chalcones displayed satisfactory pharmacokinetic parameters. In conclusion, the obtained data demonstrate that at least two of the studied chalcones, compounds 4 and 5, are promising antimycobacterial and anti-inflammatory agents, especially focusing on an anti-tuberculosis dual treatment approach. PMID:25951004

  17. Sterilization of granulomas is common in both active and latent tuberculosis despite extensive within-host variability in bacterial killing

    PubMed Central

    Lin, Philana Ling; Ford, Christopher B.; Coleman, M. Teresa; Myers, Amy J.; Gawande, Richa; Ioerger, Thomas; Sacchettini, James; Fortune, Sarah M.; Flynn, JoAnne L.

    2013-01-01

    Over 30% of the world’s population is infected with Mycobacterium tuberculosis (Mtb), yet only ~5–10% will develop clinical disease1. Despite considerable effort, we understand little about what distinguishes individuals who progress to active tuberculosis (TB) from those who remain latent for decades. The variable course of disease is recapitulated in cynomolgus macaques infected with Mtb2. Active disease in macaques is defined by clinical, microbiologic and immunologic signs and occurs in ~45% of animals, while the remaining are clinically asymptomatic2,3. Here, we use barcoded Mtb isolates and quantitative measures of culturable and cumulative bacterial burden to show that most lesions are likely founded by a single bacterium and reach similar maximum burdens. Despite common origins, the fate of individual lesions varies substantially within the same host. Strikingly, in active disease, the host sterilizes some lesions even while others progress. Our data suggest that lesional heterogeneity arises, in part, through differential killing of bacteria after the onset of adaptive immunity. Thus, individual lesions follow diverse and overlapping trajectories, suggesting critical responses occur at a lesional level to ultimately determine the clinical outcome of infection. Defining the local factors that dictate outcome will be important in developing effective interventions to prevent active TB. PMID:24336248

  18. Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3-heteroaryl ureas with improved in vitro pharmacokinetic properties.

    PubMed

    North, E Jeffrey; Scherman, Michael S; Bruhn, David F; Scarborough, Jerrod S; Maddox, Marcus M; Jones, Victoria; Grzegorzewicz, Anna; Yang, Lei; Hess, Tamara; Morisseau, Christophe; Jackson, Mary; McNeil, Michael R; Lee, Richard E

    2013-05-01

    Out of the prominent global ailments, tuberculosis (TB) is still one of the leading causes of death worldwide due to infectious disease. Development of new drugs that shorten the current tuberculosis treatment time and have activity against drug resistant strains is of utmost importance. Towards these goals we have focused our efforts on developing novel anti-TB compounds with the general structure of 1-adamantyl-3-phenyl urea. This series is active against Mycobacteria and previous lead compounds were found to inhibit the membrane transporter MmpL3, the protein responsible for mycolic acid transport across the plasma membrane. However, these compounds suffered from poor in vitro pharmacokinetic (PK) profiles and they have a similar structure/SAR to inhibitors of human soluble epoxide hydrolase (sEH) enzymes. Therefore, in this study the further optimization of this compound class was driven by three factors: (1) to increase selectivity for anti-TB activity over human sEH activity, (2) to optimize PK profiles including solubility and (3) to maintain target inhibition. A new series of 1-adamantyl-3-heteroaryl ureas was designed and synthesized replacing the phenyl substituent of the original series with pyridines, pyrimidines, triazines, oxazoles, isoxazoles, oxadiazoles and pyrazoles. This study produced lead isoxazole, oxadiazole and pyrazole substituted adamantyl ureas with improved in vitro PK profiles, increased selectivity and good anti-TB potencies with sub ?g/mL minimum inhibitory concentrations. PMID:23498915

  19. Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG.

    PubMed

    Mori, Giorgia; Chiarelli, Laurent R; Esposito, Marta; Makarov, Vadim; Bellinzoni, Marco; Hartkoorn, Ruben C; Degiacomi, Giulia; Boldrin, Francesca; Ekins, Sean; de Jesus Lopes Ribeiro, Ana Luisa; Marino, Leonardo B; Centárová, Ivana; Svetlíková, Zuzana; Blaško, Jaroslav; Kazakova, Elena; Lepioshkin, Alexander; Barilone, Nathalie; Zanoni, Giuseppe; Porta, Alessio; Fondi, Marco; Fani, Renato; Baulard, Alain R; Mikušová, Katarína; Alzari, Pedro M; Manganelli, Riccardo; de Carvalho, Luiz Pedro S; Riccardi, Giovanna; Cole, Stewart T; Pasca, Maria Rosalia

    2015-07-23

    To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target. PMID:26097035

  20. Design, Synthesis and Anti-tuberculosis Activity of 1-Adamantyl-3-heteroaryl Ureas with Improved in vitro Pharmacokinetic Properties

    PubMed Central

    North, E. Jeffrey; Scherman, Michael S.; Bruhn, David F.; Scarborough, Jerrod S.; Maddox, Marcus M.; Jones, Victoria; Grzegorzewicz, Anna; Yang, Lei; Hess, Tamara; Morisseau, Christophe; Jackson, Mary; McNeil, Michael R.; Lee, Richard E.

    2013-01-01

    Out of the prominent global ailments, tuberculosis (TB) is still one of the leading causes of death worldwide due to infectious disease. Development of new drugs that shorten the current tuberculosis treatment time and have activity against drug resistant strains is of utmost importance. Towards these goals we have focused our efforts on developing novel anti-TB compounds with the general structure of 1-adamantyl-3-phenyl urea. This series is active against Mycobacteria and previous lead compounds were found to inhibit the membrane transporter MmpL3, the protein responsible for mycolic acid transport across the plasma membrane. However, these compounds suffered from poor in vitro pharmacokinetic (PK) profiles and they have a similar structure/SAR to inhibitors of human soluble epoxide hydrolase (SEH) enzymes. Therefore, in this study the further optimization of this compound class was driven by three factors: 1) to increase selectivity for anti-TB activity over human sEH activity, 2) to optimize PK profiles including solubility and 3) to maintain target inhibition. A new series of 1-adamantyl-3-heteroaryl ureas was designed and synthesized replacing the phenyl substituent of the original series with pyridines, pyrimidines, triazines, oxazoles, isoxazoles, oxadiazoles and pyrazoles. This study produced lead oxadiazole and pyrazole substituted adamantyl ureas with improved in vitro PK profiles, increased selectivity and good anti-TB potencies with sub µg/mL minimum inhibitory concentrations. PMID:23498915

  1. Pediatric glaucoma suspects

    PubMed Central

    Kooner, Karanjit; Harrison, Matthew; Prasla, Zohra; Albdour, Mohannad; Adams-Huet, Beverley

    2014-01-01

    Purpose To report demographic and ocular features of pediatric glaucoma suspects in an ethnically diverse population of North Central Texas. Design Retrospective cross-sectional chart review. Participants Subjects included 75 (136 eyes) pediatric glaucoma suspects. Patients with one or more of the following risk factors were included: cup-to disc (C/D) ratio of ?0.6; intraocular pressure (IOP) ?21 mmHg; family history of glaucoma; congenital glaucoma in the opposite eye; history of blunt trauma to either eye; and presence of either Sturge-Weber or Axenfeld–Rieger syndrome, or oculodermal melanocytosis. Methods Data were extracted from electronic patient medical records. Patient records with incomplete data were excluded. The main outcome measures were race, sex, age, IOP, C/D, family history of glaucoma; and glaucoma treatment. Results Subjects included 28 (37.3%) Hispanics, 20 (26.6%) African Americans, 20 (26.6%) Caucasians, and seven (9.3%) Asians. Forty (53.3%) of the patients were male. Suspicious optic disc was seen in 57 (76%); elevated IOP in 25 (33.3%); presence of family history in 13 (17.3%), and Sturge–Weber syndrome in nine (12%) patients. The average C/D ratio was 0.58±0.2. The C/D ratios of African American (0.65±0.2), Hispanic (0.63±0.2), and Asian (0.62±0.15) patients were significantly greater than those of Caucasians (0.43±0.18; P=0.0004, 0.0003, and 0.0139, respectively). Caucasian patients were the youngest (7.9±4.8 years). Eleven cases (14.7%) required medication. Conclusion Thirty-three point seven percent of patients seen in the glaucoma clinic were glaucoma suspects. The most common risk factors for suspected glaucoma were suspicious optic discs, elevated IOP, and family history of glaucoma. Most patients required only close observation. Long-term follow-up of these patients is warranted to determine the mechanisms of conversion to glaucoma. PMID:24966666

  2. Structure–activity relationships of compounds targeting mycobacterium tuberculosis 1-deoxy- d-xylulose 5-phosphate synthase

    Microsoft Academic Search

    Jialin Mao; Hyungjin Eoh; Rong He; Yuehong Wang; Baojie Wan; Scott G. Franzblau; Dean C. Crick; Alan P. Kozikowski

    2008-01-01

    We report on a target-based approach to identify possible Mycobacteriumtuberculosis DXS inhibitors from the structure of a known transketolase inhibitor. A small focused library of analogs was assembled in order to begin elucidating some meaningful structure–activity relationships of 3-(4-chloro-phenyl)-5-benzyl-4H-pyrazolo[1,5-a]pyrimidin-7-one. Ultimately we found that 2-methyl-3- (4-fluorophenyl)-5-(4-methoxy-phenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one, although still weak, was able to inhibit M. tuberculosis DXS with an IC50 of 10.6?M.

  3. miRNA Signatures in Sera of Patients with Active Pulmonary Tuberculosis

    PubMed Central

    Valente, Ilaria C.; Norbis, Luca; Sotgiu, Giovanni; Bosu, Roberta; Ambrosi, Alessandro; Codecasa, Luigi R.; Goletti, Delia; Matteelli, Alberto; Ntinginya, Elias N.; Aloi, Francesco; Heinrich, Norbert; Reither, Klaus; Cirillo, Daniela M.

    2013-01-01

    Several studies showed that assessing levels of specific circulating microRNAs (miRNAs) is a non-invasive, rapid, and accurate method for diagnosing diseases or detecting alterations in physiological conditions. We aimed to identify a serum miRNA signature to be used for the diagnosis of tuberculosis (TB). To account for variations due to the genetic makeup, we enrolled adults from two study settings in Europe and Africa. The following categories of subjects were considered: healthy (H), active pulmonary TB (PTB), active pulmonary TB, HIV co-infected (PTB/HIV), latent TB infection (LTBI), other pulmonary infections (OPI), and active extra-pulmonary TB (EPTB). Sera from 10 subjects of the same category were pooled and, after total RNA extraction, screened for miRNA levels by TaqMan low-density arrays. After identification of “relevant miRNAs”, we refined the serum miRNA signature discriminating between H and PTB on individual subjects. Signatures were analyzed for their diagnostic performances using a multivariate logistic model and a Relevance Vector Machine (RVM) model. A leave-one-out-cross-validation (LOOCV) approach was adopted for assessing how both models could perform in practice. The analysis on pooled specimens identified selected miRNAs as discriminatory for the categories analyzed. On individual serum samples, we showed that 15 miRNAs serve as signature for H and PTB categories with a diagnostic accuracy of 82% (CI 70.2–90.0), and 77% (CI 64.2–85.9) in a RVM and a logistic classification model, respectively. Considering the different ethnicity, by selecting the specific signature for the European group (10 miRNAs) the diagnostic accuracy increased up to 83% (CI 68.1–92.1), and 81% (65.0–90.3), respectively. The African-specific signature (12 miRNAs) increased the diagnostic accuracy up to 95% (CI 76.4–99.1), and 100% (83.9–100.0), respectively. Serum miRNA signatures represent an interesting source of biomarkers for TB disease with the potential to discriminate between PTB and LTBI, but also among the other categories. PMID:24278252

  4. Photometry of 50 suspected variable stars

    Microsoft Academic Search

    James T. Hooten; Douglas S. Hall

    1990-01-01

    Fifty stars have been chosen as suspected variable stars and analyzed for variability. A large portion of this sample are stars that are either proved active chromosphere stars or are candidates for such activity. The photometric data base consists of differential V measurements of the Vanderbilt 16 inch (41 cm) automatic photoelectric telescope and 25 observers at 26 observatories worldwide.

  5. Comparison of Tuberculin Activity in the Interferon-gamma Assay for the Diagnosis of Bovine Tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cattle infected with bovine tuberculosis still represent a serious regulatory and health concern in a variety of countries. Early diagnosis using the in vitro interferon gamma (IFN-gamma) assay has been applied for more than a decade. Briefly, IFN-gamma responses in whole blood cultures stimulated w...

  6. Characterization of Molecular Evolution in Multi-Drug Resistant of Mycobacterium tuberculosis by rpoB Gene in Patient with Active Pulmonary Tuberculosis from Iranian Isolates.

    PubMed

    Saeed, Zaker Bostanabad; Karim, Rahimi Mohammad; Parvaneh, Adimi; Zahra, Tayebee; Mozhgan, Masoumi; Shahin, Pourazar; Esmail, Jabbarzadeh; Mehdi, Shekarabi; Azarmidokht, Pourmand; Konstantina, Sourkova Larisa; Petrovich, Titov Leonid

    2009-12-01

    This is the first genetic biodiversity study of Mycobacterium tuberculosis in Iran. Thus, we investigated the genetic patterns of strains isolated in the first survey of anti-tuberculosis drug-resistance by rpoB gene as part of the Global Project of Anti-tuberculosis Drug Resistance Surveillance (IAU, Iran). A 411-bp fragment of the rpoB gene, containing the sequence of the 81-bp rpoB fragment, was amplified by PCR and the rpoB gene fragments of tuberculosis strains were sequenced using the Amersham auto sequencer. For analysing tree evolution used method UPGMA and Neighbour-Joining. Clinical isolates (34/163) were analyzed by using sequencing gene rpoB and genotyped by program MEGA. The results were compared with the international database. Multi-drug resistant (MDR) was 14% in never treated patients and 8% in previously treated patients. Mutations in rpoB gene and katG genes were detected in 95% and 84% of the MDR strains, 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 strains are divided into 2 groups: group A - similar to the standard and Eastern strains (China, Taiwan) and group B - strains of another genotype. They are grouped separately on the dendrogram and became prevalent in Iran (they are called Iranian residential strains). This study gives a first overview of the M. tuberculosis strains circulating in Iran during the first survey of anti-tuberculosis drug-resistance. It may aid in the creation of a national database that will be a valuable support for further studies. PMID:23675155

  7. [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 test in Tokyo: Hideo MAEDA (Bureau of Social Welfare and Public Health, Tokyo Metropolitan Government). 2. Contact investigation of a tuberculosis outbreak: Kenichi MIYAMOTO (Takaido Community Health Center). We have experienced a TB outbreak in integrated junior and senior high school in Tokyo. Index patient was a student with persistent respiratory symptoms for six months before diagnosis of sputum smear-positive TB. Public health center started contact investigation immediately. QFT-positive rates were high in close contacts, especially in classmates. Additionally, a student outside of contact investigation was diagnosed as TB and considered to be infected from the first patient by VNTR analysis. Therefore, public health center expanded QFT-tests to all students and teachers in this school. Finally, 9 students and 2 teachers in this school were diagnosed as sputum smear-negative TB by contact investigation. 3. Utilization of molecular epidemiological procedure in contact investigation in Kyoto City: Masahiro ITO (Public Health Center of Kyoto City) Molecular epidemiological procedure using VNTR analysis has been used for contact investigation of tuberculosis since January 2011 in Kyoto City. One hundred forty four strains of Mycobacterium tuberculosis from patients with tuberculosis were investigated and 130 strains were fully analyzed. Fourteen clusters were found and the number of strains included in the cluster was ranged from two to 11. Epidemiological relationship between patients in one cluster was found, however, significant relationship in another clusters was not demonstrated. It was suggested that VNTR analysis is useful for molecular epidemiological analysis of tuberculosis. 4. The population based molecular epidemiological studies and QFT test in a contact examination: Riyo FUJIYAMA, Keisuke MATSUBAYASHI, Setsuko MIZUSHIRI, Junko HIGUCHIL Chika SHIRAI, Yuko KATAGAMI, Mieko CHIHARA, Akihiro IJICHI (Kobe City Public Health Center), Kentaro ARIKAWA, Noriko NAKANISHI, Tomotada IWAMOTO (Kobe Institute of Health). The population ba

  8. In Vitro and In Vivo Activities of Ruthenium(II) Phosphine/Diimine/Picolinate Complexes (SCAR) against Mycobacterium tuberculosis

    PubMed Central

    Pavan, Fernando R.; Poelhsitz, Gustavo V.; da Cunha, Lucas V. P.; Barbosa, Marilia I. F.; Leite, Sergio R. A.; Batista, Alzir A.; Cho, Sang H.; Franzblau, Scott G.; de Camargo, Mariana S.; Resende, Flávia A.; Varanda, Eliana A.; Leite, Clarice Q. F.

    2013-01-01

    Rifampicin, discovered more than 50 years ago, represents the last novel class of antibiotics introduced for the first-line treatment of tuberculosis. Drugs in this class form part of a 6-month regimen that is ineffective against MDR and XDR TB, and incompatible with many antiretroviral drugs. Investments in R&D strategies have increased substantially in the last decades. However, the number of new drugs approved by drug regulatory agencies worldwide does not increase correspondingly. Ruthenium complexes (SCAR) have been tested in our laboratory and showed promising activity against Mycobacterium tuberculosis. These complexes showed up to 150 times higher activity against MTB than its organic molecule without the metal (free ligand), with low cytotoxicity and high selectivity. In this study, promising results inspired us to seek a better understanding of the biological activity of these complexes. The in vitro biological results obtained with the SCAR compounds were extremely promising, comparable to or better than those for first-line drugs and drugs in development. Moreover, SCAR 1 and 4, which presented low acute toxicity, were assessed by Ames test, and results demonstrated absence of mutagenicity. PMID:23724039

  9. 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 ?-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

  10. Functional redundancy of steroid C26-monooxygenase activity in Mycobacterium tuberculosis revealed by biochemical and genetic analyses.

    PubMed

    Johnston, Jonathan B; Ouellet, Hugues; Ortiz de Montellano, Paul R

    2010-11-19

    One challenge to the development of new antitubercular drugs is the existence of multiple virulent strains that differ genetically. We and others have recently demonstrated that CYP125A1 is a steroid C(26)-monooxygenase that plays a key role in cholesterol catabolism in Mycobacterium tuberculosis CDC1551 but, unexpectedly, not in the M. tuberculosis H37Rv strain. This discrepancy suggests that the H37Rv strain possesses compensatory activities. Here, we examined the roles in cholesterol metabolism of two other cytochrome P450 enzymes, CYP124A1 and CYP142A1. In vitro analysis, including comparisons of the binding affinities and catalytic efficiencies, demonstrated that CYP142A1, but not CYP124A1, can support the growth of H37Rv cells on cholesterol in the absence of cyp125A1. All three enzymes can oxidize the sterol side chain to the carboxylic acid state by sequential oxidation to the alcohol, aldehyde, and acid. Interestingly, CYP125A1 generates oxidized sterols of the (25S)-26-hydroxy configuration, whereas the opposite 25R stereochemistry is obtained with CYP124A1 and CYP142A1. Western blot analysis indicated that CYP124A1 was not detectably expressed in either the H37Rv or CDC1551 strains, whereas CYP142A1 was found in H37Rv but not CDC1551. Genetic complementation of CDC1551 ?cyp125A1 cells with the cyp124A1 or cyp142A1 genes revealed that the latter can fully rescue the growth defect on cholesterol, whereas cells overexpressing CYP124A1 grow poorly and accumulate cholest-4-en-3-one. Our data clearly establish a functional redundancy in the essential C(26)-monooxygenase activity of M. tuberculosis and validate CYP125A1 and CYP142A1 as possible drug targets. PMID:20843794

  11. High-Content Screening Technology Combined with a Human Granuloma Model as a New Approach To Evaluate the Activities of Drugs against Mycobacterium tuberculosis

    PubMed Central

    Silva-Miranda, Mayra; Breiman, Adrien; Asehnoune, Karim; Barros-Aguirre, David; Pethe, Kevin; Ewann, Fanny; Brodin, Priscille; Ballell-Pages, Lluís

    2014-01-01

    Tuberculosis remains a major health problem due to the emergence of drug-resistant strains of Mycobacterium tuberculosis. Some models have provided valuable information about drug resistance and efficacy; however, the translation of these results into effective human treatments has mostly proven unsuccessful. In this study, we adapted high-content screening (HCS) technology to investigate the activities of antitubercular compounds in the context of an in vitro granuloma model. We observed significant shifts in the MIC50s between the activities of the compounds under extracellular and granuloma conditions. PMID:25348525

  12. Bactericidal activity of PA-824 against Mycobacterium tuberculosis under anaerobic conditions and computational analysis of its novel analogues against mutant Ddn receptor

    PubMed Central

    2013-01-01

    Background The resurgence of multi-drug resistant tuberculosis (MDR-TB) and HIV associated tuberculosis (TB) are of serious global concern. To contain this situation, new anti-tuberculosis drugs and reduced treatment regimens are imperative. Recently, a nitroimidazole, PA-824, has been shown to be active against both replicating and non-replicating bacteria. It is activated by the enzyme Deazaflavin-dependent nitroreductase (Ddn) present in Mycobacterium tuberculosis which catalyzes the reduction of PA-824, resulting in the release of lethal reactive nitrogen species (RNS) within the bacteria. In this context, PA-824 was analyzed for its activity against latent tuberculosis under anaerobic conditions and compared with rifampicin (RIF) and pyrazinamide (PZA). Recent mutagenesis studies have identified A76E mutation which affects the above mentioned catalysis and leads to PA-824 resistance. Hence, novel analogues which could cope up with their binding to mutant Ddn receptor were also identified through this study. Results PA-824 at an optimum concentration of 12.5 ?g/ml showed enhanced bactericidal activity, resulting in 0 CFU/ml growth when compared to RIF and PZA at normal pH and anaerobic condition. Further docking studies revealed that a combinatorial structure of PA-824 conjugated with moxifloxacin (ligand 8) has the highest binding affinity with the wild type and mutant Ddn receptor. Conclusions PA-824 has been demonstrated to have better activity under anaerobic condition at 12.5 ?g/ml, indicating an optimized dose that is required for overcoming the detoxifying mechanisms of M. tuberculosis and inducing its death. Further, the development of resistance through A76E mutation could be overcome through the in silico evolved ligand 8. PMID:24083570

  13. Oxidative Activation of Thiacetazone by the Mycobacterium tuberculosis Flavin Monooxygenase EtaA and Human FMO1 and FMO3

    PubMed Central

    Qian, Lian; Ortiz de Montellano, Paul R.

    2008-01-01

    Thiacetazone (TAZ) and ethionamide (ETA) are, respectively, thiourea and thioamide-containing second line antitubercular prodrugs for which there is an extensive clinical history of cross-resistance in Mycobacterium tuberculosis. EtaA, a recently identified flavin-containing monooxygenase (FMO), is responsible for the oxidative activation of ETA in M. tuberculosis. We report here that EtaA also oxidizes TAZ and identify a sulfinic acid and a carbodiimide as the isolable metabolites. Both of these metabolites are derived from an initial sulfenic acid intermediate. Oxidation of TAZ by EtaA at basic pH favors formation of the carbodiimide, whereas neutral or acidic conditions favor formation of the sulfinic acid. The same metabolites are formed from TAZ by human FMO1 and FMO3. The sulfenic acid and carbodiimide metabolites, but not the sulfinic acid product, readily react with glutathione, the first to regenerate the parent drug and the second to give a glutathione adduct. These reactions that may contribute to the antitubercular activity and/or toxicity of TAZ. PMID:16544950

  14. Active Case Finding of Tuberculosis (TB) in an Emergency Room in a Region with High Prevalence of TB in Brazil

    PubMed Central

    Silva, Denise Rossato; Müller, Alice Mânica; Tomasini, Karina da Silva; Dalcin, Paulo de Tarso Roth; Golub, Jonathan E.; Conde, Marcus Barreto

    2014-01-01

    Setting Public hospital emergency room (ER) in Porto Alegre, Brazil, a setting with high prevalence of tuberculosis (TB) and human immunodeficiency virus (HIV) infection. Objective To determine the prevalence of PTB, using a symptom based active case finding (ACF) strategy in the ER of a public hospital in an area with high prevalence of TB and HIV, as well as variables associated with pulmonary TB diagnosis. Methods Cross sectional study. All patients ?18 years seeking care at the ER were screened for respiratory symptoms and those with cough ?2 weeks were invited to provide a chest radiograph and two unsupervised samples of sputum for acid-fast bacilli smear and culture. Results Among 31,267 admissions, 6,273 (20.1%) reported respiratory symptoms; 197 reported cough ?2 weeks, of which pulmonary TB was diagnosed in 30. In multivariate analysis, the variables associated with a pulmonary tuberculosis diagnosis were: age (OR 0.94, 95% CI: 0.92–0.97; p<0.0001), sputum production (OR 0.18, 95% CI 0.06–0.56; p?=?0.003), and radiographic findings typical of TB (OR 12.11, 95% CI 4.45–32.93; p<0.0001). Conclusions This study identified a high prevalence of pulmonary TB among patients who sought care at the emergency department of a tertiary hospital, emphasizing the importance of regular screening of all comers for active TB in this setting. PMID:25211158

  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 in poorly-controlled DM patients than that in well-controlled DM patients and healthy subjects. Thus, these clinical data suggest that the high incidence of tuberculosis in DM patients is due to the impaired production of Th1-related cytokines. However, direct evidences to prove this possibility remain to be obtained. In 1980, Saiki and co-workers reported that host defense and delayed-type hypersensitivity response to M. tuberculosis was hampered in a mouse DM model established by injecting streptozotocin (Infect Immun. 1980; 28: 127-131). We followed their investigation with the similar observations. Interestingly, levels of IFN-gamma and IL-12 in serum, lung, liver and spleen after infection were significantly reduced in DM mice when compared with those in control mice. Considered collectively, these results strongly suggest that the reduced production of Th1-related cytokines leads to the susceptibility of DM to mycobacterial infection. However, it remains to be understood how DM hampers the synthesis of Th1-related cytokines. In our preliminary study, the production of these cytokines by PBMC from DM patients and healthy subjects was not affected under a high glucose condition. Thus, it is not likely that the increased level of glucose directly suppresses the cell-mediated immune responses. Further investigations are needed to make these points clear. 2. A study of gastrectomy cases in pulmonary tuberculosis patients: Takenori YAGI (Division of Thoracic Disease, National Chiba-Higashi Hospital). Patients who have undergone gastric resection are considered at increased risk of developing pulmonary tuberculosis. I have investigated the role played by gastrectomy in giving rise to pulmonary tuberculosis. Of 654 pulmonary tuberculosis patients admitted to National Chiba-Higashi Hospital from January 1999 to December 2001, 55 patients (31-84 years old, mean 63.5 +/- 12.5 years, 48 males and 7 females) had the history of gastric resection. The incidence of gastrectomy among patients with pulmonary tuberculosis was 8.4 percent. The mean age of gastric resection

  16. Characterization of the Helicase Activity and Substrate Specificity of Mycobacterium tuberculosis UvrD

    Microsoft Academic Search

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

    2007-01-01

    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

  17. Fumarate reductase activity maintains an energized membrane in anaerobic Mycobacterium tuberculosis.

    PubMed

    Watanabe, Shinya; Zimmermann, Michael; Goodwin, Michael B; Sauer, Uwe; Barry, Clifton E; Boshoff, Helena I

    2011-10-01

    Oxygen depletion of Mycobacterium tuberculosis engages the DosR regulon that coordinates an overall down-regulation of metabolism while up-regulating specific genes involved in respiration and central metabolism. We have developed a chemostat model of M. tuberculosis where growth rate was a function of dissolved oxygen concentration to analyze metabolic adaptation to hypoxia. A drop in dissolved oxygen concentration from 50 mmHg to 0.42 mmHg led to a 2.3 fold decrease in intracellular ATP levels with an almost 70-fold increase in the ratio of NADH/NAD(+). This suggests that re-oxidation of this co-factor becomes limiting in the absence of a terminal electron acceptor. Upon oxygen limitation genes involved in the reverse TCA cycle were upregulated and this upregulation was associated with a significant accumulation of succinate in the extracellular milieu. We confirmed that this succinate was produced by a reversal of the TCA cycle towards the non-oxidative direction with net CO(2) incorporation by analysis of the isotopomers of secreted succinate after feeding stable isotope ((13)C) labeled precursors. This showed that the resulting succinate retained both carbons lost during oxidative operation of the TCA cycle. Metabolomic analyses of all glycolytic and TCA cycle intermediates from (13)C-glucose fed cells under aerobic and anaerobic conditions showed a clear reversal of isotope labeling patterns accompanying the switch from normoxic to anoxic conditions. M. tuberculosis encodes three potential succinate-producing enzymes including a canonical fumarate reductase which was highly upregulated under hypoxia. Knockout of frd, however, failed to reduce succinate accumulation and gene expression studies revealed a compensatory upregulation of two homologous enzymes. These major realignments of central metabolism are consistent with a model of oxygen-induced stasis in which an energized membrane is maintained by coupling the reductive branch of the TCA cycle to succinate secretion. This fermentative process may offer unique targets for the treatment of latent tuberculosis. PMID:21998585

  18. 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 tuberculosis in order to optimize outcomes and reduce the duration of therapy. PMID:19947806

  19. [Tuberculosis of finger bones: three cases].

    PubMed

    Loussaief, C; Ammari, F; Toumi, A; Ben Brahim, H; Ben Rhomdane, F; Chakroun, M

    2012-04-01

    Tuberculosis dactylis is exceptional. We report tuberculous dactylitis in three women who were 51, 44, and 62-year-old, respectively. The diagnosis was suspected on chronic and insidious clinical presentation, and confirmed by histology. Disease course was favourable with antibuberculosis regimen but two patients had permanent hand disability. Clinical and therapeutic issues are discussed in the context of an endemic country. PMID:21549458

  20. In vitro anti Mycobacterium tuberculosis H37Rv activity of Lannea acida A. Rich from Burkina Faso.

    PubMed

    Ouattara, L; Koudou, J; Karou, D S; Giacò, L; Capelli, G; Simpore, J; Fraziano, M; Colizzi, V; Traore, A S

    2011-01-01

    The cytotoxic and anti-Mycobacterium tuberculosis H37Rv activities of hydro-alcoholic extract of Lannea acida A. Rich (Anacardiaceae) were assessed. The cytoxicity evaluation was carried out on THP1 monocytoid cell line (after 24 h at 1; 5 and 10 microg mL(-1)) and showed only a slight modification of lactate dehydrogenase (LDH) release. The rate of monocytes in different stages of mitosis had been amended in absence and presence of extract as follows: Go/G1 58.83-59.83%; synthesis 21.95-18.64%; mitosis 16.67-15.77%; necrosis 2.65-5.64%. The percentage of inhibition of Mycobacterium tuberculosis proliferation was respectively 77.6 and 36.8% at 1.2 and 0.6 mg mL(-1) of extract. This is an interesting experimental study on antimicrobial and immune-stimulating properties of Lannea acida ethanol-water (70% v/v) extract which may contain potential antibacterial and immune-stimulating agents for clinical use. PMID:21913497

  1. Decreased Frequencies of Circulating CD4+ T Follicular Helper Cells Associated with Diminished Plasma IL-21 in Active Pulmonary Tuberculosis

    PubMed Central

    Kumar, Nathella Pavan; Sridhar, Rathinam; Hanna, Luke E.; Banurekha, Vaithilingam V.; Nutman, Thomas B.; Babu, Subash

    2014-01-01

    Background Circulating T follicular helper (Tfh) cells represent a distinct subset of CD4+ T cells and are important in immunity to infections. Although they have been shown to play a role in experimental models of tuberculosis infection, their role in human tuberculosis remains unexplored. Aims/Methodology To determine the distribution of circulating Tfh cells in human TB, we measured the frequencies of Tfh cells ex vivo and following TB - antigen or polyclonal stimulation in pulmonary TB (PTB; n?=?30) and latent TB (LTB; n?=?20) individuals, using the markers CXCR5, PD-1 and ICOS. Results We found that both ex vivo and TB - antigen induced frequencies of Tfh cell subsets was significantly lower in PTB compared to LTB individuals. Similarly, antigen induced frequencies of Tfh cells expressing IL-21 was also significantly lower in PTB individuals and this was reflected in diminished circulating levels of IL-21 and IFN?. This was not accompanied by diminished frequencies of activated or memory B cell subsets. Finally, the diminution in frequency of Tfh cells in PTB individuals was dependent on IL-10, CTLA-4 and PD-L1 in vitro. Conclusions Thus, PTB is characterized by adiminution in the frequency of Tfh cell subsets. PMID:25343703

  2. Current Concepts in the Management of Tuberculosis

    PubMed Central

    Sia, Irene G.; Wieland, Mark L.

    2011-01-01

    Tuberculosis (TB) poses a serious threat to public health throughout the world but disproportionately afflicts low-income nations. Persons in close contact with a patient with active pulmonary TB and those from endemic regions of the world are at highest risk of primary infection, whereas patients with compromised immune systems are at highest risk of reactivation of latent TB infection (LTBI). Tuberculosis can affect any organ system. Clinical manifestations vary accordingly but often include fever, night sweats, and weight loss. Positive results on either a tuberculin skin test or an interferon-? release assay in the absence of active TB establish a diagnosis of LTBI. A combination of epidemiological, clinical, radiographic, microbiological, and histopathologic features is used to establish the diagnosis of active TB. Patients with suspected active pulmonary TB should submit 3 sputum specimens for acid-fast bacilli smears and culture, with nucleic acid amplification testing performed on at least 1 specimen. For patients with LTBI, treatment with isoniazid for 9 months is preferred. Patients with active TB should be treated with multiple agents to achieve bacterial clearance, to reduce the risk of transmission, and to prevent the emergence of drug resistance. Directly observed therapy is recommended for the treatment of active TB. Health care professionals should collaborate, when possible, with local and state public health departments to care for patients with TB. Patients with drug-resistant TB or coinfection with human immunodeficiency virus should be treated in collaboration with TB specialists. Public health measures to prevent the spread of TB include appropriate respiratory isolation of patients with active pulmonary TB, contact investigation, and reduction of the LTBI burden. PMID:21454737

  3. Colonic Tuberculosis

    Microsoft Academic Search

    EduardoVillanueva Sáenz; PaulinoMartínezHernández Magro; JoséFernandoÁlvarez-Tostado Fernández; MiguelValdés Ovalle

    2002-01-01

    Tubercle bacillus was discovered in 1882 by Robert Koch. With the introduction of chemotherapy for tuberculosis in the 1940s the incidence of this entity decreased. The incidence of the tuberculosis of the colon began to increase at the 1980s with the rise in numbers of patients considered as high risk for this entity, such as HIV-infected individuals, patients with chronic

  4. Environmental infection control of tuberculosis.

    PubMed

    Nardell, Edward A

    2003-12-01

    Current infection control guidelines for tuberculosis focus first on administrative interventions to promptly identify and isolate a known or suspected infectious case. Environmental control measures come next, and finally personal respiratory protection is recommended as a final strategy to prevent transmission. However, both environmental controls and the use of personal respiratory protection are also focused on known or suspected cases, and certain high-risk procedures. There is little focus on general medical areas where unsuspected cases are believed to transmit their infection before they become suspected cases. This review makes the case for increased attention to such areas as general medical wards, clinics, and waiting areas. Administrative controls are needed to improve detection and to reduce the possibility of transmission to high-risk groups. Improved air disinfection through general ventilation, filtration, and ultraviolet germicidal irradiation are needed as ways to address this overlooked source of transmission. PMID:14679478

  5. Tuberculosis: evidence review for newly arriving immigrants and refugees

    Microsoft Academic Search

    Christina Greenaway; A. Sandoe; Bilkis Vissandjee; Ian Kitai; D. Gruner; W. Wobeser; K. Pottie; E. Ueffing; D. Menzies; K. Schwartzman

    2010-01-01

    Background: The foreign-born population bears a dispro- portionate health burden from tuberculosis, with a rate of active tuberculosis 20 times that of the non-Aboriginal Canadian-born population, and could therefore benefit from tuberculosis screening programs. We reviewed evi- dence to determine the burden of tuberculosis in immigrant populations, to assess the effectiveness of screening and treatment programs for latent tuberculosis infection,

  6. New indicators proposed to assess tuberculosis control and elimination in Cuba.

    PubMed

    González, Edilberto R; Armas, Luisa

    2012-10-01

    Following 48 years of successful operation of the National Tuberculosis Control Program, Cuban health authorities have placed tuberculosis elimination on the agenda. To this end some tuberculosis control processes and their indicators need redesigned and new ones introduced, related to: number and proportion of suspected tuberculosis cases among vulnerable population groups; tuberculosis suspects with sputum microscopy and culture results useful for diagnosis (interpretable); and number of identified contacts of reported tuberculosis cases who were fully investigated. Such new indicators have been validated and successfully implemented in all provinces (2011-12) and are in the approval pipeline for generalized use in the National Tuberculosis Control Program. These indicators complement existing criteria for quality of case detection and support more comprehensive program performance assessment. PMID:23154318

  7. Colonic tuberculosis mimicking Crohn's disease: case report

    PubMed Central

    Chatzicostas, Constantinos; Koutroubakis, Ioannis E; Tzardi, Maria; Roussomoustakaki, Maria; Prassopoulos, Panagiotis; Kouroumalis, Elias A

    2002-01-01

    Background Intestinal tuberculosis is a rare disease in western countries, affecting mainly immigrants and immunocompromised patients. Intestinal tuberculosis is a diagnostic challenge, especially when active pulmonary infection is absent. It may mimic many other abdominal diseases. Case presentation Here, we report a case of isolated colonic tuberculosis where the initial diagnostic workup was suggestive of Crohn's disease. Computed tomography findings however, raised the possibility of colonic tuberculosis and the detection of acid-fast bacilli in biopsy specimens confirmed the diagnosis. Conclusions In conclusion, this case highlights the need for awareness of intestinal tuberculosis in the differential diagnosis of chronic intestinal disease PMID:12019037

  8. Rapid diagnosis of pulmonary tuberculosis

    PubMed Central

    Sarmiento, José Mauricio Hernández; Restrepo, Natalia Builes; Mejía, Gloria Isabel; Zapata, Elsa; Restrepo, Mary Alejandra; Robledo, Jaime

    2014-01-01

    Introduction World Health Organization had estimated 9.4 million tuberculosis cases on 2009, with 1.7 million of deaths as consequence of treatment and diagnosis failures. Improving diagnostic methods for the rapid and timely detection of tuberculosis patients is critical to control the disease. The aim of this study was evaluating the accuracy of the cord factor detection on the solid medium Middlebrook 7H11 thin layer agar compared to the Lowenstein Jensen medium for the rapid tuberculosis diagnosis. Methods Patients with suspected tuberculosis were enrolled and their sputum samples were processed for direct smear and culture on Lowenstein Jensen and BACTEC MGIT 960, from which positive tubes were subcultured on Middlebrook 7H11 thin layer agar. Statistical analysis was performed comparing culture results from Lowenstein Jensen and the thin layer agar, and their corresponding average times for detecting Mycobacterium tuberculosis. The performance of cord factor detection was evaluated determining its sensitivity, specificity, positive and negative predictive value. Results 111 out of 260 patients were positive for M. tuberculosis by Lowenstein Jensen medium with an average time ± standard deviation for its detection of 22.3 ± 8.5 days. 115 patients were positive by the MGIT system identifying the cord factor by the Middlebrook 7H11 thin layer agar which average time ± standard deviation was 5.5 ± 2.6 days. Conclusion The cord factor detection by Middlebrook 7H11 thin layer agar allows early and accurate tuberculosis diagnosis during an average time of 5 days, making this rapid diagnosis particularly important in patients with negative sputum smear. PMID:25419279

  9. Improved case detection of active tuberculosis associated with an antiretroviral treatment program in Lesotho.

    PubMed

    Furin, J J; Rigodon, J; Cancedda, C; Keshavjee, S; Seung, K J; Letsie, M; Kim, J Y; Joseph, J K

    2007-10-01

    Tuberculosis (TB) remains the leading infectious killer of adults with human immunodeficiency virus (HIV) globally. Lesotho has the third highest prevalence of HIV and the fourth highest prevalence of TB worldwide, and the majority of TB patients are co-infected with HIV. This paper describes an antiretroviral treatment (ART) program instituted in a health center in a mountain region of Lesotho. Although the main goal of the program was to increase HIV detection and initiate ART for patients, the program also resulted in a ten-fold increase in the detection of TB among patients with and without HIV. PMID:17945074

  10. Spectrum of tuberculosis in patients with HIV infection in British Columbia: report of 40 cases.

    PubMed Central

    Korzeniewska-Kosela, M; FitzGerald, J M; Vedal, S; Allen, E A; Schechter, M T; Lawson, L; Phillips, P; Black, W; Montaner, J S

    1992-01-01

    OBJECTIVE: To review the clinical features, treatment and outcome of all known cases of tuberculosis in patients with human immunodeficiency virus (HIV) infection in British Columbia between 1984 and 1990. DESIGN: Retrospective case review. SETTING: Provincial tuberculosis registry and university-affiliated HIV clinic. PATIENTS: All people with HIV infection in whom active tuberculosis was diagnosed during the study period. RESULTS: All 40 patients identified were men; their mean age was 38 years. Of the subjects 30 (75%) were homosexual, 6 (15%) were homosexual and used intravenous drugs, 2 (5%) just used intravenous drugs, and 1 (2%) had had heterosexual contact with prostitutes; for the remaining subject the risk factor for HIV infection was not established. In all cases cultures of specimens from 15 body sources yielded Mycobacterium tuberculosis. Thirty-five of the patients had acquired immunodeficiency syndrome (AIDS), and five had HIV infection uncomplicated except for tuberculosis. In 28 (70%) of the cases no AIDS-defining disease had previously been diagnosed, and in 23 (58%) extrapulmonary tuberculosis represented the AIDS-defining disease. Symptoms at presentation included weight loss (in 80% of the cases), fever (in 75%), cough (in 70%) and night sweats (in 55%). The mean CD4 lymphocyte count was 0.2 x 10(9)/L (in 15 cases). Tuberculin skin test results were positive in 8 of 16 cases. The most striking radiologic finding was intrathoracic adenopathy. All except one of the 36 patients who received appropriate treatment responded favourably at first. Adverse reactions necessitating changes in treatment occurred in 12 (33%) of the cases. Relapse occurred after completion of therapy in two cases (one at 3 weeks and the other at 9 months after treatment was stopped). Tuberculosis was the cause of death in five cases. CONCLUSIONS: Tuberculosis in people with HIV infection commonly presents as extrapulmonary disease and precedes or coincides with other AIDS-defining opportunistic infections. In most cases tuberculosis is the AIDS-defining disease. Even though radiologic findings are often unusual physicians should suspect tuberculosis. A careful examination for evidence of disease at multiple sites should be done. The duration and choice of therapy must be adequate to avoid relapse. PMID:1596841

  11. Cyclospora cayetanensis oocysts in sputum of a patient with active pulmonary tuberculosis, case report in Ismailia, Egypt.

    PubMed

    Hussein, Eman M; Abdul-Manaem, Ahmed H; el-Attary, Said L

    2005-12-01

    Observation of acid fast C. cavetanensis oocysts were proved in a sputum sample of a 45 years-old male HIV negative patient who was admitted to Chest Hospital due to loss of weight, cough with expectoration of purulent sputum and dyspnea. The radiological picture suggested active pulmonary tuberculosis (TB). Sputum samples which were positive for acid fast bacilli as proved by Ziehl-Neelsen stain technique showed large (8-10 microm) spherical acid-fast C. cayetanensis oocysts and their identify was confirmed by molecular techniques (Nested PCR). The patient was successfully treated for TB since 4 years. However, this was the second time to report C. cayetanensis oocysts in human sputum. The first one was in Argentina. So, C. cayetanensis is a new respiratory system pathogen which must be considered in the differential diagnosis. PMID:16333888

  12. Increased Interleukin-4 production by CD8 and gammadelta T cells in health-care workers is associated with the subsequent development of active tuberculosis.

    PubMed

    Ordway, Diane J; Costa, Leonor; Martins, Marta; Silveira, Henrique; Amaral, Leonard; Arroz, Maria J; Ventura, Fernando A; Dockrell, Hazel M

    2004-08-15

    We evaluated immune responses to Mycobacterium tuberculosis in 10 health-care workers (HCWs) and 10 non-HCWs and correlated their immune status with the development of active tuberculosis (TB). Twenty individuals were randomly recruited, tested, and monitored longitudinally for TB presentation. Peripheral blood mononuclear cells (PBMCs) from donors were stimulated with M. tuberculosis and tested for cell proliferation and the production of interferon (IFN)- gamma, interleukin (IL)-5, and IL-4, by use of enzyme-linked immunosorbent or flow-cytometric assays. HCWs had higher levels of cell proliferation (24,258 cpm) and IFN- gamma (6373 pg/mL) to M. tuberculosis than did non-HCWs (cell proliferation, 11,462 cpm; IFN- gamma, 3228 pg/mL). Six of 10 HCWs showed increased median percentages of CD8+IL-4+ (4.7%) and gammadelta +IL-4+ (2.3%) T cells and progressed to active TB. HCWs who remained healthy showed increased median percentages of CD8+IFN- gamma+ (25.0%) and gammadelta +IFN- gamma+ (8.0%) and lower percentages of CD8+IL-4+ (0.05%) and gammadelta +IL-4+ (0.03%) T cells. PMID:15272404

  13. Interaction of N-methyl-2-alkenyl-4-quinolones with ATP-dependent MurE ligase of Mycobacterium tuberculosis: antibacterial activity, molecular docking and inhibition kinetics

    PubMed Central

    Guzman, Juan David; Wube, Abraham; Evangelopoulos, Dimitrios; Gupta, Antima; Hüfner, Antje; Basavannacharya, Chandrakala; Rahman, Md. Mukhleshur; Thomaschitz, Christina; Bauer, Rudolf; McHugh, Timothy Daniel; Nobeli, Irene; Prieto, Jose M.; Gibbons, Simon; Bucar, Franz; Bhakta, Sanjib

    2011-01-01

    Objectives The aim of this study was to comprehensively evaluate the antibacterial activity and MurE inhibition of a set of N-methyl-2-alkenyl-4-quinolones found to inhibit the growth of fast-growing mycobacteria. Methods Using the spot culture growth inhibition assay, MICs were determined for Mycobacterium tuberculosis H37Rv, Mycobacterium bovis BCG and Mycobacterium smegmatis mc2155. MICs were determined for Mycobacterium fortuitum, Mycobacterium phlei, methicillin-resistant Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa using microplate dilution assays. Inhibition of M. tuberculosis MurE ligase activity was determined both by colorimetric and HPLC methods. Computational modelling and binding prediction of the quinolones in the MurE structure was performed using Glide. Kinetic experiments were conducted for understanding possible competitive relations of the quinolones with the endogenous substrates of MurE ligase. Results The novel synthetic N-methyl-2-alkenyl-4-quinolones were found to be growth inhibitors of M. tuberculosis and rapid-growing mycobacteria as well as methicillin-resistant S. aureus, while showing no inhibition for E. coli and P. aeruginosa. The quinolones were found to be inhibitory to MurE ligase of M. tuberculosis in the micromolar range (IC50 ?40–200 ?M) when assayed either spectroscopically or by HPLC. Computational docking of the quinolones on the published M. tuberculosis MurE crystal structure suggested that the uracil recognition site is a probable binding site for the quinolones. Conclusions N-methyl-2-alkenyl-4-quinolones are inhibitors of mycobacterial and staphylococcal growth, and show MurE ligase inhibition. Therefore, they are considered as a starting point for the development of increased affinity MurE activity disruptors. PMID:21622974

  14. Indirect Estimates of Jaw Muscle Tension in Children with Suspected Hypertonia, Children with Suspected Hypotonia, and Matched Controls

    ERIC Educational Resources Information Center

    Connaghan, Kathryn P.; Moore, Christopher A.

    2013-01-01

    Purpose: In this study, the authors compared indirect estimates of jaw-muscle tension in children with suspected muscle-tone abnormalities with age- and gender-matched controls. Method: Jaw movement and muscle activation were measured in children (ages 3 years, 11 months, to 10 years) with suspected muscle-tone abnormalities (Down syndrome or…

  15. Mycobacterium tuberculosis Differentially Activates cGAS- and Inflammasome-Dependent Intracellular Immune Responses through ESX-1.

    PubMed

    Wassermann, Ruth; Gulen, Muhammet F; Sala, Claudia; Perin, Sonia Garcia; Lou, Ye; Rybniker, Jan; Schmid-Burgk, Jonathan L; Schmidt, Tobias; Hornung, Veit; Cole, Stewart T; Ablasser, Andrea

    2015-06-10

    Cytosolic detection of microbial products is essential for the initiation of an innate immune response against intracellular pathogens such as Mycobacterium tuberculosis (Mtb). During Mtb infection of macrophages, activation of cytosolic surveillance pathways is dependent on the mycobacterial ESX-1 secretion system and leads to type I interferon (IFN) and interleukin-1? (IL-1?) production. Whereas the inflammasome regulates IL-1? secretion, the receptor(s) responsible for the activation of type I IFNs has remained elusive. We demonstrate that the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) is essential for initiating an IFN response to Mtb infection. cGAS associates with Mtb DNA in the cytosol to stimulate cyclic GAMP (cGAMP) synthesis. Notably, activation of cGAS-dependent cytosolic host responses can be uncoupled from inflammasome activation by modulating the secretion of ESX-1 substrates. Our findings identify cGAS as an innate sensor of Mtb and provide insight into how ESX-1 controls the activation of specific intracellular recognition pathways. PMID:26048138

  16. A Novel Reporter Phage To Detect Tuberculosis and Rifampin Resistance in a High-HIV-Burden Population.

    PubMed

    O'Donnell, Max R; Pym, Alexander; Jain, Paras; Munsamy, Vanisha; Wolf, Allison; Karim, Farina; Jacobs, William R; Larsen, Michelle H

    2015-07-01

    Improved diagnostics and drug susceptibility testing for Mycobacterium tuberculosis are urgently needed. We developed a more powerful mycobacteriophage (?(2)GFP10) with a fluorescent reporter. Fluorescence-activated cell sorting (FACS) allows for rapid enumeration of metabolically active bacilli after phage infection. We compared the reporter phage assay to GeneXpert MTB/RIF for detection of M. tuberculosis and rifampin (RIF) resistance in sputum. Patients suspected to have tuberculosis were prospectively enrolled in Durban, South Africa. Sputum was incubated with ?(2)GFP10, in the presence and absence of RIF, and bacilli were enumerated using FACS. Sensitivity and specificity were compared to those of GeneXpert MTB/RIF with an M. tuberculosis culture as the reference standard. A total of 158 patients were prospectively enrolled. Overall sensitivity for M. tuberculosis was 95.90% (95% confidence interval (CI), 90.69% to 98.64%), and specificity was 83.33% (95% CI, 67.18% to 93.59%). In acid-fast bacillus (AFB)-negative sputum, sensitivity was 88.89% (95% CI, 73.92% to 96.82%), and specificity was 83.33% (95% CI, 67.18% to 93.59%). Sensitivity for RIF-resistant M. tuberculosis in AFB-negative sputum was 90.00% (95% CI, 55.46% to 98.34%), and specificity was 91.94% (95% CI, 82.16% to 97.30%). Compared to GeneXpert, the reporter phage was more sensitive in AFB smear-negative sputum, but specificity was lower. The ?(2)GFP10 reporter phage showed high sensitivity for detection of M. tuberculosis and RIF resistance, including in AFB-negative sputum, and has the potential to improve phenotypic testing for complex drug resistance, paucibacillary sputum, response to treatment, and detection of mixed infection in clinical specimens. PMID:25926493

  17. [Extrapulmonary tuberculosis].

    PubMed

    Ketata, W; Rekik, W K; Ayadi, H; Kammoun, S

    2015-01-01

    Each year, there are more than eight million new cases of tuberculosis and 1.3 million deaths. There is a renewed interest in extrapulmonary forms of tuberculosis as its relative frequency increases. Among extrapulmonary organs, pleura and lymph nodes are the most common. Their diagnosis is often difficult and is based on clinical, radiological, bacteriological and histological findings. Extrapulmonary lesions are paucibacillary and samplings, in most cases, difficult to obtain, so diagnosis is often simply presumptive. Nucleic acid amplification tests, which are fast and specific, have greatly facilitated the diagnosis of some forms of extrapulmonary tuberculosis. However, their sensitivity is poor and a negative test does not eliminate the diagnosis. Treatment is the same as for pulmonary forms, but its duration is nine to 12 months for central nervous system and for bone tuberculosis. Corticosteroids are indicated in meningeal and pericardial localizations. Complementary surgery is used for certain complicated forms. PMID:25131362

  18. [Tuberculosis epidemiology].

    PubMed

    Mjid, M; Cherif, J; Ben Salah, N; Toujani, S; Ouahchi, Y; Zakhama, H; Louzir, B; Mehiri-Ben Rhouma, N; Beji, M

    2015-01-01

    Tuberculosis is a contagious disease caused by Mycobacterium tuberculosis. It represents, according to World Health Organization (WHO), one of the most leading causes of death worldwide. With nearly 8 million new cases each year and more than 1 million deaths per year, tuberculosis is still a public health problem. Despite of the decrease in incidence, morbidity and mortality remain important partially due to co-infection with human immunodeficiency virus and emergence of resistant bacilli. All WHO regions are not uniformly affected by TB. Africa's region has the highest rates of morbidity and mortality. The epidemiological situation is also worrying in Eastern European countries where the proportion of drug-resistant tuberculosis is increasing. These regional disparities emphasize to develop screening, diagnosis and monitoring to the most vulnerable populations. In this context, the Stop TB program, developed by the WHO and its partner's, aims to reduce the burden of disease in accordance with the global targets set for 2015. PMID:25131367

  19. Activated THP1 Cells: an Attractive Model for the Assessment of Intracellular Growth Rates of Mycobacterium tuberculosis Isolates

    Microsoft Academic Search

    S. A. Theus; M. D. Cave; K. D. Eisenach

    2004-01-01

    Virulence of Mycobacterium tuberculosis strains has been traditionally assessed in terms of the ability of organisms to replicate within specific organs of mice and guinea pigs follow- ing aerosol infection. Human monocyte models have been used to examine intracellular growth rates of M. tuberculosis reference strains and clinical isolates to determine if these correlate with virulence as previously defined in

  20. Healthcare Worker Preferences for Active Tuberculosis Case Finding Programs in South Africa: A Best-Worst Scaling Choice Experiment

    PubMed Central

    O’Hara, Nathan N.; Roy, Lilla; O’Hara, Lyndsay M.; Spiegel, Jerry M.; Lynd, Larry D.; FitzGerald, J. Mark; Yassi, Annalee; Nophale, Letshego E.; Marra, Carlo A.

    2015-01-01

    Objective Healthcare workers (HCWs) in South Africa are at a high risk of developing active tuberculosis (TB) due to their occupational exposures. This study aimed to systematically quantify and compare the preferred attributes of an active TB case finding program for HCWs in South Africa. Methods A Best–Worst Scaling choice experiment estimated HCW’s preferences using a random-effects conditional logit model. Latent class analysis (LCA) was used to explore heterogeneity in preferences. Results “No cost”, “the assurance of confidentiality”, “no wait” and testing at the occupational health unit at one’s hospital were the most preferred attributes. LCA identified a four class model with consistent differences in preference strength. Sex, occupation, and the time since a previous TB test were statistically significant predictors of class membership. Conclusions The findings support the strengthening of occupational health units in South Africa to offer free and confidential active TB case finding programs for HCWs with minimal wait times. There is considerable variation in active TB case finding preferences amongst HCWs of different gender, occupation, and testing history. Attention to heterogeneity in preferences should optimize screening utilization of target HCW populations. PMID:26197344

  1. Antibody Profiles Characteristic of Mycobacterium tuberculosis Infection State

    Microsoft Academic Search

    Amy Davidow; Ganga V. Kanaujia; Lanbo Shi; Justin Kaviar; XuDong Guo; Nackmoon Sung; Gilla Kaplan; Dick Menzies; Maria L. Gennaro

    2005-01-01

    The relationship between specific antibody profiles and tuberculosis (TB) state was investigated by mea- suring serum antibody levels to six Mycobacterium tuberculosis antigens in human subjects grouped into four diagnostic categories: active disease, inactive (past) tuberculosis, latent infection without radiographic chest abnormalities, and infection free. Statistical data analyses showed that the latter two groups were serologically indistinguishable and that active

  2. Structure and Proposed Activity of a Member of the VapBC Family of Toxin-Antitoxin Systems: VapBC-5 from Mycobacterium tuberculosis

    SciTech Connect

    Miallau, L.; Faller, M.; Chiang, J.; Arbing, M.; Guo, F.; Cascio, D.; Eisenberg, D.; (UCLA)

    2009-03-02

    In prokaryotes, cognate toxin-antitoxin pairs have long been known, but no three-dimensional structure has been available for any given complex from Mycobacterium tuberculosis. Here we report the crystal structure and activity of a member of the VapBC family of complexes from M. tuberculosis. The toxin VapC-5 is a compact, 150 residues, two domain {alpha}/{beta} protein. Bent around the toxin is the VapB-5 antitoxin, a 33-residue {alpha}-helix. Assays suggest that the toxin is an Mg-enabled endoribonuclease, inhibited by the antitoxin. The lack of DNase activity is consistent with earlier suggestions that the complex represses its own operon. Furthermore, analysis of the interactions in the binding of the antitoxin to the toxin suggest that exquisite control is required to protect the bacteria cell from toxic VapC-5.

  3. Childhood tuberculosis in general practice.

    PubMed

    Kumar, Prawin; Kumar, Amber; Lodha, Rakesh; Kabra, S K

    2015-04-01

    Tuberculosis (TB) in children is a common cause of morbidity. Diagnosis is difficult because of paucibacillary nature of illness and difficulty in obtaining appropriate samples. Children presenting with poor weight gain, fever with or without cough for more than two weeks or contact with an adult in family with pulmonary tuberculosis should be investigated for TB. In all suspected cases of tuberculosis initial investigations include radiograph of chest (CXR) and Mantoux test. If CXR is suggestive of TB, an ambulatory gastric aspirate and induced sputum for acid fast bacilli (AFB) smear may be carried out in two days. Children with AFB positive or abnormal CXR with positive Mantoux test should be started on Antitubercular therapy (ATT). Rest of the patients require more investigations and should be referred to a specialist. All children with newly diagnosed tuberculosis should be treated with 6 mo of ATT (two months with 4 drugs, followed by four months with 2 drugs). Children on ATT should be monitored for improvement in symptoms and weight gain along with side effects of medications. CXR should be done after completion of treatment. PMID:25280927

  4. Renal tuberculosis: a case report

    PubMed Central

    TOCCACELI, S.; STELLA, L. PERSICO; DIANA, M.; TACCONE, A.; GIULIANI, G.; DE PAOLA, L.; VALVANO, M.; DE PADUA, C.; DI BIASIO, G.; RANUCCI, C.; ORSI, E.; LA TORRE, F.

    2015-01-01

    Tuberculosis or TB (tubercle bacillus) remains a major public health problem in developing countries. Over the last decades extra-pulmonary locations of the disease have become more frequent due to the increased prevalence of acquired immune deficiency syndrome and the increase number of organ transplants. The urogenital localization represents about 27% of all extra-pulmonary localizations of TB and may be due either to a disseminated infection or to a primitive genitourinary localization. The majority of patients, has pyuria, sometimes with hematuria. The diagnosis of urinary tuberculosis is based on the finding of pyuria in the absence of infection by common bacteria. The initial medical treatment includes isoniazide, rifampicin, pyrazinami-de, ethambutol and streptomycin. This disease should be suspected in patients with unexplained urinary tract infections, especially if immunocompromised and/or coming from endemic areas. PMID:26017107

  5. Evaluating the efficacy of tuberculosis Advocacy, Communication and Social Mobilization (ACSM) activities in Pakistan: a cross-sectional study

    PubMed Central

    2013-01-01

    Background Tuberculosis (TB) continues to be a major public health and development problem within many low- and middle-income countries. Although Advocacy, Communication and Social Mobilization (ACSM) activities have been undertaken in high TB burden countries to remediate these issues, there is little empirical evidence of the efficacy of these approaches. The purpose of this study was therefore to examine the efficacy of an ACSM program undertaken within Pakistan. Pakistan was chosen because it has received considerable funding for ACSM related activities and is one of 22 high-burden TB countries. Methods The program was evaluated by surveying a stratified random sample of 2,400 participants across 57 districts of Pakistan. Participants were categorized into one of three groups: aware of both media and community ACSM activities (AwareMedia&Community), aware of ACSM media activities only (AwareMedia), or unaware of any ACSM activities (UnawareMedia&Community). Results Independent measures ANCOVA revealed complex differences in knowledge, attitudes, and intended behaviors towards TB between the three groups. In general, UnawareMedia&Community cases had a poorer understanding of TB and its treatment, whilst awareness of ACSM activities was highest among literate and urban dwelling Pakistanis. Preferred sources of TB information were also found to vary by gender, geographic location, and literacy. Conclusions Whilst highlighting improvements in knowledge and attitudes toward TB, the results also provide invaluable insights into areas where further work needs to be done to address deficits in TB understanding, particularly among rural and illiterate Pakistanis. Equally important, the findings have implications for future TB ACSM initiatives in Pakistan in terms of leveraging the preferred media channels of key demographic segments and exploring the degree to which exposure to multiple channels of communication may have an additive effect on health knowledge. PMID:24295034

  6. 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

  7. Critical role of TRIF and MyD88 in Mycobacterium tuberculosis Hsp70-mediated activation of dendritic cells.

    PubMed

    Kim, Tae-Hyoun; Shin, Sung Jae; Park, Yeong-Min; Jung, In Duk; Ryu, Seung-Wook; Kim, Dong-Jae; Park, Jae-Hak; Park, Jong-Hwan

    2015-02-01

    As a potent immune regulator, heat shock protein 70 derived from Mycobacterium tuberculosis (Mtb Hsp70) has adjuvant effect and activates immune cells such as macrophages and dendritic cells (DCs). Although Toll-like receptors (TLRs) are known to involve in DCs activation by Mtb Hsp70, there is still a controversy and the underlying mechanism is not well understood. In this study, we examined whether TRIF and MyD88, the core adaptor molecules for TLRs signaling, regulate Mtb Hsp70-induced DCs activation. Although Mtb Hsp70 produced substantial level of cytokines (IL-6, IL-12p40, and TNF-?) in TRIF-deficient DCs in a dose-dependent manner, each level was significantly lower than that in WT cells. The cytokines production was almost abolished in MyD88-deficient DCs. Consistent with cytokine results, Mtb Hsp70-induced activation of NF-?B and MAPKs was also impaired in both TRIF- and MyD88-deficient DCs, as compared with WT cells. Inhibitor assay revealed that NF-?B, ERK, and JNK, but not p38, regulate Mtb Hsp70-induced production of cytokines. In addition, the up-regulation of co-stimulatory molecules and MHC class II was mostly TRIF-dependent in DCs in response Mtb Hsp70, whereas MyD88 was only partially involved. Finally, mixed leukocytes reaction (MLR) assay revealed that both TRIF and MyD88 are critical for DCs ability promoted by Mtb Hsp70 to differentiate naïve T cells into effector T cells of producing IFN-?. Our findings suggest that both TRIF and MyD88 are essential for the activation and maturation of DCs in response to Mtb Hsp70. PMID:25461391

  8. Facing multi-drug resistant tuberculosis.

    PubMed

    Sotgiu, Giovanni; Migliori, Giovanni Battista

    2015-06-01

    Multi-drug resistant tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis strains resistant to at least two of the most effective anti-tuberculosis drugs (i.e., isoniazid and rifampicin). Therapeutic regimens based on second- and third-line anti-tuberculosis medicines showed poor efficacy, safety, and tolerability profiles. It was estimated that in 2012 the multi-drug resistant tuberculosis incidence ranged from 300,000 to 600,000 cases, mainly diagnosed in the Eastern European and Central Asian countries. The highest proportion of cases is among individuals previously exposed to anti-tuberculosis drugs. Three main conditions can favour the emergence and spread of multi-drug resistant tuberculosis: the poor implementation of the DOTS strategy, the shortage or the poor quality of the anti-tuberculosis drugs, and the poor therapeutic adherence of the patients to the prescribed regimens. Consultation with tuberculosis experts (e.g., consilium) is crucial to tailor the best anti-tuberculosis therapy. New therapeutic options are necessary: bedaquiline and delamanid seem promising drugs; in particular, during the development phase they demonstrated a protective effect against the emergence of further resistances towards the backbone drugs. In the recent past, other antibiotics have been administered off-label: the most relevant efficacy, safety, and tolerability profile was proved in linezolid-, meropenem/clavulanate-, cotrimoxazole-containing regimens. New research and development activities are needed in the diagnostic, therapeutic, preventive fields. PMID:24792579

  9. Role of Mitogen-Activated Protein Kinase Pathways in the Production of Tumor Necrosis Factor-?, Interleukin10, and Monocyte Chemotactic Protein1 by Mycobacterium tuberculosis H37Rv-Infected Human Monocytes

    Microsoft Academic Search

    Chang-Hwa Song; Ji-Sook Lee; So-Hyun Lee; Kyu Lim; Hwa-Jung Kim; Jeong-Kyu Park; Tae-Hyun Paik; Eun-Kyeong Jo

    2003-01-01

    The role of mitogen-activated protein kinase (MAPK) pathways in the secretion of tumor necrosis factor (TNF)-a, interleukin (IL)-10, IL-8, and monocyte chemotactic protein-1 (MCP-1) was investigated in human monocytes that were infected with Mycobacterium tuberculosis H37Rv. Analysis of extracellular signal-regulated kinases 1 and 2 (ERK1\\/2) and p38 kinase showed rapid phosphorylation of both subfamilies in response to M. tuberculosis H37Rv.

  10. Synthesis, anti-tuberculosis activity, and 3D-QSAR study of ring-substituted-2\\/4-quinolinecarbaldehyde derivatives

    Microsoft Academic Search

    Amit Nayyar; Alpeshkumar Malde; Evans Coutinho; Rahul Jain

    2006-01-01

    We have previously identified ring-substituted quinolines as a new structural class of anti-tuberculosis agents. In our ongoing efforts at structural optimization of this class, four series of ring-substituted-2\\/4-quinolinecarbaldehyde derivatives were synthesized. All twenty-four compounds were synthesized using short and convenient one to two high yielding steps. The newly synthesized compounds were tested in vitro against drug-sensitive Mycobacterium tuberculosis H37Hv strain.

  11. Contribution of the nitroimidazoles PA-824 and TBA-354 to the activity of novel regimens in murine models of tuberculosis.

    PubMed

    Tasneen, Rokeya; Williams, Kathy; Amoabeng, Opokua; Minkowski, Austin; Mdluli, Khisimuzi E; Upton, Anna M; Nuermberger, Eric L

    2015-01-01

    New regimens based on two or more novel agents are sought in order to shorten or simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. PA-824 is a nitroimidazo-oxazine now in phase II trials and has shown significant early bactericidal activity alone and in combination with the newly approved agent bedaquiline or with pyrazinamide with or without moxifloxacin. While the development of PA-824 continues, a potential next-generation derivative, TBA-354, has been discovered to have in vitro potency superior to that of PA-824 and greater metabolic stability than that of the other nitroimidazole derivative in clinical development, delamanid. In the present study, we compared the activities of PA-824 and TBA-354 as monotherapies in murine models of the initial intensive and continuation phases of treatment, as well as in combination with bedaquiline plus pyrazinamide, sutezolid, and/or clofazimine. The monotherapy studies demonstrated that TBA-354 is 5 to 10 times more potent than PA-824, but selected mutants are cross-resistant to PA-824 and delamanid. The combination studies revealed that TBA-354 is 2 to 4 times more potent than PA-824 when combined with bedaquiline, and when administered at a dose equivalent to that of PA-824, TBA-354 demonstrated superior sterilizing efficacy. Perhaps most importantly, the addition of either nitroimidazole significantly improved the sterilizing activities of bedaquiline and sutezolid, with or without pyrazinamide, confirming the value of each agent in this potentially universally active short-course regimen. PMID:25331697

  12. Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis.

    PubMed

    Lisa, María-Natalia; Gil, Magdalena; André-Leroux, Gwénaëlle; Barilone, Nathalie; Durán, Rosario; Biondi, Ricardo M; Alzari, Pedro M

    2015-06-01

    Tuberculosis remains one of the world's deadliest human diseases, with a high prevalence of antibiotic-resistant Mycobacterium tuberculosis (Mtb) strains. A molecular understanding of processes underlying regulation and adaptation of bacterial physiology may provide novel avenues for the development of antibiotics with unconventional modes of action. Here, we focus on the multidomain S/T protein kinase PknG, a soluble enzyme that controls central metabolism in Actinobacteria and has been linked to Mtb infectivity. Our biochemical and structural studies reveal how different motifs and domains flanking the catalytic core regulate substrate selectivity without significantly affecting the intrinsic kinase activity, whereas a rubredoxin-like domain is shown to downregulate catalysis through specific intramolecular interactions that modulate access to a profound substrate-binding site. Our findings provide the basis for the selective and specific inhibition of PknG, and open new questions about regulation of related bacterial and eukaryotic protein kinases. PMID:25960409

  13. [Change in the survival of Cuban AIDS patients with tuberculosis in the Highly Active Antiretroviral Therapy (HAART) era].

    PubMed

    Reyes-Corcho, Andrés; Capo de Paz, Virginia; Díaz-Jidy, Manuel; Pérez-Avila, Jorge; Bouza-Jiménez, Yadira

    2008-09-01

    HIV infection affected 0.06% of the Cuban population and AIDS associated tuberculosis (TB) represented 4.4% of cases in 2004. The objective of this study was to determine the survival of AIDS patients with TB. 167 individuals of both sexes and ages between 15 and 60 years old were studied; all of them were diagnosed in the Havana's Tropical Medicine Institute "Pedro Kourí", Cuba, between January 1st 1997 and May 31st 2005. The Kaplan-Meier's method and the Long-rank test were used for the survival, and the Cox's multivariate method to identify the variables associated with mortality by means of SPSS 9.0. 78 individuals of the total died at the end of study, 71.8% belonged to the pre highly active antiretroviral therapy (HAART) era and 28.2% to the later period. From all deceased cases due to TB, 82.1% were diagnosed in the pre HAART era. The median survival was 41 months (CI=20-62). TB diagnosis in the pre HAART period, TB not being the first disease indicator of AIDS, suffering from candidiasis of esophagus before TB and a LTCD4+ count < 200 at the diagnosis of TB, were all independently associated with mortality. This study demonstrated the positive impact of HAART in the survival of Cuban AIDS patients with TB and also identified advanced immunodepression and opportunistic infections as predictors of mortality. PMID:18846772

  14. Prime Suspect, Second Row Center

    ERIC Educational Resources Information Center

    Laird, Ellen A.

    2011-01-01

    His father had been hacked to death in his own bed with an ax the previous November. His mother was similarly brutalized and left for dead with her husband but survived. On the last Monday of that August, after several months and many investigative twists, turns, and fumbles, there sat the son--the prime suspect--in Ellen Laird's literature class,…

  15. Chest tuberculosis with mediastinal asymptomatic lymphadenitis without lung involvement in an immunocompetent patient.

    PubMed

    Pirina, Pietro; Spada, Valentina; Santoru, Luigi; Polo, Maria Francesca; Molicotti, Paola; Marras, Vincenzo; Cossu Rocca, Paolo; Canu, Sara; Zanetti, Stefania; Fois, Alessandro Giuseppe

    2013-03-01

    Tuberculosis remains the major cause of morbidity and mortality by a single infectious agent, particularly in developing countries. In recent years, we have witnessed the emergence of uncommon radiographic patterns of chest tuberculosis. Lymphadenitis is the most common extrapulmonary tuberculosis (TB) manifestation which, in developed countries, occurs more frequently in childhood, but also among adult immigrants from endemic countries and in HIV-infected people. Isolated and asymptomatic mediastinal lymphadenitis is uncommon in immunocompetent adults. We report a case of a young adult man from Senegal affected by sovraclavear and mediastinal TB lymphadenitis, which contains some uncommon elements: no compromised immunity, especially no HIV-infection, no lung lesions, no symptoms of infection or of mediastinum involvement, and rapid response to therapy in terms of mass size reduction. Examination of extra-thoracic lymph nodes and the patient's characteristics guided our diagnostic process to suspect TB. Surgical biopsy and subsequent histopathological and microbiological examinations of lymph material, first by Lowestein-Jensen and BACTEC cultures that remain the gold standard of diagnosis, confirmed the diagnosis. Chest X-ray was inconclusive; however, CT played an important role in the diagnostic course and in the management of the patient, particularly in determining disease activity, offering mediastinum and parenchymal details, as well as in identifying typical features of tuberculous lymph nodes and also of active/non active disease. Six months of antimycobacterial regimen is the recommended treatment in TB lymphadenitis of HIV-negative adults. PMID:23493008

  16. Urinary tuberculosis

    PubMed Central

    Riddle, P. R.

    1971-01-01

    The present incidence, clinical features and classification of urinary tuberculosis are discussed. Chemotherapy is the mainstay of treatment. The indications for surgical intervention are reviewed and procedures briefly described. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5 PMID:5169185

  17. Qualitative Evaluation of a Text Messaging Intervention to Support Patients With Active Tuberculosis: Implementation Considerations

    PubMed Central

    Sward, Katherine A; Beck, Susan L; Pearce, Patricia F; Thurston, Diana; Chirico, Cristina

    2015-01-01

    Background Tuberculosis (TB) remains a major global public health problem and mobile health (mHealth) interventions have been identified as a modality to improve TB outcomes. TextTB, an interactive text-based intervention to promote adherence with TB medication, was pilot-tested in Argentina with results supporting the implementation of trials at a larger scale. Objective The objective of this research was to understand issues encountered during pilot-testing in order to inform future implementation in a larger-scale trial. Methods A descriptive, observational qualitative design guided by a sociotechnical framework was used. The setting was a clinic within a public pulmonary-specialized hospital in Argentina. Data were collected through workflow observation over 115 days, text messages (n=2286), review of the study log, and stakeholder input. Emerging issues were categorized as organizational, human, technical, or sociotechnical considerations. Results Issues related to the intervention included workflow issues (eg, human, training, security), technical challenges (eg, data errors, platform shortcomings), and message delivery issues (eg, unintentional sending of multiple messages, auto-confirmation problems). System/contextual issues included variable mobile network coverage, electrical and Internet outages, and medication shortages. Conclusions Intervention challenges were largely manageable during pilot-testing, but need to be addressed systematically before proceeding with a larger-scale trial. Potential solutions are outlined. Findings may help others considering implementing an mHealth intervention to anticipate and mitigate certain challenges. Although some of the issues may be context dependent, other issues such as electrical/Internet outages and limited resources are not unique issues to our setting. Release of new software versions did not result in solutions for certain issues, as specific features used were removed. Therefore, other software options will need to be considered before expanding into a larger-scale endeavor. Improved automation of some features will be necessary, however, a goal will be to retain the intervention capability to be interactive, user friendly, and patient focused. Continued collaboration with stakeholders will be required to conduct further research and to understand how such an mHealth intervention can be effectively integrated into larger health systems. PMID:25802968

  18. A species-specific nucleotide sequence of Mycobacterium tuberculosis encodes a protein that exhibits hemolytic activity when expressed in Escherichia coli.

    PubMed Central

    Leão, S C; Rocha, C L; Murillo, L A; Parra, C A; Patarroyo, M E

    1995-01-01

    Species-specific proteins may be implicated in the unique pathogenic mechanisms characteristic of Mycobacterium tuberculosis. In previous studies, a 3.0-kb species-specific DNA fragment of M. tuberculosis was identified (C. A. Parra, L. P. Londoño, P. del Portillo, and M. E. Patarroyo, Immun. 59:3411-3417, 1991). The nucleotide sequence of this 3.0-kb fragment has been obtained. This sequence was shown to contain two open reading frames (ORFs) whose putative gene products share 68.9% identity between each other. The major ORF shows 57.8% similarity with PLC-N and 53.2% similarity with PLC-H, two phospholipase C enzymes from Pseudomonas aeruginosa. The major ORF was amplified by PCR and cloned into the pGEX-5T expression vector. Cell extracts of Escherichia coli overexpressing this glutathione S-transferase fusion protein were shown to produce beta-hemolysis suggestive of phospholipase activity. Since phospholipase C enzymes have been reported as virulence factors of P. aeruginosa and also of the intracellular pathogen Listeria monocytogenes, it is possible that the proteins identified in this study could also play a role in sustaining tuberculosis infection in humans. PMID:7591062

  19. Gold(I) Analogues of a Platinum–Acridine Antitumor Agent are only Moderately Cytotoxic but Show Potent Activity Against Mycobacterium Tuberculosis

    PubMed Central

    Eiter, Lauren C.; Hall, Nathan W.; Day, Cynthia S.; Saluta, Gilda; Kucera, Gregory L.; Bierbach, Ulrich

    2011-01-01

    A series of cationic gold(I) complexes containing 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea (1), [AuL(1)]n+ (where L is Cl?, Br-, SCN?, PEt3, PPh3, or 1), derived from a class of analogous platinum(II) antitumor agents, has been synthesized. Unlike platinum, gold does not form permanent adducts with DNA, and its complexes are two orders of magnitude less cytotoxic in non-small-cell lung cancer cells than the most active platinum-based agent. Instead, several gold analogues show submicromolar and selective antimicrobial activity against Mycobacterium tuberculosis. PMID:19803526

  20. Immunodiagnosis of tuberculosis: An update.

    PubMed

    Bhatia, A S; Kumar, Satish; Harinath, B C

    2003-07-01

    Tuberculosis is still a major health problem in most developing countries and its incidence is rising in many developed countries. This resurgence has been attributed to the HIV epidemic and TB has been declared as a global health emergency by WHO in 1993. The diagnosis of tuberculosis mainly depends upon initial clinical suspicion and radiographic findings with subsequent bacteriological confirmation by sputum smear examination and culture. Lack of sensitivity in smear examination, non specificity of radiological findings, extended tum around time ofMycobacterium tuberculosis culture and difficulties in diagnosing paucibacillary, childhood and extrapulmonary tuberculosis has necessitated to explore the utility of immunodiagnosis of tuberculosis as a convenient and cost effective test to supplement clinical information for definite diagnosis. Many commercial tests are available in the market for diagnosis of TB. Most of these tests are based on the detection of IgG, IgA and IgM antibodies to specific mycobacterial antigen or mixture of antigens. Indigenous immunoassay systems have explored excretory-secretory ES-31 mycobacterial antigen for immunodiagnosis of TB. Many a time there is lack of consistent elevation in all the three Ig classes in active infection thus making it more important to determine the ideal antibody isotype assay for reliable diagnosis of tuberculosis and to save the costs of the patient for unnecessary investigations. PMID:23105384

  1. High Extracellular Levels of Mycobacterium tuberculosis Glutamine Synthetase and Superoxide Dismutase in Actively Growing Cultures Are Due to High Expression and Extracellular Stability Rather than to a Protein-Specific Export Mechanism

    PubMed Central

    Tullius, Michael V.; Harth, Günter; Horwitz, Marcus A.

    2001-01-01

    Glutamine synthetase (GS) and superoxide dismutase (SOD), large multimeric enzymes that are thought to play important roles in the pathogenicity of Mycobacterium tuberculosis, are among the bacterium's major culture filtrate proteins in actively growing cultures. Although these proteins lack a leader peptide, their presence in the extracellular medium during early stages of growth suggested that they might be actively secreted. To understand their mechanism of export, we cloned the homologous genes (glnA1 and sodA) from the rapid-growing, nonpathogenic Mycobacterium smegmatis, generated glnA1 and sodA mutants of M. smegmatis by allelic exchange, and quantitated expression and export of both mycobacterial and nonmycobacterial GSs and SODs in these mutants. We also quantitated expression and export of homologous and heterologous SODs from M. tuberculosis. When each of the genes was expressed from a multicopy plasmid, M. smegmatis exported comparable proportions of both the M. tuberculosis and M. smegmatis GSs (in the glnA1 strain) or SODs (in the sodA strain), in contrast to previous observations in wild-type strains. Surprisingly, recombinant M. smegmatis and M. tuberculosis strains even exported nonmycobacterial SODs. To determine the extent to which export of these large, leaderless proteins is expression dependent, we constructed a recombinant M. tuberculosis strain expressing green fluorescent protein (GFP) at high levels and a recombinant M. smegmatis strain coexpressing the M. smegmatis GS, M. smegmatis SOD, and M. tuberculosis BfrB (bacterioferritin) at high levels. The recombinant M. tuberculosis strain exported GFP even in early stages of growth and at proportions very similar to those of the endogenous M. tuberculosis GS and SOD. Similarly, the recombinant M. smegmatis strain exported bacterioferritin, a large (?500-kDa), leaderless, multimeric protein, in proportions comparable to GS and SOD. In contrast, high-level expression of the large, leaderless, multimeric protein malate dehydrogenase did not lead to extracellular accumulation because the protein was highly unstable extracellularly. These findings indicate that, contrary to expectations, export of M. tuberculosis GS and SOD in actively growing cultures is not due to a protein-specific export mechanism, but rather to bacterial leakage or autolysis, and that the extracellular abundance of these enzymes is simply due to their high level of expression and extracellular stability. The same determinants likely explain the presence of other leaderless proteins in the extracellular medium of actively growing M. tuberculosis cultures. PMID:11553579

  2. Contact Investigation in Households of Patients with Tuberculosis in Hanoi, Vietnam: A Prospective Cohort Study

    PubMed Central

    Fox, Gregory James; Nhung, Nguyen Viet; Sy, Dinh Ngoc; Lien, Luu Thi; Cuong, Nguyen Kim; Britton, Warwick John; Marks, Guy Barrington

    2012-01-01

    Setting Existing tuberculosis control strategies in Vietnam are based on symptomatic patients attending health services for investigation. This approach has not resulted in substantial reductions in the prevalence of tuberculosis disease, despite the National Tuberculosis Program achieving high treatment completion rates. Alternative approaches are being considered. Objective To determine the feasibility and yield of contact investigation in households of patients with smear positive pulmonary tuberculosis among household members of tuberculosis patients in Hanoi, Vietnam. Methods Household contacts of patients with smear positive pulmonary tuberculosis were recruited at four urban and rural District Tuberculosis Units in Hanoi. Clinical and radiological screening was conducted at baseline, six months and 12 months. Sputum microscopy and culture was performed in contacts suspected of having tuberculosis. MIRU-VNTR molecular testing was used to compare the strains of patients and their contacts with disease. Results Among 545 household contacts of 212 patients, four were diagnosed with tuberculosis at baseline (prevalence 734 cases per 100,000 persons, 95% CI 17–1451) and one was diagnosed with tuberculosis during the subsequent 12 months after initial screening (incidence 180 cases per 100,000 person-years, 95% CI 44–131). Two of these cases were culture positive for M. tuberculosis and both had identical or near-identical MIRU-VNTR strain types. Conclusion Household contacts of patients with potentially infectious forms of tuberculosis have a high prevalence of disease. Household contact investigation is feasible in Vietnam. Further research is required to investigate its effectiveness. PMID:23166785

  3. Thiolates Chemically Induce Redox Activation of BTZ043 and Related Potent Nitro Aromatic Anti-Tuberculosis Agents

    PubMed Central

    Tiwari, Rohit; Moraski, Garrett C.; Krch?ák, Viktor; Miller, Patricia A.; Colon-Martinez, Mariangelli; Herrero, Eliza; Oliver, Allen G.; Miller, Marvin J.

    2013-01-01

    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. Nitro aromatic 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-?-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 nitro aromatic compounds synthesized by us and the others confirmed the postulated reactivity. The results indicate that nucleophiles such as thiolates, cyanide and hydride induce non-enzymatic 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 hypotheses for the mechanism of action of nitro aromatic 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

  4. Nocardia Co-Infection in Patients With Pulmonary Tuberculosis

    PubMed Central

    Ekrami, Alireza; Khosravi, Azar Dokht; Samarbaf Zadeh, Ali Reza; Hashemzadeh, Mohammad

    2014-01-01

    Background: Tuberculosis (TB) remains as one of the most serious infectious diseases in the world. Pulmonary tuberculosis can occur with other pulmonary diseases caused by opportunistic organisms such as Nocardia spp. particularly in immunocompromised patients. Therefore, diagnosis of co-infection at the early stage of the disease could be lifesaving. Objectives: The goal of this study was to detect Mycobacterium tuberculosis and Nocardia spp. in sputum specimens in order to assess the concomitant nocardiosis and tuberculosis in patients with suspected pulmonary tuberculosis. Patients and Methods: From March 2011 to April 2012, 189 sputum specimens were obtained from patients who were suspected of having pulmonary tuberculosis. Out of 189 samples, 32 of the samples belonged to hospitalized HIV-infected patients. Samples were examined by Gram and Ziehl-Nelsen staining, culture and PCR methods. Results: From 157 sputum specimens, positive samples by acid fast staining, culture and PCR for M. tuberculosis were reported for 7.6% (12/157), 10.1% (16/157) and 7% (11/157) of samples, respectively. No results were obtained by the described methods for Nocardia spp. Among 32 samples of HIV-infected patients, four (12.5%) had positive results for acid fast staining, culture and PCR detecting M. tuberculosis while only two samples had positive results for Nocardia spp. by PCR and no results were reported by culture, Gram and acid fast staining for this organism. Conclusions: Concurrent pulmonary nocardiosis and tuberculosis is frequent in HIV-infected patients. Rapid and sensitive methods such as PCR are recommended for detection of such co-infections. PMID:25741428

  5. Identification of CD244-expressing myeloid-derived suppressor cells in patients with active tuberculosis.

    PubMed

    Yang, Bingfen; Wang, Xinjing; Jiang, Jing; Zhai, Fei; Cheng, Xiaoxing

    2014-01-01

    Development of active TB is accompanied by immune suppression and the underlining mechanisms have been explored extensively in recent years. MDSCs are a heterogeneous group of immature and progenitor myeloid cells with strong immunosuppressive ability for both natural and adaptive immunity. In our analysis of CD244 (2B4)-expressing cells in PBMCs from patients with active TB, a CD3(-)CD244(high) subpopulation was identified. A match of cell population in flow cytometry showed that nearly all CD3(-)CD244(high) cells were CD3(-)HLA-DR(-)CD11b(int)CD33(+) cells. The CD3(-)CD244(high) cell population has phenotypes of CD3(-)CD19(-)CD56(-)CD15(-)CD66b(-)CD33(+)CD11b(+)CD14(-)HLA-DR(neg/low), which was consistent with MDSCs in humans as previously reported. Patients with active TB had higher frequencies of CD3(-)CD244(high) cells as compared with healthy controls. The CD3(-)CD244(high) cell population had high levels of NOS2 expression and was negatively correlated with activation and effective molecule production of CD4(+) and CD8(+) T cells. In conclusion, CD3(-)CD244(high) cells had phenotypes of MDSCs and CD244 might be used as a marker for human CD3(-)HLA-DR(-)CD11b(int)CD33(+) MDSCs. PMID:24333340

  6. High Utility of Contact Investigation for Latent and Active Tuberculosis Case Detection among the Contacts: A Retrospective Cohort Study in Tbilisi, Georgia, 2010–2011

    PubMed Central

    Chakhaia, Tsira; Magee, Matthew J.; Kempker, Russell R.; Gegia, Medea; Goginashvili, Leila; Nanava, Ucha; Blumberg, Henry M.

    2014-01-01

    Setting The study was conducted at the National Center for Tuberculosis and Lung Diseases (NCTBLD) in Tbilisi, Georgia. Objective To assess the utility of contact investigation for tuberculosis (TB) case detection. We also assessed the prevalence and risk factors for active TB disease and latent TB infection (LTBI) among contacts of active pulmonary TB cases. Design A retrospective cohort study was conducted among the contacts of active pulmonary TB cases registered in 2010–2011 at the NCTBLD in Tbilisi, Georgia. Contacts of active TB patients were investigated according to an “invitation model”: they were referred to the NCTBLD by the index case; were queried about clinical symptoms suggestive of active TB disease; tuberculin skin testing and chest radiographs were performed. Demographic, laboratory, and clinical data of TB patients and their contacts were abstracted from existing records up to February 2013. Results 869 contacts of 396 index cases were enrolled in the study; a median of 2 contacts were referred per index case. Among the 869 contacts, 47 (5.4%) were found to have or developed active TB disease: 30 (63.8%) were diagnosed with TB during the baseline period (co-prevalent cases) and 17 (36.2%) developed active TB disease during the follow-up period (mean follow up of 21 months) (incident TB cases). The incidence rate of active TB disease among contacts was 1126.0 per 100 000 person years (95% CI 655.7–1802.0 per 100,000 person-years). Among the 402 contacts who had a tuberculin skin test (TST) performed, 52.7% (95% CI 47.7–57.7%) had LTBI. Conclusions A high prevalence of LTBI and active TB disease was found among the contacts of TB cases in Tbilisi, Georgia. Our findings demonstrated that an “invitation” model of contact investigation was an effective method of case detection. Therefore, contact investigation should be scaled up in Georgia. PMID:25379809

  7. IL-4R?-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 ? on macrophages (LysMcreIL-4R?-/lox) with Mtb. We show that absence of IL-4R? 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-4R?-/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-4R? driven pathway. Together, these results suggest that IL-4R?-macrophages do not play a central role in TB disease progression. PMID:25790379

  8. Identification, Activity and Disulfide Connectivity of C-di-GMP Regulating Proteins in Mycobacterium tuberculosis

    Microsoft Academic Search

    Kajal Gupta; Prasun Kumar; Dipankar Chatterji; Niyaz Ahmed

    2010-01-01

    C-di-GMP, a bacterial second messenger plays a key role in survival and adaptation of bacteria under different environmental conditions. The level of c-di-GMP is regulated by two opposing activities, namely diguanylate cyclase (DGC) and phosphodiesterase (PDE-A) exhibited by GGDEF and EAL domain, respectively in the same protein. Previously, we reported a bifunctional GGDEF–EAL domain protein, MSDGC-1 from Mycobacterium smegmatis showing

  9. Photometry of 50 suspected variable stars

    SciTech Connect

    Hooten, J.T.; Hall, D.S. (Dyer Observatory, Nashville, TN (USA))

    1990-09-01

    Fifty stars have been chosen as suspected variable stars and analyzed for variability. A large portion of this sample are stars that are either proved active chromosphere stars or are candidates for such activity. The photometric data base consists of differential V measurements of the Vanderbilt 16 inch (41 cm) automatic photoelectric telescope and 25 observers at 26 observatories worldwide. Published photometric data have also been utilized, with proper adjustments made to ensure that all magnitudes are differential. Searches for photometric period, amplitudes, and times of minimum light showed 68 percent of the sample to be photometrically variable with periods found for 34. Two stars were deemed norvariable for the period of observation. Conclusive statements could not be made concerning the photometric variability of the 14 remaining stars. 81 refs.

  10. Photometry of 50 suspected variable stars

    NASA Technical Reports Server (NTRS)

    Hooten, James T.; Hall, Douglas S.

    1990-01-01

    Fifty stars have been chosen as suspected variable stars and analyzed for variability. A large portion of this sample are stars that are either proved active chromosphere stars or are candidates for such activity. The photometric data base consists of differential V measurements of the Vanderbilt 16 inch (41 cm) automatic photoelectric telescope and 25 observers at 26 observatories worldwide. Published photometric data have also been utilized, with proper adjustments made to ensure that all magnitudes are differential. Searches for photometric period, amplitudes, and times of minimum light showed 68 percent of the sample to be photometrically variable with periods found for 34. Two stars were deemed norvariable for the period of observation. Conclusive statements could not be made concerning the photometric variability of the 14 remaining stars.

  11. Abdominal tuberculosis.

    PubMed Central

    Ahmed, M. E.; Hassan, M. A.

    1994-01-01

    The abdomen is involved in 10% to 30% of patients with pulmonary tuberculosis. The diagnosis is not difficult in societies where the disease is common and clinicians are aware of it. While previously rare in Western countries, the incidence is now rising among immigrants, and patients with AIDS. In HIV-infected patients, the disease is of a rapidly progressive nature, often fatal through usually treatable, but the diagnosis is difficult and often delayed. Treatment is essentially medical but occasionally surgical operation is necessary. PMID:8154817

  12. Surgical management of renal tuberculosis

    PubMed Central

    Krishnamoorthy, Sriram; Gopalakrishnan, Ganesh

    2008-01-01

    Tuberculosis (TB) is one of the major health problems that our country is facing today. Despite active interventions by our government, control of TB still remains to be achieved. The emergence and exponential growth of the human immunodeficiency virus and drug-resistant strains threaten to further complicate the TB situation in our country. Even in this era of advanced chemotherapy, many lives are lost every day in our country. Tuberculosis of the urinary tract, despite being one of the commonest forms of extra-pulmonary TB, is generally overlooked. Most patients present with vague lower urinary symptoms typical of urinary tract infection. In this article, we shall highlight the various issues related to the surgical management of renal and ureteral tuberculosis. PMID:19468471

  13. Substituted benzyl-pyrimidines targeting thymidine monophosphate kinase of Mycobacterium tuberculosis: Synthesis and in vitro anti-mycobacterial activity

    Microsoft Academic Search

    Cécile Gasse; Dominique Douguet; Valérie Huteau; Gilles Marchal; Hélène Munier-Lehmann; Sylvie Pochet

    2008-01-01

    A series of N1-(4-substituted-benzyl)-pyrimidines were synthesized as potential inhibitors of thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt). Key SAR parameters included the chain length substitution in para position of the benzyl ring, the functional group terminating the alkyl chain, and the substituent on the C-5 pyrimidine ring. Synthesized molecules were assayed against both recombinant enzyme and mycobacteria cultures. The most

  14. Expression and purification of a functionally active recombinant GDP-mannosyltransferase (PimA) from Mycobacterium tuberculosis H37Rv

    Microsoft Academic Search

    Xiaoling Gu; Mao Chen; Qingzhong Wang; Min Zhang; Baolin Wang; Honghai Wang

    2005-01-01

    Lipoarabinomannans (LAM), especially mannose-capped LAM, abundant in the cell wall of Mycobacterium tuberculosis (Mtb) exhibit a broad spectrum of immunomodulatory functions and emerge as key virulence factors that may be relevant drug targets. The pimA gene of mycobacteria encodes a ?-mannosyltransferase involved in the transfer reaction of the very first mannose from GDP–mannose to the carrier lipid phosphatidyl-myo-inositol, a precursor

  15. Activation of the eis gene in a W-Beijing strain of Mycobacterium tuberculosis correlates with increased SigA levels and enhanced intracellular growth.

    PubMed

    Wu, Shiping; Barnes, Peter F; Samten, Buka; Pang, Xiuhua; Rodrigue, Sébastien; Ghanny, Saleena; Soteropoulos, Patricia; Gaudreau, Luc; Howard, Susan T

    2009-04-01

    There is growing evidence that strains of Mycobacterium tuberculosis differ in pathogenicity and transmissibility, but little is understood about the contributory factors. We have previously shown that increased expression of the principal sigma factor, SigA, mediates the capacity of M. tuberculosis strain 210 to grow more rapidly in human monocytes, compared with other strains. Strain 210 is part of the widespread W-Beijing family of M. tuberculosis strains and includes clinical isolate TB294. To identify genes that respond to changes in SigA levels and that might enhance intracellular growth, we examined RNA and protein expression patterns in TB294-pSigA, a recombinant strain of TB294 that overexpresses sigA from a multicopy plasmid. Lysates from broth-grown cultures of TB294-pSigA contained high levels of Eis, a protein known to modulate host-pathogen interactions. DNA microarray analysis indicated that the eis gene, Rv2416c, was expressed at levels in TB294-pSigA 40-fold higher than in the vector control strain TB294-pCV, during growth in the human monocyte cell line MonoMac6. Other genes with elevated expression in TB294-pSigA showed much smaller changes from TB294-pCV, and the majority of genes with expression differences between the two strains had reduced expression in TB294-pSigA, including an unexpected number of genes associated with the DNA-damage response. Real-time PCR analyses confirmed that eis was expressed at very high levels in TB294-pSigA in monocytes as well as in broth culture, and further revealed that, like sigA, eis was also more highly expressed in wild-type TB294 than in the laboratory strain H37Rv, during growth in monocytes. These findings suggested an association between increased SigA levels and eis activation, and results of chromatin immunoprecipitation confirmed that SigA binds the eis promoter in live TB294 cells. Deletion of eis reduced growth of TB294 in monocytes, and complementation of eis reversed this effect. We conclude that SigA regulates eis, that there is a direct correlation between upregulation of SigA and high expression levels of eis, and that eis contributes to the enhanced capacity of a clinical isolate of M. tuberculosis strain 210 to grow in monocytes. PMID:19332828

  16. [The comparative value of quantiferonic test, neopterin and specific anti-tuberculosis antibodies in clinical diagnostic of tuberculosis of lungs].

    PubMed

    Vasiliyeva, Ye V; Lapin, S V; Blinova, T V; Nikitina, I Yu; Liyadova, I V; Verbov, V N; Totolyan, A A

    2013-05-01

    The article deals with comparison of clinical diagnostic value of laboratory techniques of tuberculosis. The sample included 63 patients with tuberculosis of lungs. 49 persons of long-time contact with patients with tuberculosis and 28 healthy donors. The QuantiFERON-TB Gold In-Tube test was applied to total sampling. The content of neopterin and specific anti-tuberculosis antibodies in blood plasma was determined. According study data, the mentioned test is mostly informative for detection of tuberculosis contamination (sensitivity 64%, specificity 89%). However, the obvious shortcoming of this technique is the fact that it can't provide the differentiation between active and latent tuberculosis infection. As opposed to QuantiFERON-TB Gold In-Tube test, the detection of specific anti-tuberculosis antibodies (sensitivity 54%, specificity 94%) and neopterin (sensitivity 51%, specificity 92%) makes it possible to differentiate these two groups of patients. PMID:24006641

  17. Mycobacterium tuberculosis Serine/Threonine Protein Kinases

    PubMed Central

    PRISIC, SLADJANA; HUSSON, ROBERT N.

    2014-01-01

    The Mycobacterium tuberculosis genome encodes 11 serine/threonine protein kinases (STPKs). A similar number of two-component systems are also present, indicating that these two signal transduction mechanisms are both important in the adaptation of this bacterial pathogen to its environment. The M. tuberculosis phosphoproteome includes hundreds of Ser- and Thr-phosphorylated proteins that participate in all aspects of M. tuberculosis biology, supporting a critical role for the STPKs in regulating M. tuberculosis physiology. Nine of the STPKs are receptor type kinases, with an extracytoplasmic sensor domain and an intracellular kinase domain, indicating that these kinases transduce external signals. Two other STPKs are cytoplasmic and have regulatory domains that sense changes within the cell. Structural analysis of some of the STPKs has led to advances in our understanding of the mechanisms by which these STPKs are activated and regulated. Functional analysis has provided insights into the effects of phosphorylation on the activity of several proteins, but for most phosphoproteins the role of phosphorylation in regulating function is unknown. Major future challenges include characterizing the functional effects of phosphorylation for this large number of phosphoproteins, identifying the cognate STPKs for these phosphoproteins, and determining the signals that the STPKs sense. Ultimately, combining these STPK-regulated processes into larger, integrated regulatory networks will provide deeper insight into M. tuberculosis adaptive mechanisms that contribute to tuberculosis pathogenesis. Finally, the STPKs offer attractive targets for inhibitor development that may lead to new therapies for drug-susceptible and drug-resistant tuberculosis. PMID:25429354

  18. Characterization of the memory/activated T cells that mediate the long-lived host response against tuberculosis after bacillus Calmette–Guérin or DNA vaccination

    PubMed Central

    Silva, C L; Bonato, V L D; Lima, V M F; Faccioli, L H; Leão, S C

    1999-01-01

    The memory/activated T cells, which mediate the long-lived host response against tuberculosis, in mice immunized with either bacillus Calmette–Guérin (BCG) or mycobacterium heat-shock protein 65 (hsp 65) antigen expressed from plasmid DNA (DNA-hsp 65), were characterized. Protection against Mycobacterium tuberculosis challenge by DNA-hsp 65 vaccination was associated with the presence of lymph node T-cell populations in which CD8+/CD44hi interferon-? (IFN-?)-producing/cytotoxic cells were prominent even after 8 or 15 months of plasmid DNA-mediated immunizations, whereas after BCG vaccination the majority were CD4+/CD44lo IFN-?-producing T cells. When the cells were separated into CD4+CD8? and CD8+CD4? and then into CD44hi and CD44lo types, CD44lo cells were essentially unable to transfer protection in adoptive transfer experiments, the most protective CD44hi cells were CD8+CD4? and those from DNA-vaccinated mice were much more protective than those from BCG-immunized mice. The frequency of protective T cells and the level of protection were increased up to 8 months and decreased after 15 months following DNA or BCG immunizations. PMID:10457209

  19. Antimycobacterial activity of peptide conjugate of pyridopyrimidine derivative against Mycobacterium tuberculosis in a series of in vitro and in vivo models.

    PubMed

    Horváti, Kata; Bacsa, Bernadett; Szabó, Nóra; Fodor, Kinga; Balka, Gyula; Rusvai, Miklós; Kiss, Éva; Mez?, Gábor; Grolmusz, Vince; Vértessy, Beáta; Hudecz, Ferenc; B?sze, Szilvia

    2015-06-01

    New pyridopyrimidine derivatives were defined using a novel HTS in silico docking method (FRIGATE). The target protein was a dUTPase enzyme (EC 3.6.1.23; Rv2697) which plays a key role in nucleotide biosynthesis of Mycobacterium tuberculosis (Mtb). Top hit molecules were assayed in vitro for their antimycobacterial effect on Mtb H37Rv culture. In order to enhance the cellular uptake rate, the TB820 compound was conjugated to a peptid-based carrier and a nanoparticle type delivery system (polylactide-co-glycolide, PLGA) was applied. The conjugate had relevance to in vitro antitubercular activity with low in vitro and in vivo toxicity. In a Mtb H37Rv infected guinea pig model the in vivo efficacy of orally administrated PLGA encapsulated compound was proven: animals maintained a constant weight gain and no external clinical signs of tuberculosis were observed. All tissue homogenates from lung, liver and kidney were found negative for Mtb, and diagnostic autopsy showed that no significant malformations on the tissues occurred. PMID:25728610

  20. Mycobacterium tuberculosis RbpA protein is a new type of transcriptional activator that stabilizes the ? A-containing RNA polymerase holoenzyme.

    PubMed

    Hu, Yangbo; Morichaud, Zakia; Chen, Shiyun; Leonetti, Jean-Paul; Brodolin, Konstantin

    2012-08-01

    RbpA is an RNA polymerase (RNAP)-binding protein whose presence increases the tolerance levels of Mycobacteria to the first-line anti-tuberculosis drug rifampicin by an unknown mechanism. Here, we show that the role of Mycobacterium tuberculosis RbpA in resistance is indirect because it does not affect the sensitivity of RNAP to rifampicin while it stimulates transcription controlled by the housekeeping ?(A)-factor. The transcription regulated by the stress-related ?(F) was not affected by RbpA. The binding site of RbpA maps to the RNAP ? subunit Sandwich-Barrel Hybrid Motif, which has not previously been described as an activator target and does not overlap the rifampicin binding site. Our data suggest that RbpA modifies the structure of the core RNAP, increases its affinity for ?(A) and facilitates the assembly of the transcriptionally competent promoter complexes. We propose that RbpA is an essential partner which advantages ?(A) competitiveness for core RNAP binding with respect to the alternative ? factors. The RbpA-driven stimulation of the housekeeping gene expression may help Mycobacteria to tolerate high rifampicin levels and to adapt to the stress conditions during infection. PMID:22570422

  1. 48 CFR 1303.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...2010-10-01 false Reporting suspected antitrust violations. 1303.303 Section 1303...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 1303.303 Reporting suspected antitrust violations. Suspected...

  2. Mycobacterium tuberculosis-specific and MHC class I-restricted CD8+ T-cells exhibit a stem cell precursor-like phenotype in patients with active pulmonary tuberculosis.

    PubMed

    Axelsson-Robertson, Rebecca; Ju, Ji Hyeon; Kim, Ho-Youn; Zumla, Alimuddin; Maeurer, Markus

    2015-03-01

    The nature and longevity of the T-cell response directed against Mycobacterium tuberculosis (MTB) are important for effective pathogen containment. We analyzed ex vivo the nature of MTB antigen-specific T-cell responses directed against the MTB secreted antigens Rv0288, Rv1886c, Rv3875, the antigens Rv2958c, Rv2957, and Rv0447c (intracellular, non-secreted enzymes) in blood from Korean patients with active tuberculosis (TB). MTB-specific T-cell function was defined by intracellular cytokine production (interleukin (IL)-2, interferon gamma, tumour necrosis factor alpha, and IL-17) and by multimer-guided (HLA-A*02:01 and HLA-A*24:02) analysis of epitope-specific CD8+ T-cells, along with phenotypic markers (CD45RA and CCR7), CD107a, a marker for degranulation, and CD127 co-staining for T-cell differentiation and homing. Cytokine production analysis underestimated the frequencies of MTB antigen-specific T-cells defined by major histocompatibility complex (MHC) class I-peptide multimer analysis. We showed that MTB antigen-specific CD8+ T-cells exhibit a distinct marker profile associated with the nature of the MTB antigens, i.e., Rv0288, Rv1886c, and Rv3875-reactive T-cells clustered in the precursor T-cell compartment, whereas Rv2958c, Rv2957, and Rv0447c-reactive T-cells were associated with the terminally differentiated T-cell phenotype, in the patient cohort. Rv0288, Rv1886c, and Rv3875-specific CD8+ T-cells were significantly enriched for CD107a+ T-cells in HLA-A*02:01 (p<0.0001) and HLA-A*24:02 (p=0.0018) positive individuals, as compared to Rv2958c, Rv2957, and Rv0447c antigens. CD127 (IL-7 receptor)-expressing T-cells were enriched in HLA-A*02:01-positive individuals for the Rv0288, Rv1886c, and Rv3875 specificities (p=0.03). A high proportion of antigen-specific T-cells showed a precursor-like phenotype (CD45RA+CCR7+) and expressed the stem cell-associated markers CD95 and c-kit. These data show that MTB-specific T-cells can express stem cell-like features; this is associated with the nature of the MTB antigen and the genetic background of the individual. PMID:25809750

  3. Play the Tuberculosis Game

    MedlinePLUS

    ... Malaria MRI Nerve Signaling Pavlov's Dog Split Brain Experiments The Cell and its Organelles The Genetic Code ... Life and Work Teachers' Questionnaire Tuberculosis Play Tuberculosis Experiments & Discoveries About the game Discover and experience some ...

  4. Acute Myeloid Leukemia Presenting with Pulmonary Tuberculosis

    PubMed Central

    Thomas, Merlin; AlGherbawe, Mushtak

    2014-01-01

    We report the case of a 58-year-old immunocompetent man presenting with fever, cough, anorexia, weight loss, and cervical lymphadenopathy. Blood investigations revealed severe neutropenia with monocytosis. Chest imaging showed bilateral reticular infiltrates with mediastinal widening. Bronchoalveolar lavage culture and molecular test were positive for Mycobacterium tuberculosis and treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol was started. Although pulmonary tuberculosis could explain this clinical presentation we suspected associated blood dyscrasias in view of significant monocytosis and mild splenomegaly. Bone marrow aspiration revealed acute myeloid leukemia. Thereafter the patient received induction chemotherapy and continued antituberculous treatment. After first induction of chemotherapy patient was in remission and successfully completed 6 months antituberculosis therapy without any complications. To our knowledge there has been no such case reported from the State of Qatar to date. PMID:24987539

  5. Risk factors for reactivation of tuberculosis in Manitoba

    PubMed Central

    Johnson, I.L.; Thomson, M.; Manfreda, J.; Hershfield, E.S.

    1985-01-01

    Although rates of reported cases of active tuberculosis have been declining in Manitoba and throughout Canada over the past two decades, the percentage of active cases due to reactivated tuberculosis has remained relatively constant. From 1976 to 1981, 113 cases of reactivated tuberculosis were listed in the Manitoba tuberculosis registry. We found that 36 cases did not meet our criteria for reactivation, primarily because there was no 6-month period of inactivity; another 5 cases could not be verified. In more than half of the remaining 72 the initial episode had occurred before 1960. We also randomly selected from the registry as controls 118 age- and sex-matched cases of nonreactivated tuberculosis. We found that registered Indian status was significantly associated with risk of reactivation, especially when the initial disease had been extensive. Awareness of high-risk groups, earlier diagnosis and adequate treatment are needed to prevent reactivated tuberculosis. PMID:4063933

  6. Evaluation of Mycobacterium tuberculosis Genes Involved in Resistance to Killing by Human Macrophages

    Microsoft Academic Search

    BARBARA H. MILLER; THOMAS M. SHINNICK

    2000-01-01

    A coinfection assay was developed to examine Mycobacterium tuberculosis genes suspected to be involved in resistance to killing by human macrophages. THP-1 macrophages were infected with a mixture of equal numbers of recombinant Mycobacterium smegmatis LR222 bacteria expressing an M. tuberculosis gene and wild-type M. smegmatis LR222 bacteria expressing the xylE gene. At various times after infection, the infected macrophages

  7. Tobacco Smoking, Alcohol Drinking, Diabetes, Low Body Mass Index and the Risk of Self-Reported Symptoms of Active Tuberculosis: Individual Participant Data (IPD) Meta-Analyses of 72,684 Individuals in 14 High Tuberculosis Burden Countries

    PubMed Central

    Patra, Jayadeep; Jha, Prabhat; Rehm, Jürgen; Suraweera, Wilson

    2014-01-01

    Background The effects of multiple exposures on active tuberculosis (TB) are largely undetermined. We sought to establish a dose-response relationship for smoking, drinking, and body mass index (BMI) and to investigate the independent and joint effects of these and diabetes on the risk of self-reported symptoms of active TB disease. Methods and Findings We analyzed 14 national studies in 14 high TB-burden countries using self-reports of blood in cough/phlegm and cough lasting >?=?3 weeks in the last year as the measures of symptoms of active TB. The random effect estimates of the relative risks (RR) between active TB and smoking, drinking, diabetes, and BMI<18.5 kg/m2 were reported for each gender. Floating absolute risks were used to examine dyads of exposure. Adjusted for age and education, the risks of active TB were significantly associated with diabetes and BMI<18.5 kg/m2 in both sexes, with ever drinking in men and with ever smoking in women. Stronger dose-response relationships were seen in women than in men for smoking amount, smoking duration and drinking amount but BMI<18.5 kg/m2 showed a stronger dose-response relationship in men. In men, the risks from joint exposures were statistically significant for diabetics with BMI<18.5 kg/m2 (RR?=?6.4), diabetics who smoked (RR?=?3.8), and diabetics who drank alcohol (RR?=?3.2). The risks from joint risk factors were generally larger in women than in men, with statistically significant risks for diabetics with BMI<18.5 kg/m2 (RR?=?10.0), diabetics who smoked (RR?=?5.4) and women with BMI<18.5 kg/m2 who smoked (RR?=?5.0). These risk factors account for 61% of male and 34% of female estimated TB incidents in these 14 countries. Conclusions Tobacco, alcohol, diabetes, and low BMI are significant individual risk factors but in combination are associated with triple or quadruple the risk of development of recent active TB. These risk factors might help to explain the wide variation in TB across countries. PMID:24789311

  8. Re-thinking global health sector efforts for HIV and tuberculosis epidemic control: promoting integration of programme activities within a strengthened health system

    Microsoft Academic Search

    Dermot Maher

    2010-01-01

    BACKGROUND: The global financial crisis threatens global health, particularly exacerbating diseases of inequality, e.g. HIV\\/AIDS, and diseases of poverty, e.g. tuberculosis. The aim of this paper is to reconsider established practices and policies for HIV and tuberculosis epidemic control, aiming at delivering better results and value for money. This may be achieved by promoting greater integration of HIV and tuberculosis

  9. Structure of Mycobacterium tuberculosis phosphopantetheine adenylyltransferase in complex with the feedback inhibitor CoA reveals only one active-site conformation

    SciTech Connect

    Wubben, T.; Mesecar, A.D. (Purdue); (UIC)

    2014-10-02

    Phosphopantetheine adenylyltransferase (PPAT) catalyzes the penultimate step in the coenzyme A (CoA) biosynthetic pathway, reversibly transferring an adenylyl group from ATP to 4'-phosphopantetheine to form dephosphocoenzyme A (dPCoA). To complement recent biochemical and structural studies on Mycobacterium tuberculosis PPAT (MtPPAT) and to provide further insight into the feedback regulation of MtPPAT by CoA, the X-ray crystal structure of the MtPPAT enzyme in complex with CoA was determined to 2.11 {angstrom} resolution. Unlike previous X-ray crystal structures of PPAT-CoA complexes from other bacteria, which showed two distinct CoA conformations bound to the active site, only one conformation of CoA is observed in the MtPPAT-CoA complex.

  10. Suspected adverse reactions to medicines during 1989

    Microsoft Academic Search

    A Gray; C Evans; A Kidd

    1990-01-01

    There was an increase in reports of suspected adverse reactions to veterinary medicines in 1989 with 329 reports (compared with 206 in 1988), from veterinary surgeons, farmers and the public, comments the Veterinary Medicines Directorate (VMD). Suspected adverse reactions to clostridial\\/pasteurella vaccines in sheep were a dominant feature and important experience was gained both in terms of liaison with the

  11. Recent developments in epidemiology, treatment, and diagnosis of tuberculosis

    Microsoft Academic Search

    Carol Dukes Hamilton

    1999-01-01

    The resurgence in cases of active tuberculosis in North America in the past decade has prompted increases in funding for tuberculosis\\u000a treatment, research, and education. As a result, the number of new cases of tuberculosis has declined and cases occur in smaller\\u000a pockets of well-characterized populations, such as communities of foreign-born persons and socioeconomically disadvantaged\\u000a groups. New strategies for the

  12. Structure-based design of diverse inhibitors of Mycobacterium tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase: combined molecular docking, dynamic simulation, and biological activity.

    PubMed

    Soni, Vijay; Suryadevara, Priyanka; Sriram, Dharmarajan; Kumar, Santhosh; Nandicoori, Vinay Kumar; Yogeeswari, Perumal

    2015-07-01

    Persistent nature of Mycobacterium tuberculosis is one of the major factors which make the drug development process monotonous against this organism. The highly lipophilic cell wall, which constituting outer mycolic acid and inner peptidoglycan layers, acts as a barrier for the drugs to enter the bacteria. The rigidity of the cell wall is imparted by the peptidoglycan layer, which is covalently linked to mycolic acid by arabinogalactan. Uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) serves as the starting material in the biosynthesis of this peptidoglycan layers. This UDP-GlcNAc is synthesized by N-acetylglucosamine-1-phosphate uridyltransferase (GlmU(Mtb)), a bi-functional enzyme with two functional sites, acetyltransferase site and uridyltransferase site. Here, we report design and screening of nine inhibitors against UTP and NAcGlc-1-P of uridyltransferase active site of glmU(Mtb). Compound 4 was showing good inhibition and was selected for further analysis. The isothermal titration calorimetry (ITC) experiments showed the binding energy pattern of compound 4 to the uridyltransferase active site is similar to that of substrate UTP. In silico molecular dynamics (MD) simulation studies, for compound 4, carried out for 10 ns showed the protein-compound complex to be stable throughout the simulation with relative rmsd in acceptable range. Hence, these compounds can serve as a starting point in the drug discovery processes against Mycobacterium tuberculosis. Graphical Abstract Superimposed structures of glmu(Mtb) - compound 4 complex collected at various intervals during molecular dynamics simulations displaying the stability of the complex. PMID:26078037

  13. Congenital transmission of multidrug-resistant tuberculosis.

    PubMed

    Espiritu, Nora; Aguirre, Lino; Jave, Oswaldo; Sanchez, Luis; Kirwan, Daniela E; Gilman, Robert H

    2014-07-01

    This article presents a case of multidrug-resistant tuberculosis (TB) in a Peruvian infant. His mother was diagnosed with disseminated TB, and treatment commenced 11 days postpartum. The infant was diagnosed with TB after 40 days and died at 2 months and 2 days of age. Congenital transmission of TB to the infant was suspected, because direct postpartum transmission was considered unlikely; also, thorough screening of contacts for TB was negative. Spoligotyping confirmed that both mother and baby were infected with identical strains of the Beijing family (SIT1). PMID:24821847

  14. [Childhood tuberculosis].

    PubMed

    Hamzaoui, A

    2015-01-01

    Childhood TB is an indication of failing TB control in the community. It allows disease persistence in the population. Mortality and morbidity due to TB is high in children. Moreover, HIV co-infection and multidrug-resistant diseases are as frequent in children as in adults. Infection is more frequent in younger children. Disease risk after primary infection is greatest in infants younger than 2 years. In case of exposure, evidence of infection can be obtained using the tuberculin skin test (TST) or an interferon-gamma assay (IGRA). There is no evidence to support the use of IGRA over TST in young children. TB suspicion should be confirmed whenever possible, using new available tools, particularly in case of pulmonary and lymph node TB. Induced sputum, nasopharyngeal aspiration and fine needle aspiration biopsy provide a rapid and definitive diagnosis of mycobacterial infection in a large proportion of patients. Analysis of paediatric samples revealed higher sensitivity and specificity values of molecular techniques in comparison with the ones originated from adults. Children require higher drugs dosages than adults. Short courses of steroids are associated with TB treatment in case of respiratory distress, bronchoscopic desobstruction is proposed for severe airways involvement and antiretroviral therapy is mandatory in case of HIV infection. Post-exposure prophylaxis in children is a highly effective strategy to reduce the risk of TB disease. The optimal therapy for treatment of latent infection with a presumably multidrug-resistant Mycobacterium tuberculosis strain is currently not known. PMID:24932504

  15. Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery

    PubMed Central

    Schmitz, Karl R.; Carney, Daniel W.; Sello, Jason K.; Sauer, Robert T.

    2014-01-01

    Caseinolytic peptidase P (ClpP), a double-ring peptidase with 14 subunits, collaborates with ATPases associated with diverse activities (AAA+) partners to execute ATP-dependent protein degradation. Although many ClpP enzymes self-assemble into catalytically active homo-tetradecamers able to cleave small peptides, the Mycobacterium tuberculosis enzyme consists of discrete ClpP1 and ClpP2 heptamers that require a AAA+ partner and protein–substrate delivery or a peptide agonist to stabilize assembly of the active tetradecamer. Here, we show that cyclic acyldepsipeptides (ADEPs) and agonist peptides synergistically activate ClpP1P2 by mimicking AAA+ partners and substrates, respectively, and determine the structure of the activated complex. Our studies establish the basis of heteromeric ClpP1P2 assembly and function, reveal tight coupling between the conformations of each ring, show that ADEPs bind only to one ring but appear to open the axial pores of both rings, provide a foundation for rational drug development, and suggest strategies for studying the roles of individual ClpP1 and ClpP2 rings in Clp-family proteolysis. PMID:25267638

  16. Tuberculosis in the aftermath of the 2010 earthquake in Haiti

    PubMed Central

    Rouzier, Vanessa; Vilbrun, Stalz Charles; Morose, Willy; Collins, Sean E; Joseph, Patrice; Decome, Diessy; Ocheretina, Oksana; Galbaud, Stanislas; Hashiguchi, Lauren; Pierrot, Julma; Pape, Jean William

    2015-01-01

    Abstract Problem In 2010, Haiti sustained a devastating earthquake that crippled the health-care infrastructure in the capital city, Port-au-Prince, and left 1.5 million people homeless. Subsequently, there was an increase in reported tuberculosis in the affected population. Approach We conducted active tuberculosis case finding in a camp for internally displaced persons and a nearby slum. Community health workers screened for tuberculosis at the household level. People with persistent cough were referred to a physician. The National Tuberculosis Program continued its national tuberculosis reporting system. Local setting Even before the earthquake, Haiti had the highest tuberculosis incidence in the Americas. About half of the tuberculosis cases occur in the Port-au-Prince region. Relevant changes The number of reported tuberculosis cases in Haiti has increased after the earthquake, but data are too limited to determine if this is due to an increase in tuberculosis burden or to improved case detection. Compared to previous national estimates (230 per 100?000 population), undiagnosed tuberculosis was threefold higher in a camp for internally displaced persons (693 per 100?000) and fivefold higher in an urban slum (1165 per 100?000). With funding from the World Health Organization (WHO), active case finding is now being done systematically in slums and camps. Lessons learnt Household-level screening for prolonged cough was effective in identifying patients with active tuberculosis in this study. Without accurate data, early detection of rising tuberculosis rates is challenging; data collection should be incorporated into pragmatic disease response programmes. PMID:26170508

  17. Tuberculosis: evidence review for newly arriving immigrants and refugees

    PubMed Central

    Greenaway, Christina; Sandoe, Amelia; Vissandjee, Bilkis; Kitai, Ian; Gruner, Doug; Wobeser, Wendy; Pottie, Kevin; Ueffing, Erin; Menzies, Dick; Schwartzman, Kevin

    2011-01-01

    Background: The foreign-born population bears a disproportionate health burden from tuberculosis, with a rate of active tuberculosis 20 times that of the non-Aboriginal Canadian-born population, and could therefore benefit from tuberculosis screening programs. We reviewed evidence to determine the burden of tuberculosis in immigrant populations, to assess the effectiveness of screening and treatment programs for latent tuberculosis infection, and to identify potential interventions to improve effectiveness. Methods: We performed a systematic search for evidence of the burden of tuberculosis in immigrant populations and the benefits and harms, applicability, clinical considerations, and implementation issues of screening and treatment programs for latent tuberculosis infection in the general and immigrant populations. The quality of this evidence was assessed and ranked using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation). Results: Chemoprophylaxis with isoniazid is highly efficacious in decreasing the development of active tuberculosis in people with latent tuberculosis infection who adhere to treatment. Monitoring for hepatotoxicity is required at all ages, but close monitoring is required in those 50 years of age and older. Adherence to screening and treatment for latent tuberculosis infection is poor, but it can be increased if care is delivered in a culturally sensitive manner. Interpretation: Immigrant populations have high rates of active tuberculosis that could be decreased by screening for and treating latent tuberculosis infection. Several patient, provider and infrastructure barriers, poor diagnostic tests, and the long treatment course, however, limit effectiveness of current programs. Novel approaches that educate and engage patients, their communities and primary care practitioners might improve the effectiveness of these programs. PMID:20634392

  18. Tuberculosis of the ear, a professional disease?

    PubMed

    Sens, Patrícia Maria; Almeida, Clemente I R; Valle, Lupércio O do; Costa, Luís H C; Angeli, Miguel L S

    2008-01-01

    Tuberculosis is a rare cause of chronic suppurative otitis media and mastoiditis; the predisposing factors of this association, however, are not commonly described. There has been an alarming increase in the incidence of tuberculosis in Brazil, including tuberculous otitis media. These patients typically present multiple perforations of the tympanic membrane, an ear discharge, and progressive hearing loss. This diagnosis should be taken into account in patients that do not respond to routine therapy for fungal external otitis or bacterial otitis media. In this retrospective study, the authors describe four cases of patients with tuberculous otitis media. This sample consisted of two physicians, a chemical engineer and an underage child in whose family there were cases of active tuberculosis. Predisposing factors for tuberculous otitis were contact with family members that had tuberculosis, professional contact with patients and exposure to pathogenic microorganisms in airways. PMID:18852993

  19. Endocrine dysfunction among adult patients with tuberculosis: An African experience

    PubMed Central

    Kibirige, Davis

    2014-01-01

    A broad spectrum of endocrine conditions has been reported among adult patients with tuberculosis in Africa. This review aims to describe the magnitude and pathogenesis of the following endocrinopathies among patients with tuberculosis in Africa: adrenal insufficiency, diabetes mellitus, disorders of calcium and vitamin D metabolism, thyroid dysfunction and hypogonadism. PubMed database and Google scholar were used to search for the relevant published English language studies and case reports relating to endocrine abnormalities and tuberculosis in Africa up to July 2013. The search terms used were endocrine dysfunction, endocrine abnormalities, adrenal insufficiency, diabetes mellitus, thyroid dysfunction, hypogonadism, disorders of calcium and vitamin D metabolism, tuberculosis, Africa. Reference lists of the identified articles were further used to identify other studies. Adrenal insufficiency, diabetes mellitus and calcium-vitamin D abnormalities were the most prevalent and frequently reported endocrine disorders among adult patients with tuberculosis in Africa. A meticulous endocrine evaluation among tuberculosis patients with suspected endocrine abnormalities should be encouraged in Africa and other high TB endemic regions. Treatment of these endocrine disorders has generally been shown to improve quality of life and reduce mortality. PMID:24944920

  20. Risk factors for poor tuberculosis treatment outcomes in Makassar, Indonesia.

    PubMed

    Scheelbeek, Pauline F D; Wirix, Aleid J G; Hatta, Mohammad; Usman, Romi; Bakker, Mirjam I

    2014-07-01

    Resistant tuberculosis is an important public health problem in South Sulawesi, Indonesia. We conducted a retrospective cohort study of 1,582 smear positive tuberculosis patients registered with the National Tuberculosis Program during 2007 in Makassar, Indonesia, to assess risk factors associated with poor tuberculosis treatment outcomes. Of the 1,582 patients, 265 had a poor treatment outcome. Of the 265 patients with a poor treatment outcome, 216 had defaulted on treatment, 7 failed treatment, 9 died and 33 transferred to another area. After adjusting for sex, age and BCG status, failure acid-fast bacilli (AFB) positive sputum to convert to AFB negative by 2-3 months was the only risk factor significantly associated with a poor treatment outcome (odds ratio 7.57; 95% CI: 1.22-47.1). We hypothesise this could represent resistant tuberculosis. Early identification of resistant tuberculosis is important and should be suspected in patients whose AFB positive sputum samples fail to convert to AFB negative by 2-3 months. PMID:25507603

  1. Risk factors for poor tuberculosis treatment outcomes in Makassar, Indonesia.

    PubMed

    Scheelbeek, Pauline F D; Wirix, Aleid J G; Hatta, Mohammad; Usman, Romi; Bakker, Mirjam I

    2014-07-01

    Resistant tuberculosis is an important public health problem in South Sulawesi, Indonesia. We conducted a retrospective cohort study of 1,582 smear positive tuberculosis patients registered with the National Tuberculosis Program during 2007 in Makassar, Indonesia, to assess risk factors associated with poor tuberculosis treatment outcomes. Of the 1,582 patients, 265 had a poor treatment outcome. Of the 265 patients with a poor treatment outcome, 216 had defaulted on treatment, 7 failed treatment, 9 died and 33 transferred to another area. After adjusting for sex, age and BCG status, failure acid-fast bacilli (AFB) positive sputum to convert to AFB negative by 2-3 months was the only risk factor significantly associated with a poor treatment outcome (odds ratio 7.57; 95% CI: 1.22-47.1). We hypothesise this could represent resistant tuberculosis. Early identification of resistant tuberculosis is important and should be suspected in patients whose AFB positive sputum samples fail to convert to AFB negative by 2-3 months. PMID:25427353

  2. Analysis of microRNA expression profiling identifies miR-155 and miR-155* as potential diagnostic markers for active tuberculosis: a preliminary study.

    PubMed

    Wu, Jing; Lu, Chanyi; Diao, Ni; Zhang, Shu; Wang, Sen; Wang, Feifei; Gao, Yan; Chen, Jiazhen; Shao, Lingyun; Lu, Jingning; Zhang, Xuelian; Weng, Xinhua; Wang, Honghai; Zhang, Wenhong; Huang, Yuxian

    2012-01-01

    To explore biologic behaviors and disease relevance of microRNAs (miRNAs) in the development of active tuberculosis (ATB), we investigated the expression profile of Mycobacterium tuberculosis (MTB) purified protein derivative (PPD)-induced miRNAs to determine the specific miRNAs involved in the pathogenesis of ATB. The expression profile of miRNA under PPD challenge was first measured using microarray analysis in peripheral blood mononuclear cells isolated from ATB patients and healthy controls (HC). The remarkably reactive miRNAs were then validated in a larger cohort by quantitative real-time polymerase chain reaction (qRT-PCR). The receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic value of the determined PPD-responsive miRNAs. The potential targets for those miRNAs were also predicted by computational programs. Fourteen of 866 human miRNAs exhibited at least 1.8-fold difference in the ratio of expression level before and after stimulation with PPD between the ATB and HC groups. The qRT-PCR study validated the findings from microarray-based screening, in which miR-155 exhibited a fold change of 1.4 in the HC group and 3.7 in the ATB group upon PPD stimulation (p < 0.0001); miR-155* exhibited a fold change of 1.9 in the HC and 4.6 in the ATB group (p < 0.005). In ROC plots, the area under the curve was 0.8972 for miR-155 and 0.7945 for miR-155*. The background expression of these 2 microRNAs exhibited no differences between the ATB and HC groups. miR-155 and miR-155* exhibited characteristic expression by TB-specific antigen, suggesting that they can be potential diagnostic markers under the challenge of specific MTB antigens. PMID:22037148

  3. Advancement of Imidazo[1,2-a]pyridines with Improved Pharmacokinetics and nM Activity vs. Mycobacterium tuberculosis

    PubMed Central

    2013-01-01

    A set of 14 imidazo[1,2-a]pyridine-3-carboxamides was synthesized and screened against Mycobacterium tuberculosis H37Rv. The minimum inhibitory concentrations of 12 of these agents were ?1 ?M against replicating bacteria and 5 compounds (9, 12, 16, 17, and 18) had MIC values ?0.006 ?M. Compounds 13 and 18 were screened against a panel of MDR and XDR drug resistant clinical Mtb strains with the potency of 18 surpassing that of clinical candidate PA-824 by nearly 10-fold. The in vivo pharmacokinetics of compounds 13 and 18 were evaluated in male mice by oral (PO) and intravenous (IV) routes. These results indicate that readily synthesized imidazo[1,2-a]pyridine-3-carboxamides are an exciting new class of potent, selective anti-TB agents that merit additional development opportunities. PMID:23930153

  4. Activation of the eis gene in a W-Beijing strain of Mycobacterium tuberculosis correlates with increased SigA levels and enhanced intracellular growth

    Microsoft Academic Search

    Shiping Wu; Peter F. Barnes; Buka Samten; Xiuhua Pang; Sebastien Rodrigue; Saleena Ghanny; Patricia Soteropoulos; Luc Gaudreau; Susan T. Howard

    2009-01-01

    There is growing evidence that strains of Mycobacterium tuberculosis differ in pathogenicity and transmissibility, but little is understood about the contributory factors. We have previously shown that increased expression of the principal sigma factor, SigA, mediates the capacity of M. tuberculosis strain 210 to grow more rapidly in human monocytes, compared with other strains. Strain 210 is part of the

  5. Substituted 4-methylquinolines as a new class of anti-tuberculosis agents

    Microsoft Academic Search

    Rahul Jain; Balasubramanian Vaitilingam; Amit Nayyar; Prakash B Palde

    2003-01-01

    We report synthesis and anti-tuberculosis activities of a series of novel ring-substituted quinolines. The most effective compound of the series 3d (MIC=6.25 ?g\\/mL, Mycobacterium tuberculosis H37Rv strain) was synthesized in one step; thus is an attractive lead molecule for anti-tuberculosis drug development. The results of this study represent the discovery of ring-substituted 4-methylquinolines as new class of potential anti-tuberculosis agents.

  6. Tuberculosis: Medico-Legal Aspects

    PubMed Central

    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

  7. Tuberculosis in the 1990s. Issues for primary care physicians.

    PubMed Central

    Fitzgerald, J. M.

    1995-01-01

    After declining for many years, tuberculosis rates have begun to level off in Canada. Groups at particularly high risk include aboriginal Canadians, immigrants from high-prevalence countries, HIV-infected people, and elderly men. If disease is suspected, appropriate investigations, including sputum tests for bacteriology and chest x-ray examinations, should be done. Response to treatment is excellent. Chemoprophylaxis is recommended for certain patients. Vaccination with BCG has a limited but important role, especially for aboriginal Canadians. PMID:7780315

  8. Pulmonary tuberculosis as differential diagnosis of lung cancer

    PubMed Central

    Bhatt, MLB; Kant, Surya; Bhaskar, Ravi

    2012-01-01

    Patients with lung cancer are often misdiagnosed as pulmonary tuberculosis leading to delay in the correct diagnosis as well as exposure to inappropriate medication. Several factors are responsible for this situation in developing countries, including lack of awareness, inadequate infrastructure and socio-economic factors. This article outlines the differences between the two diseases as well as features that would make a clinician suspect the right diagnosis early. PMID:24455507

  9. [Pharyngeal tuberculosis: Case report].

    PubMed

    Spini, Roxana Gabriela; Bordino, Lucas; Cohen, Daniela; Martins, Andrea; Ramírez, Zaida; González, Norma E

    2015-08-01

    Pharyngeal tuberculosis is a rare extrapulmonary manifestation. In Argentina, the number of cases of tuberculosis reported in children under 19 years in 2012 was 1752. Only 12.15% had extrapulmonary manifestation. A case of a 17 year old girl with pharyngeal tuberculosis is reported. The patient presented intermittent fever and swallowing pain for 6 months, without response to conventional antibiotic treatment. Chest X-ray showedbilateral micronodular infiltrate, so hospitalization was decided to study and treat. The sputum examination for acid-fast resistant bacilli was positive and treatment with four antituberculous drugs was started, with good evolution and disappearance of symptoms. Diagnostic confirmation with the isolation of Mycobacterium tuberculosis in sputum culture was obtained. The main symptoms of pharyngeal tuberculosis are sore throat and difficulty in swallowing of long evolution. It is important to consider tuberculosis as differential diagnosis in patients with chronic pharyngitis unresponsive to conventional treatment. PMID:26172025

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

    PubMed

    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

    2014-09-01

    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. [Tuberculosis, the old fellow].

    PubMed

    Tresselt, Christiane; Hösli, Irene

    2008-12-01

    There are many issues concerning tuberculosis during pregnancy. In our case report we discuss a 24-year-old Portuguese woman with unclear weight loss and non-specific symptoms such as fatigue and nausea during pregnancy. After diagnostic work up a pulmonary tuberculosis was diagnosed close to delivery. The treatment and outcome of tuberculosis during pregnancy and the question of breastfeeding after delivery are discussed. PMID:19048529

  12. Automated Tuberculosis Detection

    Microsoft Academic Search

    George Hripcsak; Charles A Knirsch; Nilesh L Jain; Ariel Pablos-Mendez

    1997-01-01

    ObjectiveTo measure the accuracy of automated tuberculosis case detection.SettingAn inner-city medical center.InterventionAn electronic medical record and a clinical event monitor with a natural language processor were used to detect tuberculosis cases according to Centers for Disease Control criteria.MeasurementCases identified by the automated system were compared to the local health department's tuberculosis registry, and positive predictive value and sensitivity were calculated.ResultsThe

  13. [Management of tuberculosis during pregnancy and puerperium].

    PubMed

    Toyota, Emiko; Minoura, Shigeki; Miyazawa, Hirofumi

    2002-11-01

    We reported 22 cases with tuberculosis in pregnancy and puerperium, who were treated in our hospital from 1993 to 2001. Nine out of 22 cases were foreign women and the onset of tuberculosis was not clear and the diagnosis tended to be delayed in most cases. In the reports from industrial countries, most of those patients are foreign bone and the delay in diagnosis is common because symptoms are apt to be mixed up those for pregnancy and puerperium. In 10 of 22 cases, extrapulmonary lesions were noted. Most of our cases were treated with INH, RFP and EB, and in some severer cases PZA was added. WHO and BTS recommend standard therapy with PZA but ATS recommends INH, RFP and EB without PZA. Generally SM is contraindicated because of adverse effect of hearing loss for all pregnant periods, and the data for PZA and other second line drugs are insufficient. Our cases and their neonates showed normal course and no malformation nor congenital tuberculosis. 2 cases could not keep adherence for drugs and 2 babies got active tuberculosis. Precaution for infection is one of most important problem to deal with cases with tuberculosis during pregnancy and postpartum in the hospital. If she is still infectious on delivery, we should consider prevention for transmission and manage her in isolated manner. CDC recommends not to treat for latent tuberculosis during pregnancy because of high frequency of hepatic damage due to INH. It is the best way to check and treat latent tuberculosis before gestation if she is at high risk with tuberculosis. PMID:12494507

  14. TUBERCULOSIS COMO ENFERMEDAD OCUPACIONAL

    PubMed Central

    Mendoza-Ticona, Alberto

    2014-01-01

    Existe evidencia suficiente para declarar a la tuberculosis como enfermedad ocupacional en diversos profesionales especialmente entre los trabajadores de salud. En el Perú están normados y reglamentados los derechos laborales inherentes a la tuberculosis como enfermedad ocupacional, como la cobertura por discapacidad temporal o permanente. Sin embargo, estos derechos aún no han sido suficientemente socializados. En este trabajo se presenta información sobre el riesgo de adquirir tuberculosis en el lugar de trabajo, se revisan las evidencias para declarar a la tuberculosis como enfermedad ocupacional en trabajadores de salud y se presenta la legislación peruana vigente al respecto. PMID:22858771

  15. 48 CFR 903.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...2010-10-01 false Reporting suspected antitrust violations. 903.303 Section 903...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 903.303 Reporting suspected antitrust violations. (a) Potential...

  16. 48 CFR 1203.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...2010-10-01 false Reporting suspected antitrust violations. 1203.303 Section 1203...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 1203.303 Reporting suspected antitrust violations. (b) The same...

  17. 48 CFR 303.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...2010-10-01 false Reporting suspected antitrust violations. 303.303 Section 303...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 303.303 Reporting suspected antitrust violations. (h) The HCA shall...

  18. 48 CFR 803.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...2010-10-01 false Reporting suspected antitrust violations. 803.303 Section 803...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 803.303 Reporting suspected antitrust violations. (a) Any VA...

  19. 48 CFR 403.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...2010-10-01 false Reporting suspected antitrust violations. 403.303 Section 403...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 403.303 Reporting suspected antitrust violations. Contracting officers...

  20. 48 CFR 3.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...2010-10-01 false Reporting suspected antitrust violations. 3.303 Section 3.303...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 3.303 Reporting suspected antitrust violations. (a) Agencies are...

  1. Mycobacterial Antigen Driven Activation of CD14++CD16? Monocytes Is a Predictor of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

    PubMed Central

    Andrade, Bruno B.; Singh, Amrit; Narendran, Gopalan; Schechter, Melissa E.; Nayak, Kaustuv; Subramanian, Sudha; Anbalagan, Selvaraj; Jensen, Stig M. R.; Porter, Brian O.; Antonelli, Lis R.; Wilkinson, Katalin A.; Wilkinson, Robert J.; Meintjes, Graeme; van der Plas, Helen; Follmann, Dean; Barber, Daniel L.; Swaminathan, Soumya; Sher, Alan; Sereti, Irini

    2014-01-01

    Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co-infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa. Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14++CD16? monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment. PMID:25275318

  2. Cleavage Specificity of Mycobacterium tuberculosis ClpP1P2 Protease and Identification of Novel Peptide Substrates and Boronate Inhibitors with Anti-bacterial Activity.

    PubMed

    Akopian, Tatos; Kandror, Olga; Tsu, Christopher; Lai, Jack H; Wu, Wengen; Liu, Yuxin; Zhao, Peng; Park, Annie; Wolf, Lisa; Dick, Lawrence R; Rubin, Eric J; Bachovchin, William; Goldberg, Alfred L

    2015-04-24

    The ClpP1P2 protease complex is essential for viability in Mycobacteria tuberculosis and is an attractive drug target. Using a fluorogenic tripeptide library (Ac-X3X2X1-aminomethylcoumarin) and by determining specificity constants (kcat/Km), we show that ClpP1P2 prefers Met ? Leu > Phe > Ala in the X1 position, basic residues or Trp in the X2 position, and Pro ? Ala > Trp in the X3 position. We identified peptide substrates that are hydrolyzed up to 1000 times faster than the standard ClpP substrate. These positional preferences were consistent with cleavage sites in the protein GFPssrA by ClpXP1P2. Studies of ClpP1P2 with inactive ClpP1 or ClpP2 indicated that ClpP1 was responsible for nearly all the peptidase activity, whereas both ClpP1 and ClpP2 contributed to protein degradation. Substrate-based peptide boronates were synthesized that inhibit ClpP1P2 peptidase activity in the submicromolar range. Some of them inhibited the growth of Mtb cells in the low micromolar range indicating that cleavage specificity of Mtb ClpP1P2 can be used to design novel anti-bacterial agents. PMID:25759383

  3. A Systems Chemical Biology Study of Malate Synthase and Isocitrate Lyase Inhibition in Mycobacterium tuberculosis During Active and NRP Growth

    PubMed Central

    May, Elebeoba E.; Leitão, Andrei; Tropsha, Alexander; Oprea, Tudor I.

    2013-01-01

    The ability of Mycobacterium tuberculosis (Mtb) to survive in low oxygen environments enables the bacterium to persist in a latent state within host tissues. In vitro studies of Mtb growth have identified changes in isocitrate lyase (ICL) and malate synthase (MS) that enable bacterial persistent under low oxygen and other environmentally limiting conditions. Systems chemical biology (SCB) enables us to evaluate the effects of small molecule inhibitors not only on the reaction catalyzed by malate synthase and isocitrate lyase, but the effect on the complete tricarboxylic acid cycle (TCA) by taking into account complex network relationships within that system. To study the kinetic consequences of inhibition on persistent bacilli, we implement a systems-chemical biology (SCB) platform and perform a chemistry-centric analysis of key metabolic pathways believed to impact Mtb latency. We explore consequences of disrupting the function of malate synthase (MS) and isocitrate lyase (ICL) during aerobic and hypoxic non-replicating persistence (NRP) growth by using the SCB method to identify small molecules that inhibit the function of MS and ICL, and simulating the metabolic consequence of the disruption. Results indicate variations in target and non-target reaction steps, clear differences in the normal and low oxygen models, as well as dosage dependent response. Simulation results from singular and combined enzyme inhibition strategies suggest ICL may be the more effective target for chemotherapeutic treatment against Mtb growing in a microenvironment where oxygen is slowly depleted, which may favor persistence. PMID:24121675

  4. Rapid Diagnosis of Extrapulmonary Tuberculosis by PCR: Impact of Sample Preparation and DNA Extraction

    Microsoft Academic Search

    S. Honore-Bouakline; J. P. Vincensini; V. Giacuzzo; P. H. Lagrange; J. L. Herrmann

    2003-01-01

    In cases of suspected extrapulmonary tuberculosis, rapid and accurate laboratory diagnosis is of prime importance, since traditional techniques of detecting acid-fast bacilli have limitations. The major difficulty with mycobacteria is achieving optimal cell lysis. Buffers used in commercial kits do not allow this complete lysis in a number of clinical specimens. A comparison of two sample preparation methods, pretreatment with

  5. The Residue Threonine 82 of DevR (DosR) Is Essential for DevR Activation and Function in Mycobacterium tuberculosis Despite Its Atypical Location?

    PubMed Central

    Gautam, Uma Shankar; Sikri, Kriti; Tyagi, Jaya Sivaswami

    2011-01-01

    The DevR (DosR) response regulator initiates the bacterial adaptive response to a variety of signals, including hypoxia in in vitro models of dormancy. Its receiver domain works as a phosphorylation-mediated switch to activate the DNA binding property of its output domain. Receiver domains are characterized by the presence of several highly conserved residues, and these sequence features correlate with structure and hence function. In response regulators, interaction of phosphorylated aspartic acid at the active site with the conserved threonine is believed to be crucial for phosphorylation-mediated conformational change. DevR contains all the conserved residues, but the structure of its receiver domain in the unphosphorylated protein is strikingly different, and key threonine (T82), tyrosine (Y101), and lysine (K104) residues are placed uncharacteristically far from the D54 phosphorylation site. In view of the atypical location of T82 in DevR, the present study aimed to examine the importance of this residue in the activation mechanism. Mycobacterium tuberculosis expressing a DevR T82A mutant protein is defective in autoregulation and supports hypoxic induction of the DevR regulon only very weakly. These defects are ascribed to slow and partial phosphorylation and the failure of T82A mutant protein to bind cooperatively with DNA. Our results indicate that the T82 residue is crucial in implementing conformational changes in DevR that are essential for cooperative binding and for subsequent gene activation. We propose that the function of the T82 residue in the activation mechanism of DevR is conserved in spite of the unusual architecture of its receiver domain. PMID:21764934

  6. [Formation of population groups with a higher risk of tuberculosis].

    PubMed

    Kucherov, A L; Rybkina, T A; Matveeva, T I

    1990-01-01

    During the years when tuberculosis was diagnosed among all age, sex, social and occupational groups of the population, methodological approaches to the organization of antituberculosis care based on annual antituberculosis preventive activities and covering practically all populations were the only proper measures bringing about their own positive results. Nowadays the annual preventive activities should be launched in those population groups where cases of tuberculosis are detected most frequently. To classify risk factors directly responsible for tuberculosis endemia, questionnaires were sent to 477 newly diagnosed adult patients. The obtained data were computer processed. Unfavourable social and biomedical factors, including alcoholism, unsatisfactory economic, working and living conditions, contact with tuberculosis patients, concurrent diseases and other social factors, have a decisive effect on the tuberculosis morbidity. PMID:2150436

  7. Improving vaccines against tuberculosis

    Microsoft Academic Search

    Warwick J Britton; Umaimainthan Palendira

    2003-01-01

    Tuberculosis remains a major cause of mortality and physical and economic deprivation worldwide. There have been significant recent advances in our understanding of the Mycobacterium tuberculosis genome, mycobacterial genetics and the host determinants of protective immunity. Nevertheless, the challenge is to harness this information to develop a more effective vaccine than BCG, the attenuated strain of Mycobacterium bovis derived by

  8. Tuberculosis terpene targets.

    PubMed

    Oldfield, Eric

    2015-04-23

    In this issue, Young, Moody, and colleagues report the discovery of an isomer of the Mycobacterium tuberculosis (Mtb) virulence factor 1-tuberculosinyl adenosine, N(6)-tuberculosinyl adenosine, in mice infected with tuberculosis. These Mtb-derived terpene compounds may serve as sensitive and specific biomarkers of infection. PMID:25910241

  9. Spinal tuberculosis: A review

    PubMed Central

    Garg, Ravindra Kumar; Somvanshi, Dilip Singh

    2011-01-01

    Spinal tuberculosis is a destructive form of tuberculosis. It accounts for approximately half of all cases of musculoskeletal tuberculosis. Spinal tuberculosis is more common in children and young adults. The incidence of spinal tuberculosis is increasing in developed nations. Genetic susceptibility to spinal tuberculosis has recently been demonstrated. Characteristically, there is destruction of the intervertebral disk space and the adjacent vertebral bodies, collapse of the spinal elements, and anterior wedging leading to kyphosis and gibbus formation. The thoracic region of vertebral column is most frequently affected. Formation of a ‘cold’ abscess around the lesion is another characteristic feature. The incidence of multi-level noncontiguous vertebral tuberculosis occurs more frequently than previously recognized. Common clinical manifestations include constitutional symptoms, back pain, spinal tenderness, paraplegia, and spinal deformities. For the diagnosis of spinal tuberculosis magnetic resonance imaging is more sensitive imaging technique than x-ray and more specific than computed tomography. Magnetic resonance imaging frequently demonstrates involvement of the vertebral bodies on either side of the disk, disk destruction, cold abscess, vertebral collapse, and presence of vertebral column deformities. Neuroimaging-guided needle biopsy from the affected site in the center of the vertebral body is the gold standard technique for early histopathological diagnosis. Antituberculous treatment remains the cornerstone of treatment. Surgery may be required in selected cases, e.g. large abscess formation, severe kyphosis, an evolving neurological deficit, or lack of response to medical treatment. With early diagnosis and early treatment, prognosis is generally good. PMID:22118251

  10. Tuberculosis of the oesophagus

    Microsoft Academic Search

    A. R. Fahmy; R. Guindi; A. Farid

    1969-01-01

    A case of primary tuberculosis of the oesophagus is presented; the patient was successfully treated by oesophagectomy. The condition, being rare, has stimulated the authors to review the literature concerning primary and secondary oesophageal tuberculosis. The history, modes of infection, the pathology, clinical picture, diagnosis, investigations, and methods of treatment are discussed. In contradistinction to the secondary disease, which is

  11. Mycobacterium tuberculosis Peptides Presented by HLA-E Molecules Are Targets for Human CD8+ T-Cells with Cytotoxic as well as Regulatory Activity

    Microsoft Academic Search

    Simone A. Joosten; Krista E. van Meijgaarden; Pascale C. van Weeren; Fatima Kazi; Annemieke Geluk; Nigel D. L. Savage; Jan W. Drijfhout; Darren R. Flower; Willem A. Hanekom; Michèl R. Klein; Tom H. M. Ottenhoff

    2010-01-01

    Tuberculosis (TB) is an escalating global health problem and improved vaccines against TB are urgently needed. HLA-E restricted responses may be of interest for vaccine development since HLA-E displays very limited polymorphism (only 2 coding variants exist), and is not down-regulated by HIV-infection. The peptides from Mycobacterium tuberculosis (Mtb) potentially presented by HLA-E molecules, however, are unknown. Here we describe

  12. Characterization of the Mycobacterium tuberculosis H37Rv alkyl hydroperoxidase AhpC points to the importance of ionic interactions in oligomerization and activity

    Microsoft Academic Search

    Radha CHAUHAN; Shekhar C. MANDE

    2001-01-01

    An alkyl hydroperoxidase (AhpC) has been found frequently to be overexpressed in isoniazid-resistant strains of Mycobacterium tuberculosis. These strains have an inactivated katG gene encoding a catalase peroxidase, which might render mycobacteria susceptible to the toxic peroxide radicals, thus leading to the concomitant overexpression of the AhpC. Although the over- expressed AhpC in isoniazid-resistant strains of M. tuberculosis may not

  13. Identification of a restriction fragment length polymorphism associated with a deletion that maps in a transcriptionally active open-reading frame, orfX , in Mycobacterium tuberculosis Erdman

    Microsoft Academic Search

    N. Dasgupta; J. Sivaswami Tyagi

    1998-01-01

    A two-component system of Mycobacterium tuberculosis H37Rv, designated as devR-devS , was identified in our laboratory, that encodes a response regulator and a histidine sensor-kinase respectively. Southern analysis of the devR-devS locus in the genomes of M. tuberculosis H37Rv, H37Ra and Erdman indicated the presence of anEco RI restriction fragment length polymorphism (RFLP) in the Erdman strain. Studies employing polymerase

  14. Acceptability of sputum specimens for diagnosing pulmonary tuberculosis.

    PubMed

    Lee, Yeon Joo; Shin, Sue; Roh, Eun Youn; Yoon, Jong Hyun; Kim, Deog Kyeom; Chung, Hee Soon; Lee, Chang-Hoon

    2015-06-01

    The evaluation of the quality of a sputum specimen prior to bacterial culture has been an accepted practice. However, optimal sputum criteria for pulmonary tuberculosis (TB) are not well established. We investigated indicators for sputum acceptability in tuberculosis cultures and acid-fast bacilli (AFB) smear. A post-hoc analysis of a randomized trial with 228 sputum specimens from 77 patients was conducted. In the trial, pulmonary TB suspects were requested for collecting three sputum specimens. We performed both TB study (AFB smear and M. tuberculosis culture) and Gram staining in each specimen. By using generalized estimating equations, the association between sputum characteristics and positive TB testings were analyzed. Although acceptable specimens for bacterial pneumonia showed higher TB-culture positive rates than unacceptable specimens (adjusted odds ratio [aOR]=1.66; 95% confidence interval [CI]=1.11-2.49), a specimen with ?25 white blood cells/low-power field was the better predictor for positive M. tuberculosis cultures (aOR=2.30; 95% CI=1.48-3.58) and acid-fast bacilli smears (aOR=1.85; 95% CI=1.05-3.25). Sputum leukocytosis could be an indicator of sputum acceptability for diagnosing pulmonary tuberculosis. PMID:26028925

  15. Doubly end-on azido bridged mixed-valence cobalt trinuclear complex: Spectral study, VTM, inhibitory effect and antimycobacterial activity on human carcinoma and tuberculosis cells.

    PubMed

    Datta, Amitabha; Das, Kuheli; Sen, Chandana; Karan, Nirmal Kumar; Huang, Jui-Hsien; Lin, Chia-Her; Garribba, Eugenio; Sinha, Chittaranjan; Askun, Tulin; Celikboyun, Pinar; Mane, Sandeep B

    2015-09-01

    Doubly end-on azido-bridged mixed-valence trinuclear cobalt complex, [Co3(L)2(N3)6(CH3OH)2] (1) is afforded by employing a potential monoanionic tetradentate-N2O2 Schiff base precursor (2-[{[2-(dimethylamino)ethyl]imino}methyl]-6-methoxyphenol; HL). Single crystal X-ray structure reveals that in 1, the adjacent Co(II) and Co(III) ions are linked by double end-on azido bridges and thus the full molecule is generated by the site symmetry of a crystallographic twofold rotation axis. Complex 1 is subjected on different spectral analysis such as IR, UV-vis, emission and EPR spectroscopy. On variable temperature magnetic study, we observe that during cooling, the ?MT values decrease smoothly until 15K and then reaches to the value 1.56cm(3)Kmol(-1) at 2K. Complex 1 inhibits the cell growth on human lung carcinoma (A549 cells), human colorectal (COLO 205 and HT-29 cells), and human heptacellular (PLC5 cells) carcinoma cells. Complex 1 exhibits anti-mycobacterial activity and considerable efficacy on Mycobacterium tuberculosis H37Rv ATCC 27294 and H37Ra ATCC 25177 strains. PMID:25932976

  16. Disseminated tuberculosis presenting as febrile seizures with fatal evolution in an infant.

    PubMed

    Petrescu, Ileana Octavia; Gheonea, Cristian; Voican, Cosmin Sebastian; Ciobanu, Daniela; Ni?u, Mimi; Petrescu, Florin

    2014-01-01

    Disseminated tuberculosis with the involvement of brain, liver and gut is a rare disease in immunocompetent infant. Early diagnostic and instauration of anti-tuberculosis therapy is capital because the outcome is poor. Here, we report the case of an 11-month-old boy with disseminated tuberculosis of brain, liver abdominal lymph nodes, small bowel and lung, which presented with fever, generalized tonic-clonic seizure, hemodynamic instability and a history of recurrent respiratory tract infections. His father was diagnosed with active pulmonary tuberculosis six month ago and family members completed an anti-tuberculosis chemoprophylaxis regimen. PMID:25611286

  17. Helminth Infections Coincident with Active Pulmonary Tuberculosis Inhibit Mono- and Multifunctional CD4+ and CD8+ T Cell Responses in a Process Dependent on IL-10

    PubMed Central

    George, Parakkal Jovvian; Anuradha, Rajamanickam; Kumar, Nathella Pavan; Sridhar, Rathinam; Banurekha, Vaithilingam V.; Nutman, Thomas B.; Babu, Subash

    2014-01-01

    Tissue invasive helminth infections and tuberculosis (TB) are co-endemic in many parts of the world and can trigger immune responses that might antagonize each other. We have previously shown that helminth infections modulate the Th1 and Th17 responses to mycobacterial-antigens in latent TB. To determine whether helminth infections modulate antigen-specific and non-specific immune responses in active pulmonary TB, we examined CD4+ and CD8+ T cell responses as well as the systemic (plasma) cytokine levels in individuals with pulmonary TB with or without two distinct helminth infections—Wuchereria bancrofti and Strongyloides stercoralis infection. By analyzing the frequencies of Th1 and Th17 CD4+ and CD8+ T cells and their component subsets (including multifunctional cells), we report a significant diminution in the mycobacterial–specific frequencies of mono- and multi–functional CD4+ Th1 and (to a lesser extent) Th17 cells when concomitant filarial or Strongyloides infection occurs. The impairment in CD4+ and CD8+ T cell cytokine responses was antigen-specific as polyclonal activated T cell frequencies were equivalent irrespective of helminth infection status. This diminution in T cell responses was also reflected in diminished circulating levels of Th1 (IFN-?, TNF-? and IL-2)- and Th17 (IL-17A and IL-17F)-associated cytokines. Finally, we demonstrate that for the filarial co-infections at least, this diminished frequency of multifunctional CD4+ T cell responses was partially dependent on IL-10 as IL-10 blockade significantly increased the frequencies of CD4+ Th1 cells. Thus, co-existent helminth infection is associated with an IL-10 mediated (for filarial infection) profound inhibition of antigen-specific CD4+ T cell responses as well as protective systemic cytokine responses in active pulmonary TB. PMID:25211342

  18. Eicosanoid pathways regulate adaptive immunity to Mycobacterium tuberculosis

    PubMed Central

    Divangahi, Maziar; Desjardins, Danielle; Nunes-Alves, Cláudio; Remold, Heinz G; Behar, Samuel M

    2011-01-01

    The fate of infected macrophages has an essential role in protection against Mycobacterium tuberculosis by regulating innate and adaptive immunity. M. tuberculosis exploits cell necrosis to exit from macrophages and spread. In contrast, apoptosis, which is characterized by an intact plasma membrane, is an innate mechanism that results in lower bacterial viability. Virulent M. tuberculosis inhibits apoptosis and promotes necrotic cell death by inhibiting production of prostaglandin E2. Here we show that by activating the 5-lipoxygenase pathway, M. tuberculosis not only inhibited apoptosis but also prevented cross-presentation of its antigens by dendritic cells, which impeded the initiation of T cell immunity. Our results explain why T cell priming in response to M. tuberculosis is delayed and emphasize the importance of early immunity. PMID:20622882

  19. Commercial Serological Tests for the Diagnosis of Active Pulmonary and Extrapulmonary Tuberculosis: An Updated Systematic Review and Meta-Analysis

    PubMed Central

    Steingart, Karen R.; Flores, Laura L.; Dendukuri, Nandini; Schiller, Ian; Laal, Suman; Ramsay, Andrew; Hopewell, Philip C.; Pai, Madhukar

    2011-01-01

    Background Serological (antibody detection) tests for tuberculosis (TB) are widely used in developing countries. As part of a World Health Organization policy process, we performed an updated systematic review to assess the diagnostic accuracy of commercial serological tests for pulmonary and extrapulmonary TB with a focus on the relevance of these tests in low- and middle-income countries. Methods and Findings We used methods recommended by the Cochrane Collaboration and GRADE approach for rating quality of evidence. In a previous review, we searched multiple databases for papers published from 1 January 1990 to 30 May 2006, and in this update, we add additional papers published from that period until 29 June 2010. We prespecified subgroups to address heterogeneity and summarized test performance using bivariate random effects meta-analysis. For pulmonary TB, we included 67 studies (48% from low- and middle-income countries) with 5,147 participants. For all tests, estimates were variable for sensitivity (0% to 100%) and specificity (31% to 100%). For anda-TB IgG, the only test with enough studies for meta-analysis, pooled sensitivity was 76% (95% CI 63%–87%) in smear-positive (seven studies) and 59% (95% CI 10%–96%) in smear-negative (four studies) patients; pooled specificities were 92% (95% CI 74%–98%) and 91% (95% CI 79%–96%), respectively. Compared with ELISA (pooled sensitivity 60% [95% CI 6%–65%]; pooled specificity 98% [95% CI 96%–99%]), immunochromatographic tests yielded lower pooled sensitivity (53%, 95% CI 42%–64%) and comparable pooled specificity (98%, 95% CI 94%–99%). For extrapulmonary TB, we included 25 studies (40% from low- and middle-income countries) with 1,809 participants. For all tests, estimates were variable for sensitivity (0% to 100%) and specificity (59% to 100%). Overall, quality of evidence was graded very low for studies of pulmonary and extrapulmonary TB. Conclusions Despite expansion of the literature since 2006, commercial serological tests continue to produce inconsistent and imprecise estimates of sensitivity and specificity. Quality of evidence remains very low. These data informed a recently published World Health Organization policy statement against serological tests. Please see later in the article for the Editors' Summary PMID:21857806

  20. Determinants Outside the DevR C-Terminal Domain Are Essential for Cooperativity and Robust Activation of Dormancy Genes in Mycobacterium tuberculosis

    PubMed Central

    Gautam, Uma Shankar; Chauhan, Santosh; Tyagi, Jaya Sivaswami

    2011-01-01

    Background DevR (also called as DosR) is a two-domain response regulator of the NarL subfamily that controls dormancy adaptation of Mycobacterium tuberculosis (M. tb). In response to inducing signals such as hypoxia and ascorbic acid, the N-terminal receiver domain of DevR (DevRN) is phosphorylated at Asp54. This results in DevR binding to DNA via its C-terminal domain (DevRC) and subsequent induction of the DevR regulon. The mechanism of phosphorylation-mediated activation is not known. The present study was designed to understand the role of the N- and C-terminal domains of DevR in DevR regulon genes activation. Methodology/Principal Findings Towards deciphering the activation mechanism of DevR, we compared the DNA binding properties of DevRC and DevR and correlated the findings with their ability to activate gene expression. We show that isolated DevRC can interact with DNA, but only with the high affinity site of a representative target promoter. Therefore, one role of DevRN is to mask the intrinsic DNA binding function of DevRC. However, unlike phosphorylated DevR, isolated DevRC does not interact with the adjacent low affinity binding site suggesting that a second role of DevRN is in cooperative binding to the secondary site. Transcriptional analysis shows that consistent with unmasking of its DNA binding property, DevRC supports the aerobic induction, albeit feebly, of DevR regulon genes but is unable to sustain gene activation during hypoxia. Conclusions/Significance DevR is a unique response regulator that employs a dual activation mechanism including relief of inhibition and cooperative interaction with binding sites. Importantly, both these functions reside outside the C-terminal domain. DevRN is also essential for stabilizing DevR and sustaining autoregulation under hypoxia. Hence, both domains of DevR are required for robust transcription activation. PMID:21304599

  1. The sampling of ignitable liquids on suspects' hands.

    PubMed

    Montani, Isabelle; Comment, Stéfane; Delémont, Olivier

    2010-01-30

    In arson cases, the collection and detection of traces of ignitable liquids on a suspect's hands can provide information to a forensic investigation. Police forces currently lack a simple, robust, efficient and reliable solution to perform this type of swabbing. In this article, we describe a study undertaken to develop a procedure for the collection of ignitable liquid residues on the hands of arson suspects. Sixteen different collection supports were considered and their applicability for the collection of gasoline traces present on hands and their subsequent analysis in a laboratory was evaluated. Background contamination, consisting of volatiles emanating from the collection supports, and collection efficiencies of the different sampling materials were assessed by passive headspace extraction with an activated charcoal strip (DFLEX device) followed by gas chromatography-mass spectrometry (GC-MS) analysis. After statistical treatment of the results, non-powdered latex gloves were retained as the most suitable method of sampling. On the basis of the obtained results, a prototype sampling kit was designed and tested. This kit is made of a three compartment multilayer bag enclosed in a sealed metal can and containing three pairs of non-powdered latex gloves: one to be worn by the sampler, one consisting of a blank sample and the last one to be worn by the person suspected to have been in contact with ignitable liquids. The design of the kit was developed to be efficient in preventing external and cross-contaminations. PMID:19954905

  2. pncA Mutations as a Major Mechanism of Pyrazinamide Resistance in Mycobacterium tuberculosis: Spread of a Monoresistant Strain in Quebec, Canada

    Microsoft Academic Search

    SHAO-JI CHENG; LOUISE THIBERT; TRACY SANCHEZ; LEONID HEIFETS; YING ZHANG

    2000-01-01

    Pyrazinamide (PZA) is an important first-line tuberculosis drug that is part of the currently used short- course tuberculosis chemotherapy. PZA is a prodrug that has to be converted to the active form pyrazinoic acid by pyrazinamidase (PZase) activity, encoded by the pncA gene of Mycobacterium tuberculosis, and loss of PZase activity is associated with PZA resistance. To further define the

  3. Computer image retrieval by features: suspect identification

    Microsoft Academic Search

    Eric S. Lee; Thomas Whalen

    1993-01-01

    Correct suspect identification of known offenders by witnesses deteriorates rapidly as more are examined in mugshot albums. Feature approaches, where mugshots are displayed in order of similarity to witnesses' descriptions, attempt to increase identification success by reducing this number. A methodology is proposed for system design and evaluation based on experiments, computer simulations, and four classes of system performance measures:

  4. Suspected panosteitis in a crossbred calf.

    PubMed

    Sato, Reiichiro; Ito, Tetsuo; Suganuma, Tsunenori; Une, Yumi; Kudo, Tomoo; Kayanuma, Hideki; Kanai, Eiichi; Suzuki, Takehito; Ochiai, Hideharu; Enomoto, Nahoko; Itoh, Seigo; Onda, Ken; Wada, Yasunori

    2015-05-01

    A male crossbred calf developed a limp and pain upon deep pressure on the right hind limb and the right forelimb. The radiographic findings of affected limbs and pathological findings of bone biopsy were similar to those observed in canine panosteitis. This is the first case of suspected panosteitis reported in cattle. PMID:25969576

  5. Recurrence due to Relapse or Reinfection With Mycobacterium tuberculosis: A Whole-Genome Sequencing Approach in a Large, Population-Based Cohort With a High HIV Infection Prevalence and Active Follow-up

    PubMed Central

    Guerra-Assunção, José Afonso; Houben, Rein M. G. J.; Crampin, Amelia C.; Mzembe, Themba; Mallard, Kim; Coll, Francesc; Khan, Palwasha; Banda, Louis; Chiwaya, Arthur; Pereira, Rui P. A.; McNerney, Ruth; Harris, David; Parkhill, Julian; Clark, Taane G.; Glynn, Judith R.

    2015-01-01

    Background.?Recurrent tuberculosis is a major health burden and may be due to relapse with the original strain or reinfection with a new strain. Methods.?In a population-based study in northern Malawi, patients with tuberculosis diagnosed from 1996 to 2010 were actively followed after the end of treatment. Whole-genome sequencing with approximately 100-fold coverage was performed on all available cultures. Results of IS6110 restriction fragment-length polymorphism analyses were available for cultures performed up to 2008. Results.?Based on our data, a difference of ?10 single-nucleotide polymorphisms (SNPs) was used to define relapse, and a difference of >100 SNPs was used to define reinfection. There was no evidence of mixed infections among those classified as reinfections. Of 1471 patients, 139 had laboratory-confirmed recurrences: 55 had relapse, and 20 had reinfection; for 64 type of recurrence was unclassified. Almost all relapses occurred in the first 2 years. Human immunodeficiency virus infection was associated with reinfection but not relapse. Relapses were associated with isoniazid resistance, treatment before 2007, and lineage-3 strains. We identified several gene variants associated with relapse. Lineage-2 (Beijing) was overrepresented and lineage-1 underrepresented among the reinfecting strains (P = .004). Conclusions.?While some of the factors determining recurrence depend on the patient and their treatment, differences in the Mycobacterium tuberculosis genome appear to have a role in both relapse and reinfection. PMID:25336729

  6. Development of a simple high-throughput screening protocol based on biosynthetic activity of Mycobacterium tuberculosis glutamine synthetase for the identification of novel Inhibitors.

    PubMed

    Singh, Upasana; Sarkar, Dhiman

    2006-12-01

    A high-throughput screening protocol has been developed for Mycobacterium tuberculosis glutamine synthetase by quantitative estimation of inorganic phosphate. The K(m) values determined at pH 6.8 are 22 mM for L-glutamic acid, 0.75 mM for NH(4)Cl, 3.25 mM for MgCl(2), and 2.5 mM for adenosine triphosphate. The K(m) value for glutamine is affected significantly by the increase in pH of assay buffer. At the saturating level of the substrate, the enzyme activity at pH 6.8 and 25 degrees C is found to be linear up to 3 h. The reduction of enzyme activity is negligible even in presence of 10% DMSO. The Z' factor and signal-to-noise ratio are found to be 0.75 and 6.18, respectively, when the enzyme is used at 62.5 microg/ml concentration. The IC(50) values obtained at pH 6.8 for both L-methionine S-sulfoximine and DL-phosphothriacin are 500 microM and 30 microM, respectively, which is lowest compared to the values obtained at other pH levels. The Beckman Coulter high-throughput screening platform was found to take 5 h 9 min to complete the screening of 60 plates. For each assay plate, a replica plate is used to normalize the data. Screening of 1164 natural product fractions/extracts and synthetic molecules from an in-house library was able to identify 12 samples as confirmed hits. Altogether, the validation data from screening of a small set of an in-house library coupled with Z' and signal-to-noise values indicate that the protocol is robust for high-throughput screening of a diverse chemical library. PMID:16973920

  7. Significant risk and associated factors of active tuberculosis infection in Korean patients with inflammatory bowel disease using anti-TNF agents

    PubMed Central

    Kim, Eun Soo; Song, Geun Am; Cho, Kwang Bum; Park, Kyung Sik; Kim, Kyeong Ok; Jang, Byung Ik; Kim, Eun Young; Jeon, Seong Woo; Lee, Hyun Seok; Yang, Chang Heon; Lee, Yong Kook; Lee, Dong Wook; Kim, Sung Kook; Kim, Tae Oh; Lee, Jonghun; Kim, Hyung Wook; Jee, Sam Ryong; Park, Seun Ja; Kim, Hyun Jin

    2015-01-01

    AIM: To evaluate the incidence and risk factors of Korean tuberculosis (TB) infection in patients with inflammatory bowel disease (IBD) undergoing anti-TNF treatment. METHODS: The data of IBD patients treated with anti-TNFs in 13 tertiary referral hospitals located in the southeastern region of Korea were collected retrospectively. They failed to show response or were intolerant to conventional treatments, including steroids or immunomodulators. Screening measures for latent TB infection (LTBI) and the incidence and risk factors of active TB infection after treatment with anti-TNFs were identified. RESULTS: Overall, 376 IBD patients treated with anti-TNF agents were recruited (male 255, mean age of anti-TNF therapy 32.5 ± 13.0 years); 277 had Crohn’s disease, 99 had ulcerative colitis, 294 used infliximab, and 82 used adalimumab. Before anti-TNF treatment, screening tests for LTBI including an interferon gamma release assay or a tuberculin skin test were performed in 82.2% of patients. Thirty patients (8%) had LTBI. Sixteen cases of active TB infection including one TB-related mortality occurred during 801 person-years (PY) follow-up (1997.4 cases per 100000 PY) after anti-TNF treatment. LTBI (OR = 5.76, 95%CI: 1.57-21.20, P = 0.008) and WBC count < 5000 mm3 (OR = 4.5, 95%CI: 1.51-13.44, P = 0.007) during follow-up were identified as independently associated risk factors. CONCLUSION: Anti-TNFs significantly increase the risk of TB infection in Korean patients with IBD. The considerable burden of TB and marked immunosuppression might be attributed to this risk. PMID:25805938

  8. Activity of 3-Ketosteroid 9?-Hydroxylase (KshAB) Indicates Cholesterol Side Chain and Ring Degradation Occur Simultaneously in Mycobacterium tuberculosis*

    PubMed Central

    Capyk, Jenna K.; Casabon, Israël; Gruninger, Robert; Strynadka, Natalie C.; Eltis, Lindsay D.

    2011-01-01

    Mycobacterium tuberculosis (Mtb), a significant global pathogen, contains a cholesterol catabolic pathway. Although the precise role of cholesterol catabolism in Mtb remains unclear, the Rieske monooxygenase in this pathway, 3-ketosteroid 9?-hydroxylase (KshAB), has been identified as a virulence factor. To investigate the physiological substrate of KshAB, a rhodococcal acyl-CoA synthetase was used to produce the coenzyme A thioesters of two cholesterol derivatives: 3-oxo-23,24-bisnorchol-4-en-22-oic acid (forming 4-BNC-CoA) and 3-oxo-23,24-bisnorchola-1,4-dien-22-oic acid (forming 1,4-BNC-CoA). The apparent specificity constant (kcat/Km) of KshAB for the CoA thioester substrates was 20–30 times that for the corresponding 17-keto compounds previously proposed as physiological substrates. The apparent KmO2 was 90 ± 10 ?m in the presence of 1,4-BNC-CoA, consistent with the value for two other cholesterol catabolic oxygenases. The ?1 ketosteroid dehydrogenase KstD acted with KshAB to cleave steroid ring B with a specific activity eight times greater for a CoA thioester than the corresponding ketone. Finally, modeling 1,4-BNC-CoA into the KshA crystal structure suggested that the CoA moiety binds in a pocket at the mouth of the active site channel and could contribute to substrate specificity. These results indicate that the physiological substrates of KshAB are CoA thioester intermediates of cholesterol side chain degradation and that side chain and ring degradation occur concurrently in Mtb. This finding has implications for steroid metabolites potentially released by the pathogen during infection and for the design of inhibitors for cholesterol-degrading enzymes. The methodologies and rhodococcal enzymes used to generate thioesters will facilitate the further study of cholesterol catabolism. PMID:21987574

  9. Detection of Mycobacterium tuberculosis complex organisms in the stools of patients with pulmonary tuberculosis.

    PubMed

    El Khéchine, Amel; Henry, Mireille; Raoult, Didier; Drancourt, Michel

    2009-07-01

    The laboratory diagnosis of pulmonary tuberculosis mainly relies on the detection of Mycobacterium tuberculosis complex (MTC) organisms in the sputum. In patients who do not give sputum, alternative respiratory tract specimens can be obtained only by invasive procedures. Based on the known survival of MTC organisms in the gastric fluid, we hypothesized that swallowed MTC organisms would be detectable in stool samples. We compared the presence of MTC organisms in respiratory tract specimens and stool specimens collected in parallel from the same patients. MTC was detected in cultures grown on egg-based medium after appropriate decontamination, by microscopic examination after Ziehl-Neelsen staining and by real-time PCR detection of IS6110 using internal controls. A case of pulmonary tuberculosis was defined by the presence of (i) clinical and radiological signs and symptoms suggestive of pulmonary tuberculosis, and (ii) culture of MTC organisms from at least one respiratory tract specimen or (iii) the presence of acid-fast bacilli in the sputum that were subsequently identified as MTC organisms by real-time PCR. The observation of 134 patients suspected to be suffering pulmonary tuberculosis led to the identification of 24 cases and 110 non-infected control patients. Cases and controls did not significantly differ with respect to sex but cases were significantly younger than controls. The sensitivity/specificity was 37.5%/100% for the microscopic examination of stools, 54.2%/100% for culturing and 100%/97.3% for real-time PCR. The positive predicted value was 100%, 100% and 88.9%, respectively, and the negative predicted value was 88%, 90.9% and 100%, respectively. In four patients, a stool specimen initially yielded the correct diagnosis of pulmonary tuberculosis before evaluation of the respiratory tract specimen confirmed the diagnosis. These data indicate that stools could be used in conjunction with sputum testing or as an alternative specimen upon which to base the diagnosis of pulmonary tuberculosis by molecular identification of acid-fast bacilli and culture. This non-invasive alternative procedure is of particular interest for patients who cannot expectorate. PMID:19389783

  10. Comprehensive Tuberculosis Testing for the Dermatologist

    PubMed Central

    Jordan, Laura

    2015-01-01

    Tuberculosis remains a noteworthy disease worldwide, rendering detection of latent tuberculosis of great importance. As healthcare workers, dermatologists should be aware of the available testing options and how they compare. In general, the tuberculin skin test has been around longer and, thus, there have been more studies performed on its sensitivity and specificity compared to interferon gamma release assays, which are newer to the market. The tuberculin skin test requires more office visits, takes longer to obtain results, is subject to healthcare worker bias, and can cause a booster phenomenon; whereas, interferon gamma release assays have a higher cost and less data available on their use in children under five years old. Both the tuberculin skin test and interferon gamma release assays fail to differentiate between recent and remote infections, have a low predictive value for active tuberculosis, and a lower sensitivity in people living with human immunodeficiency virus/acquired immunodeficiency syndrome. PMID:26060517

  11. Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction

    PubMed Central

    Vilchèze, Catherine; Hartman, Travis; Weinrick, Brian; Jacobs, William R.

    2013-01-01

    Drugs that kill tuberculosis more quickly could shorten chemotherapy significantly. In Escherichia coli, a common mechanism of cell death by bactericidal antibiotics involves the generation of highly reactive hydroxyl radicals via the Fenton reaction. Here we show that vitamin C, a compound known to drive the Fenton reaction, sterilizes cultures of drug-susceptible and drug-resistant Mycobacterium tuberculosis, the causative agent of tuberculosis. While M. tuberculosis is highly susceptible to killing by vitamin C, other Gram-positive and Gram-negative pathogens are not. The bactericidal activity of vitamin C against M. tuberculosis is dependent on high ferrous ion levels and reactive oxygen species production and causes a pleiotropic effect affecting several biological processes. This study enlightens the possible benefits of adding vitamin C to an anti-tuberculosis regimen and suggests that the development of drugs that generate high oxidative burst could be of great use in tuberculosis treatment. PMID:23695675

  12. Completeness and timeliness of tuberculosis case reporting

    Microsoft Academic Search

    Amy B Curtis; Eugene McCray; Matthew McKenna; Ida M Onorato

    2001-01-01

    Background: Tuberculosis (TB) control activities are contingent on the timely identification and reporting of cases to public health authorities to ensure complete assessment and appropriate treatment of contacts and identification of secondary cases. We report the results of a multistate evaluation of completeness and timeliness of reporting of TB cases in the United States during 1993 and 1994.Methods: To determine

  13. Inhibitory Effect of NO-Releasing Ciprofloxacin (NCX 976) on Mycobacterium tuberculosis Survival

    Microsoft Academic Search

    R. Ciccone; F. Mariani; A. Cavone; T. Persichini; G. Venturini; E. Ongini; V. Colizzi; M. Colasanti

    2003-01-01

    Here, we report the antimycobacterial activity of NCX 976, a new molecule obtained adding a NO moiety to the fluoroquinolone ciprofloxacin, on Mycobacterium tuberculosis H37Rv strain, both in a cell-free model and in infected human macrophages. Unlike unaltered ciprofloxacin, NCX976 displayed a marked activity also at low-nanomolar concentrations. Mycobacterium tuberculosis, which causes tuberculosis (TB), is the greatest single infectious cause

  14. Tuberculosis endometrial polyp.

    PubMed

    Seror, Julien; Faivre, Erika; Prevot, Sophie; Deffieux, Xavier

    2013-01-01

    Tuberculosis can cause infertility when it infects the genital tract (e.g., endometritis). A 31-year-old woman (origin: Algeria) was referred to our academic gynecological institute for unexplained primary infertility. The patient presented with no complaint. Hysteroscopy showed a 10?mm sized endometrial polyp. The polyp was removed. Pathology showed lymphocytic and plasmacytic chronic inflammatory modification, granulomatous modification, and gigantocellular modification,which lead to the diagnosis of tuberculosis. No acid fast organism was seen on Ziehl-Neelsen staining. A chest thorax X-ray revealed no sign of pulmonary tuberculosis. The patient underwent antituberculosis therapy during one year. Posttreatment hysteroscopy revealed no abnormality. This is the first reported case of endometrial tuberculosis diagnosed following removal of a polyp with classical benign appearance. PMID:23607011

  15. Tuberculosis Endometrial Polyp

    PubMed Central

    Seror, Julien; Faivre, Erika; Prevot, Sophie; Deffieux, Xavier

    2013-01-01

    Tuberculosis can cause infertility when it infects the genital tract (e.g., endometritis). A 31-year-old woman (origin: Algeria) was referred to our academic gynecological institute for unexplained primary infertility. The patient presented with no complaint. Hysteroscopy showed a 10?mm sized endometrial polyp. The polyp was removed. Pathology showed lymphocytic and plasmacytic chronic inflammatory modification, granulomatous modification, and gigantocellular modification,which lead to the diagnosis of tuberculosis. No acid fast organism was seen on Ziehl-Neelsen staining. A chest thorax X-ray revealed no sign of pulmonary tuberculosis. The patient underwent antituberculosis therapy during one year. Posttreatment hysteroscopy revealed no abnormality. This is the first reported case of endometrial tuberculosis diagnosed following removal of a polyp with classical benign appearance. PMID:23607011

  16. Multifocal tuberculosis verrucosa cutis.

    PubMed

    Chahar, Monica; Dhali, Tapan Kumar; D'souza, Paschal

    2015-01-01

    Tuberculosis Verrucosa Cutis (TBVC), a verrucous form of cutaneous tuberculosis, occurs from inoculation of tubercle bacilli into the skin of a previously sensitized patient with moderate to high degree of immunity. This disease is now rare in western countries and in India; the incidence of cutaneous tuberculosis has fallen from 2% to 0.15%. However two recent studies from the Indian subcontinent have reported the prevalence of cutaneous tuebrculosis as 0.7% (Varshney et al) and 0.26% (Patra et al) This case is reported to demonstrate the indolent and extensive nature of tuberculosis verrucosa cutis in an immunocompetent individual and to highlight the importance of histopathology and empirical antitubercular therapy as an adjunct diagnostic tool. PMID:25612118

  17. Tuberculosis and Pregnancy

    MedlinePLUS

    ... the African-American Community Summit Background Slideset Slideset Text version Websites Children Correctional Facilities Table of Contents ... Tuberculosis Laboratory Aggregate Reports Slide Sets Core Curriculum Text- only version Self-Study Modules Module 1 (text ...

  18. Tuberculosis in Blacks

    MedlinePLUS

    ... the African-American Community Summit Background Slideset Slideset Text version Websites Children Correctional Facilities Table of Contents ... Tuberculosis Laboratory Aggregate Reports Slide Sets Core Curriculum Text- only version Self-Study Modules Module 1 (text ...

  19. Global Tuberculosis (TB)

    MedlinePLUS

    ... the African-American Community Summit Background Slideset Slideset Text version Websites Children Correctional Facilities Table of Contents ... Tuberculosis Laboratory Aggregate Reports Slide Sets Core Curriculum Text- only version Self-Study Modules Module 1 (text ...

  20. Esophageal tuberculosis mimicking malignancy.

    PubMed

    Geusens, E; Verschakelen, J A; Flamaing, J; Bogaert, J; Ponette, E; Decramer, M; Baert, A L

    1996-01-01

    A case of pulmonary and esophageal tuberculosis in an 82-year-old female is presented. Esophageal tuberculosis is very rarely seen in Europe and the United States, but the disease is still endemic in India. The major differential diagnosis is esophageal malignancy. Findings that can suggest the diagnosis are tracheo-esophageal fistula formation, enlarged, centrally necrotizing lymph nodes, and a micronodular lung pattern. PMID:8797957

  1. A Multicopper Oxidase Is Required for Copper Resistance in Mycobacterium tuberculosis

    PubMed Central

    Rowland, Jennifer L.

    2013-01-01

    Mycobacterium tuberculosis, the causative agent of tuberculosis, is one of the most important bacterial pathogens. Recent work has revealed that the natural bactericidal properties of copper are utilized by the host immune system to combat infections with bacteria, including M. tuberculosis. However, M. tuberculosis employs multiple mechanisms to reduce the internal copper amount by efflux and sequestration, which are required for virulence of M. tuberculosis. Here, we describe an alternative mechanism of copper resistance by M. tuberculosis. Deletion of the rv0846c gene increased the susceptibility of M. tuberculosis to copper at least 10-fold, establishing Rv0846c as a major component of copper resistance in M. tuberculosis. In vitro assays showed that Rv0846c oxidized organic substrates and Fe(II). Importantly, mutation of the predicted copper-coordinating cysteine 486 resulted in inactive Rv0846c protein which did not protect M. tuberculosis against copper stress. Hence, Rv0846c is a multicopper oxidase of M. tuberculosis and was renamed mycobacterial multicopper oxidase (MmcO). MmcO is membrane associated, probably by lipidation after export across the inner membrane by the twin-arginine translocation system. However, mutation of the lipidation site did not affect the oxidase activity or the copper protective function of MmcO. Our study revealed MmcO as an important copper resistance mechanism of M. tuberculosis, which possibly acts by oxidation of toxic Cu(I) in the periplasm. PMID:23772064

  2. The production of consumption: addressing the impact of mineral mining on tuberculosis in southern Africa

    PubMed Central

    Basu, Sanjay; Stuckler, David; Gonsalves, Gregg; Lurie, Mark

    2009-01-01

    Background Miners in southern Africa experience incident rates of tuberculosis up to ten times greater than the general population. Migration to and from mines may be amplifying tuberculosis epidemics in the general population. Discussion Migration to and from mineral mines contributes to HIV risks and associated tuberculosis incidence. Health and safety conditions within mines also promote the risk of silicosis (a tuberculosis risk factor) and transmission of tuberculosis bacilli in close quarters. In the context of migration, current tuberculosis prevention and treatment strategies often fail to provide sufficient continuity of care to ensure appropriate tuberculosis detection and treatment. Reports from Lesotho and South Africa suggest that miners pose transmission risks to other household or community members as they travel home undetected or inadequately treated, particularly with drug-resistant forms of tuberculosis. Reducing risky exposures on the mines, enhancing the continuity of primary care services, and improving the enforcement of occupational health codes may mitigate the harmful association between mineral mining activities and tuberculosis incidence among affected communities. Summary Tuberculosis incidence appears to be amplified by mineral mining operations in southern Africa. A number of immediately-available measures to improve continuity of care for miners, change recruitment and compensation practices, and reduce the primary risk of infection may critically mitigate the negative association between mineral mining and tuberculosis. PMID:19785769

  3. Risk of Active Tuberculosis in HIV-Infected Patients in Taiwan with Free Access to HIV Care and a Positive T-Spot.TB Test

    PubMed Central

    Sun, Hsin-Yun; Hsueh, Po-Ren; Liu, Wen-Chun; Su, Yi-Ching; Chang, Sui-Yuan; Hung, Chien-Ching; Chang, Shan-Chwen

    2015-01-01

    Background Interferon-gamma release assays (IGRAs) have been used to identify individuals at risk for developing active tuberculosis (TB). However, data regarding the risk of TB development in HIV-infected patients testing positive for IGRAs remain sparse in the era of combination antiretroviral therapy. Methods Between 2011 and 2013, 608 HIV-infected patients without active TB undergoing T-Spot.TB testing were enrolled in this prospective observational study at a university hospital designated for HIV care in Taiwan with a declining TB incidence from 72 per 100,000 population in 2005 to 53 per 100,000 population in 2012. All of the subjects were followed until September 30, 2014. The national TB registry was accessed to identify any TB cases among those lost to follow-up. Results T-Spot.TB tested negative in 534 patients (87.8%), positive in 64 patients (10.5%), and indeterminate in 10 patients (1.6%). In multivariate analysis, positive T-Spot.TB was significantly associated with older age (adjusted odds ratio [AOR], 1.172 per 10-year increase; 95% confidence interval [CI], 1.022-1.344, P=0.023), past history of TB (AOR, 13.412; 95% CI, 6.106-29.460, P<0.001), and higher CD4 counts at enrollment (AOR, per 50-cell/?l increase, 1.062; 95% CI, 1.017-1.109, P=0.007). Of the 64 patients testing positive for T-Spot.TB, none received isoniazid preventive therapy and all but 5 received combination antiretroviral therapy at the end of follow-up with the latest CD4 count and plasma HIV RNA load being 592.8 cells/?L and 1.85 log10 copies/mL, respectively. One patient (1.6%) developed active TB after 167 person-years of follow-up (PYFU), resulting in an incidence rate of 0.599 per 100 PFYU. None of the 534 patients testing negative for T-Spot.TB developed TB after 1380 PYFU, nor did the 24 patients with old TB and positive T-Spot.TB tests develop TB after 62.33 PYFU. Conclusions The risk of developing active TB in HIV-infected patients with positive T-Spot.TB receiving combination antiretroviral therapy is low in Taiwan where the national TB program has led to a sustained decrease in TB incidence. PMID:25938227

  4. PICTURES OF A SUSPECT-TRU RETRIEVAL

    SciTech Connect

    GADD, R.R.

    2007-05-24

    Retrieving ''suspect'' transuranic (TRU) waste from the Hanford Site's low-level waste burial grounds is a tall order, due to conditions that have changed as the work progresses. Project personnel developed several new methods for handling the waste that other retrieval operations may find useful. The Waste Retrieval Project is operated by Fluor Hanford, a prime contractor for the U.S. Department of Energy's Richland Operations Office since 1996.

  5. Imaging in tuberculosis.

    PubMed

    Skoura, Evangelia; Zumla, Alimuddin; Bomanji, Jamshed

    2015-03-01

    Early diagnosis of tuberculosis (TB) is necessary for effective treatment. In primary pulmonary TB, chest radiography remains the mainstay for the diagnosis of parenchymal disease, while computed tomography (CT) is more sensitive in detecting lymphadenopathy. In post-primary pulmonary TB, CT is the method of choice to reveal early bronchogenic spread. Concerning characterization of the infection as active or not, CT is more sensitive than radiography, and (18)F-fluorodeoxyglucose positron emission tomography/CT ((18)F-FDG PET/CT) has yielded promising results that need further confirmation. The diagnosis of extrapulmonary TB sometimes remains difficult. Magnetic resonance imaging (MRI) is the preferred modality in the diagnosis and assessment of tuberculous spondylitis, while (18)F-FDG PET shows superior image resolution compared with single-photon-emitting tracers. MRI is considered superior to CT for the detection and assessment of central nervous system TB. Concerning abdominal TB, lymph nodes are best evaluated on CT, and there is no evidence that MRI offers added advantages in diagnosing hepatobiliary disease. As metabolic changes precede morphological ones, the application of (18)F-FDG PET/CT will likely play a major role in the assessment of the response to anti-TB treatment. PMID:25809762

  6. An intervention to stop smoking among patients suspected of TB - evaluation of an integrated approach

    PubMed Central

    2010-01-01

    Background In many low- and middle-income countries, where tobacco use is common, tuberculosis is also a major problem. Tobacco use increases the risk of developing tuberculosis, secondary mortality, poor treatment compliance and relapses. In countries with TB epidemic, even a modest relative risk leads to a significant attributable risk. Treating tobacco dependence, therefore, is likely to have benefits for controlling tuberculosis in addition to reducing the non-communicable disease burden associated with smoking. In poorly resourced health systems which face a dual burden of disease secondary to tuberculosis and tobacco, an integrated approach to tackle tobacco dependence in TB control could be economically desirable. During TB screening, health professionals come across large numbers of patients with respiratory symptoms, a significant proportion of which are likely to be tobacco users. These clinical encounters, considered to be "teachable moments", provide a window of opportunity to offer treatment for tobacco dependence. Methods/Design We aim to develop and trial a complex intervention to reduce tobacco dependence among TB suspects based on the WHO 'five steps to quit' model. This model relies on assessing personal motivation to quit tobacco use and uses it as the basis for assessing suitability for the different therapeutic options for tobacco dependence. We will use the Medical Research Council framework approach for evaluating complex interventions to: (a) design an evidence-based treatment package (likely to consist of training materials for health professionals and education tools for patients); (b) pilot the package to determine the delivery modalities in TB programme (c) assess the incremental cost-effectiveness of the package compared to usual care using a cluster RCT design; (d) to determine barriers and drivers to the provision of treatment of tobacco dependence within TB programmes; and (e) support long term implementation. The main outcomes to assess the effectiveness would be point abstinence at 4 weeks and continuous abstinence up to 6 months. Discussion This work will be carried out in Pakistan and is expected to have relevance for other low and middle income countries with high tobacco use and TB incidence. This will enhance our knowledge of the cost-effectiveness of treating tobacco dependence in patients suspected of TB. Trial Registration Trial Registration Number: ISRCTN08829879 PMID:20338041

  7. Evaluation of antibody and cell-mediated based tests for detection of bovine tuberculosis in United States' cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine tuberculosis (BTB) was detected in a United States (US) dairy in 2010 through slaughter surveillance. The high apparent bTB prevalence (29% caudal fold tuberculin test (CFT) suspects) revealed after whole herd testing, offered an opportunity to revisit the performance of US official antemort...

  8. [New diagnostic methods for tuberculosis and their clinical utilities].

    PubMed

    2002-12-01

    The clinical utilities of new diagnostic methods for Mycobacterium tuberculosis, such as primary isolation and drug susceptibility testing using MGIT, identification using anti-MPB 64 monoclonal antibodies and nucleic acid amplification assay, were studied. It was shown that these new diagnostic methods were more rapid and more accurate than currently available approaches and useful for the early and aggressive case findings. Questionnaire survey indicated that most of the laboratories had been ready to introduce these new diagnostic methods. Thus, the diagnosis for active tuberculosis along the "CDC recommendation in 1993" has become realizable in Japan. Now, Japanese TB control program is under revision due to the current stagnation of the decline in notification rates. The importance of rapid and accurate diagnosis of active tuberculosis should be declared in the new Japanese TB control program by indicating the guideline of rapid diagnostic methods for Mycobacterium tuberculosis. PMID:12607342

  9. Innate immunity in tuberculosis: myths and truth.

    PubMed

    Korbel, Daniel S; Schneider, Bianca E; Schaible, Ulrich E

    2008-07-01

    Tuberculosis is the most important bacterial infection world wide. The causative agent, Mycobacterium tuberculosis survives and proliferates within macrophages. Immune mediators such as interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha) activate macrophages and promote bacterial killing. IFN-gamma is predominantly secreted by innate cells (mainly natural killer (NK) cells) and by T cells upon instruction by interleukin 12 (IL-12) and IL-18. These cytokines are primarily produced by dendritic cells and macrophages in response to Toll-like receptor (TLR) signalling interaction with tubercle bacilli. These signals also induce pro-inflammatory cytokines (including IL-1beta and TNF-alpha), chemokines and defensins. The inflammatory environment further recruits innate effector cells such as macrophages, polymorphonuclear neutrophils (PMN) and NK cells to the infectious foci. This eventually leads to the downstream establishment of acquired T cell immunity which appears to be protective in more than 90% of infected individuals. Robust innate immune activation is considered an essential prerequisite for protective immunity and vaccine efficacy. However, data published so far provide a muddled view of the functional importance of innate immunity in tuberculosis. Here we critically discuss certain aspects of innate immunity, namely PMN, TLRs and NK cells, as characterised in tuberculosis to date, and their contribution to protection and pathology. PMID:18762264

  10. Efficacies of selected disinfectants against Mycobacterium tuberculosis.

    PubMed Central

    Best, M; Sattar, S A; Springthorpe, V S; Kennedy, M E

    1990-01-01

    The activities of 10 formulations as mycobactericidal agents in Mycobacterium tuberculosis-contaminated suspensions (suspension test) and stainless steel surfaces (carrier test) were investigated with sputum as the organic load. The quaternary ammonium compound, chlorhexidine gluconate, and an iodophor were ineffective in all tests. Ethanol (70%) was effective against M. tuberculosis only in suspension in the absence of sputum. Povidone-iodine was not as efficacious when the test organism was dried on a surface as it was in suspension, and its activity was further reduced in the presence of sputum. Sodium hypochlorite required a higher concentration of available chlorine to achieve an effective level of disinfection than did sodium dichloroisocyanurate. Phenol (5%) was effective under all test conditions, producing at least a 4-log10 reduction in CFU. The undiluted glutaraldehyde-phenate solution was effective against M. tuberculosis and a second test organism, Mycobacterium smegmatis, even in the presence of dried sputum, whereas the diluted solution (1:16) was only effective against M. smegmatis in the suspension test. A solution of 2% glutaraldehyde was effective against M. tuberculosis. This investigation presents tuberculocidal efficacy data generated by methods simulating actual practices of routine disinfection. PMID:2121783

  11. Efficacies of selected disinfectants against Mycobacterium tuberculosis.

    PubMed

    Best, M; Sattar, S A; Springthorpe, V S; Kennedy, M E

    1990-10-01

    The activities of 10 formulations as mycobactericidal agents in Mycobacterium tuberculosis-contaminated suspensions (suspension test) and stainless steel surfaces (carrier test) were investigated with sputum as the organic load. The quaternary ammonium compound, chlorhexidine gluconate, and an iodophor were ineffective in all tests. Ethanol (70%) was effective against M. tuberculosis only in suspension in the absence of sputum. Povidone-iodine was not as efficacious when the test organism was dried on a surface as it was in suspension, and its activity was further reduced in the presence of sputum. Sodium hypochlorite required a higher concentration of available chlorine to achieve an effective level of disinfection than did sodium dichloroisocyanurate. Phenol (5%) was effective under all test conditions, producing at least a 4-log10 reduction in CFU. The undiluted glutaraldehyde-phenate solution was effective against M. tuberculosis and a second test organism, Mycobacterium smegmatis, even in the presence of dried sputum, whereas the diluted solution (1:16) was only effective against M. smegmatis in the suspension test. A solution of 2% glutaraldehyde was effective against M. tuberculosis. This investigation presents tuberculocidal efficacy data generated by methods simulating actual practices of routine disinfection. PMID:2121783

  12. 48 CFR 1403.806 - Processing suspected violations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...to Influence Federal Transactions 1403.806 Processing suspected violations. Suspected violations shall be referred to the HCA. The HCA, in consultation with the SOL and OIG, shall act in accordance with FAR...

  13. 48 CFR 1403.806 - Processing suspected violations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...to Influence Federal Transactions 1403.806 Processing suspected violations. Suspected violations shall be referred to the HCA. The HCA, in consultation with the SOL and OIG, shall act in accordance with FAR...

  14. Suspected viral erythrocytic necrosis (VEN) in a juvenile blackbar triggerfish,

    E-print Network

    Grutter, Alexandra "Lexa"

    Suspected viral erythrocytic necrosis (VEN) in a juvenile blackbar triggerfish, Rhinecanthus Suspected viral erythrocytic necrosis (VEN) was detected in blood films from an immature blackbar erythrocytes affected by the VEN-like condition, but accompanying erythroblasts appeared free from infection

  15. Natural lysophospholipids reduce Mycobacterium tuberculosis-induced cytotoxicity and induce anti-mycobacterial activity by a phagolysosome maturation-dependent mechanism in A549 type II alveolar epithelial cells.

    PubMed

    Greco, Emanuela; Santucci, Marilina B; Sali, Michela; De Angelis, Francesca R; Papi, Massimiliano; De Spirito, Marco; Delogu, Giovanni; Colizzi, Vittorio; Fraziano, Maurizio

    2010-01-01

    Human alveolar epithelial cells actively contribute to the innate immune response in the lung and play an important role in mycobacterial dissemination during primary infection, by undergoing cell death and by releasing mycobacteria. In the present study, we report that natural lysophospholipids, such as lysophosphatidic acid or sphingosine 1-phosphate, reduce Mycobacterium tuberculosis-induced cytotoxicity and enhance anti-mycobacterial activity in the A549 cell line, used as a model of type II alveolar epithelial cells. Intracellular mycobacterial killing was strictly dependent on phagolysosome maturation, which in turn was promoted by the activation of a Ca(2+)dependent phospholipase D. Finally, the restriction of mycobacteria in highly microbiocidal compartments was associated, in vitro, with a significant decrease in mycobacterial dissemination to macrophages. Taken as whole, these results suggest that the pulmonary lysophospholipid microenvironment may play a protective role during the early phases of host-pathogen interaction by enhancing anti-mycobacterial activity in type II alveolar epithelial cells. PMID:19878354

  16. Natural lysophospholipids reduce Mycobacterium tuberculosis-induced cytotoxicity and induce anti-mycobacterial activity by a phagolysosome maturation-dependent mechanism in A549 type II alveolar epithelial cells

    PubMed Central

    Greco, Emanuela; Santucci, Marilina B; Sali, Michela; De Angelis, Francesca R; Papi, Massimiliano; De Spirito, Marco; Delogu, Giovanni; Colizzi, Vittorio; Fraziano, Maurizio

    2010-01-01

    Human alveolar epithelial cells actively contribute to the innate immune response in the lung and play an important role in mycobacterial dissemination during primary infection, by undergoing cell death and by releasing mycobacteria. In the present study, we report that natural lysophospholipids, such as lysophosphatidic acid or sphingosine 1-phosphate, reduce Mycobacterium tuberculosis-induced cytotoxicity and enhance anti-mycobacterial activity in the A549 cell line, used as a model of type II alveolar epithelial cells. Intracellular mycobacterial killing was strictly dependent on phagolysosome maturation, which in turn was promoted by the activation of a Ca2+dependent phospholipase D. Finally, the restriction of mycobacteria in highly microbiocidal compartments was associated, in vitro, with a significant decrease in mycobacterial dissemination to macrophages. Taken as whole, these results suggest that the pulmonary lysophospholipid microenvironment may play a protective role during the early phases of host–pathogen interaction by enhancing anti-mycobacterial activity in type II alveolar epithelial cells. PMID:19878354

  17. Tuberculosis in the United States in 2012: Current Approaches

    PubMed Central

    Gordin, Fred M.; Masur, Henry

    2014-01-01

    Tuberculosis is a major threat to global health, infecting a third of the world's population. In the US, however, control of tuberculosis has been increasingly successful. Only 3.2% of the US population is estimated to have latent tuberculosis, and there are only 11,000 cases annually of active disease. Over half the cases in this country occur in individuals born outside the US. HIV coinfection is not a major factor in the US, since only about 10% of cases are coinfected. Drug resistance is also uncommon in this country. Since the US has more resources for the diagnosis, therapy, and public health control of tuberculosis than many regions of the world, and because many hospitals have more cases of clinically significant non-tuberculous mycobacteria than tuberculosis, the management approaches to tuberculosis need to be quite different in this country than in other regions. The resurgence in interest in developing new tools and the investment in public health infrastructure will hopefully be sustained in the US so that the impact of tuberculosis on the US population will continue to diminish, and these new tools and approaches can be adapted to both high prevalence and low prevalence areas to meet the global challenge. PMID:22797646

  18. Peripheral Blood Gamma Interferon Release Assays Predict Lung Responses and Mycobacterium tuberculosis Disease Outcome in Mice

    Microsoft Academic Search

    Gillian L. Beamer; David K. Flaherty; Bridget Vesosky; Joanne Turner

    2008-01-01

    Current diagnostic tests for tuberculosis (TB) are not able to distinguish active disease from latent Myco- bacterium tuberculosis infection, nor are they able to quantify the risk of a latently infected person progressing to active TB. There is interest, however, in adapting antigen-specific gamma interferon (IFN-) release assays (IGRAs) to predict disease outcome. In this study, we used the differential

  19. Efficacy of Nitazoxanide against Clinical Isolates of Mycobacterium tuberculosis

    PubMed Central

    Shigyo, Kristina; Ocheretina, Oksana; Merveille, Yves Mary; Johnson, Warren D.; Pape, Jean William; Nathan, Carl F.

    2013-01-01

    Nitazoxanide (NTZ) has bactericidal activity against the H37Rv laboratory strain of Mycobacterium tuberculosis with a MIC of 16 ?g/ml. However, its efficacy against clinical isolates of M. tuberculosis has not been determined. We found that NTZ's MIC against 50 clinical isolates ranged from 12 to 28 ?g/ml with a median of 16 ?g/ml and was unaffected by resistance to first- or second-line antituberculosis drugs or a diversity of spoligotypes. PMID:23507275

  20. Efficacy of nitazoxanide against clinical isolates of Mycobacterium tuberculosis.

    PubMed

    Shigyo, Kristina; Ocheretina, Oksana; Merveille, Yves Mary; Johnson, Warren D; Pape, Jean William; Nathan, Carl F; Fitzgerald, Daniel W

    2013-06-01

    Nitazoxanide (NTZ) has bactericidal activity against the H37Rv laboratory strain of Mycobacterium tuberculosis with a MIC of 16 ?g/ml. However, its efficacy against clinical isolates of M. tuberculosis has not been determined. We found that NTZ's MIC against 50 clinical isolates ranged from 12 to 28 ?g/ml with a median of 16 ?g/ml and was unaffected by resistance to first- or second-line antituberculosis drugs or a diversity of spoligotypes. PMID:23507275

  1. Targeting tuberculosis through a small focused library of 1,2,3-triazoles

    Microsoft Academic Search

    Guillermo R. Labadie; Agustina de la Iglesia; Héctor R. Morbidoni

    Looking for new active molecules against Mycobacterium tuberculosis, a small focused library of 1,2,3-triazoles was efficiently prepared by click chemistry. Compounds were subsequently tested\\u000a against different pathogenic and opportunistic mycobacteria including M. avium and M. tuberculosis. Two of them showed MIC at lower ?g\\/mL concentration for M. avium and even below that for M. tuberculosis, being more potent that control drugs.

  2. Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis

    PubMed Central

    Keeton, Roanne; Allie, Nasiema; Dambuza, Ivy; Abel, Brian; Hsu, Nai-Jen; Sebesho, Boipelo; Randall, Philippa; Burger, Patricia; Fick, Elizabeth; Quesniaux, Valerie F.J.; Ryffel, Bernhard; Jacobs, Muazzam

    2014-01-01

    Development of host protective immunity against Mycobacterium tuberculosis infection is critically dependent on the inflammatory cytokine TNF. TNF signals through 2 receptors, TNFRp55 and TNFRp75; however, the role of TNFRp75-dependent signaling in immune regulation is poorly defined. Here we found that mice lacking TNFRp75 exhibit greater control of M. tuberculosis infection compared with WT mice. TNFRp75–/– mice developed effective bactericidal granulomas and demonstrated increased pulmonary recruitment of activated DCs. Moreover, IL-12p40–dependent migration of DCs to lung draining LNs of infected TNFRp75–/– mice was substantially higher than that observed in WT M. tuberculosis–infected animals and was associated with enhanced frequencies of activated M. tuberculosis–specific IFN-?–expressing CD4+ T cells. In WT mice, TNFRp75 shedding correlated with markedly reduced bioactive TNF levels and IL-12p40 expression. Neutralization of TNFRp75 in M. tuberculosis–infected WT BM-derived DCs (BMDCs) increased production of bioactive TNF and IL-12p40 to a level equivalent to that produced by TNFRp75–/– BMDCs. Addition of exogenous TNFRp75 to TNFRp75–/– BMDCs infected with M. tuberculosis decreased IL-12p40 synthesis, demonstrating that TNFRp75 shedding regulates DC activation. These data indicate that TNFRp75 shedding downmodulates protective immune function and reduces host resistance and survival; therefore, targeting TNFRp75 may be beneficial for improving disease outcome. PMID:24569452

  3. Promising drugs against tuberculosis.

    PubMed

    de Souza, Marcus Vinícius Nora

    2006-01-01

    Tuberculosis (TB) is an important public health problem worldwide due to AIDS epidemic, the advent of multidrug resistant strains (MDR) and the lack of new drugs in the market. TB is responsible for almost 3 millions deaths each year. According to WHO (World Health Organization), which declared tuberculosis a global health emergency in 1993, tuberculosis, without a coordinated control effort, will infect an estimated 1 billion people by 2020, killing 70 million. In spite of this problem, there is a lack of development of new TB drugs. For example, it has been nearly 35 years since the introduction of a new class of compounds for the treatment of TB. Thus, there is an urgent need for new drugs to fight against this disease. Considering that, this review aims promising drug candidates that are in development against TB. PMID:18221132

  4. Spoligotyping and Mycobacterium tuberculosis.

    PubMed

    Gori, Andrea; Bandera, Alessandra; Marchetti, Giulia; Degli Esposti, Anna; Catozzi, Lidia; Nardi, Gian Piero; Gazzola, Lidia; Ferrario, Giulio; van Embden, Jan D A; van Soolingen, Dick; Moroni, Mauro; Franzetti, Fabio

    2005-08-01

    We evaluated the clinical usefulness of spoligotyping, a polymerase chain reaction-based method for simultaneous detection and typing of Mycobacterium tuberculosis strains, with acid-fast bacilli-positive slides from clinical specimens or mycobacterial cultures. Overall sensitivity and specificity were 97% and 95% for the detection of M. tuberculosis and 98% and 96% when used with clinical specimens. Laboratory turnaround time of spoligotyping was less than that for culture identification by a median of 20 days. In comparison with IS6110-based restriction fragment length polymorphism typing, spoligotyping overestimated the number of isolates with identical DNA fingerprints by approximately 50%, but showed a 100% negative predictive value. Spoligotyping resulted in the modification of ongoing antimycobacterial treatment in 40 cases and appropriate therapy in the absence of cultures in 11 cases. The rapidity of this method in detection and typing could make it useful in the management of tuberculosis in a clinical setting. PMID:16102314

  5. Tuberculosis screening in a dialysis unit: detecting latent tuberculosis infection is only half the problem.

    PubMed

    Brij, S O; Beck, S C; Kleemann, F; Jack, A L; Wilkinson, C; Enoch, D A

    2014-08-01

    Patients with chronic kidney disease are at increased risk of tuberculosis. We describe the events that occurred when we encountered a patient receiving haemodialysis with pulmonary tuberculosis. Nine (of 41) patients dialysing at the same time as the index case had a positive interferon-gamma release assay (IGRA) and were offered therapy for latent tuberculosis infection (LTBI). Patients with an initial negative IGRA were rescreened at six months, identifying a further three IGRA-positive patients. All patients were then rescreened at 12 months. No new IGRA-positive cases were identified and no staff or patients developed active disease. Only five of the 12 IGRA-positive patients completed LTBI therapy. PMID:25027226

  6. Detection of Mycobacterium tuberculosis DNA on the oral mucosa of tuberculosis patients.

    PubMed

    Wood, Rachel C; Luabeya, Angelique K; Weigel, Kris M; Wilbur, Alicia K; Jones-Engel, Lisa; Hatherill, Mark; Cangelosi, Gerard A

    2015-01-01

    Diagnosis of pulmonary tuberculosis (TB) usually includes laboratory analysis of sputum, a viscous material derived from deep in the airways of patients with active disease. As a diagnostic sample matrix, sputum can be difficult to collect and analyze by microbiological and molecular techniques. An alternative, less invasive sample matrix could greatly simplify TB diagnosis. We hypothesized that Mycobacterium tuberculosis cells or DNA accumulate on the oral epithelia of pulmonary TB patients, and can be collected and detected by using oral (buccal) swabs. To test this hypothesis, 3 swabs each were collected from 20 subjects with active pulmonary TB and from 20 healthy controls. Samples were tested by using a polymerase chain reaction (PCR) specific to the M. tuberculosis IS6110 insertion element. Eighteen out of 20 confirmed case subjects (90%) yielded at least 2 positive swabs. Healthy control samples were 100% negative. This case-control study supports past reports of M. tuberculosis DNA detection in oral swabs. Oral swab samples are non-invasive, non-viscous, and easy to collect with or without active TB symptoms. These characteristics may enable simpler and more active TB case finding strategies. PMID:25727773

  7. Quest for correlates of protection against tuberculosis.

    PubMed

    Bhatt, Kamlesh; Verma, Sheetal; Ellner, Jerrold J; Salgame, Padmini

    2015-03-01

    A major impediment to tuberculosis (TB) vaccine development is the lack of reliable correlates of immune protection or biomarkers that would predict vaccine efficacy. Gamma interferon (IFN-?) produced by CD4(+) T cells and, recently, multifunctional CD4(+) T cells secreting IFN-?, tumor necrosis factor (TNF), and interleukin-2 (IL-2) have been used in vaccine studies as a measurable immune parameter, reflecting activity of a vaccine and potentially predicting protection. However, accumulating experimental evidence suggests that host resistance against Mycobacterium tuberculosis infection is independent of IFN-? and TNF secretion from CD4(+) T cells. Furthermore, the booster vaccine MVA85A, despite generating a high level of multifunctional CD4(+) T cell response in the host, failed to confer enhanced protection in vaccinated subjects. These findings suggest the need for identifying reliable correlates of protection to determine the efficacy of TB vaccine candidates. This article focuses on alternative pathways that mediate M. tuberculosis control and their potential for serving as markers of protection. The review also discusses the significance of investigating the natural human immune response to M. tuberculosis to identify the correlates of protection in vaccination. PMID:25589549

  8. New weapons in the war on tuberculosis.

    PubMed

    Sharma, Sujata; Yoder, Mark A

    2011-07-01

    Tuberculosis continues to be a global threat. Efforts to eradicate this disease are hampered by the long course and potential toxicity of currently available treatment regimens, the increasing prevalence of tuberculosis-HIV coinfection, the evolution of drug resistant organisms, and the lack of a highly effective vaccine. Recent studies have suggested methods to improve the cost effectiveness of existing treatment strategies. Decreasing the relapse rate among high-risk individuals by extending therapy can be balanced by the cost savings of self-administered therapy for low-risk individuals. For the first time in over 30 years, new medications are flowing through the drug discovery pipeline. New agents with activity against slowly dividing bacilli have the potential to shorten the duration of therapy. Many have a more favorable side-effect profile than currently available medications. And even extensively drug-resistant organisms will be susceptible to these secret weapons. The fully sequenced genome of Mycobacterium tuberculosis has been exploited to develop safer and more effective candidate vaccines. Highly immunogenic mycobacterial fragments, revved-up versions of the existing vaccine, and toned-down versions of M. tuberculosis are all in various phases of clinical testing. This expanded arsenal has the potential to deliver a fatal blow to one of humanity's greatest enemies. PMID:21743301

  9. New tuberculosis drugs in development.

    PubMed

    Laughon, Barbara E

    2007-01-01

    Over the past 50 years, no new drug classes have been introduced to treat tuberculosis. Tuberculosis (TB) kills nearly two million people a year mainly in the poorest communities in the developing world. It afflicts millions more. About one third of the world's population is silently infected with TB that may erupt into disease with increased age or suppression of the immune system. Nearly nine million new active cases develop every year. The World Health Organization (WHO) declared the disease a global emergency as long ago as 1993. Although huge efforts in public health control have reduced the disease burden within most established market economies, in Africa and Asia the epidemic continues to accelerate, particularly fueled by the HIV epidemic. Furthermore, resistance to the standard drugs isoniazid and rifampicin is increasing worldwide. Since the 1990s, mycobacteria have emerged with resistance patterns rendering all currently available antibiotics ineffectual. The pharmaceutical industry has mostly abandoned TB drug development due to perceived non-profitable consumer market and the diminishing number of companies engaged in anti-infective research. The public sector and infectious disease researchers have responded to advance fundamental science and to create new chemical entities as early drug candidates. With support from research funding agencies, philanthropic donors, and the STOP-TB Partnership, new chemical tools and new approaches to effectively implement TB control programs are evolving. Advanced preclinical development and strategies for Phase III clinical trials remain gap areas that will require additional engagement from all sectors. PMID:17346192

  10. Perspectives on tuberculosis in pregnancy.

    PubMed

    Bates, Matthew; Ahmed, Yusuf; Kapata, Nathan; Maeurer, Markus; Mwaba, Peter; Zumla, Alimuddin

    2015-03-01

    Tuberculosis (TB) has been recognized as an important cause of morbidity and mortality in pregnancy for nearly a century, but research and efforts to roll out comprehensive TB screening and treatment in high-risk populations such as those with a high prevalence of HIV or other diseases of poverty, have lagged behind similar efforts to address HIV infection in pregnancy and the prevention of mother-to-child-transmission. Immunological changes during pregnancy make the activation of latent TB infection or de novo infection more likely than among non-pregnant women. TB treatment in pregnancy poses several problems that have been under-researched, such as contraindications to anti-TB and anti-HIV drugs and potential risks to the neonate, which are particularly important with respect to second-line TB treatment. Whilst congenital TB is thought to be rare, data from high HIV burden settings suggest this is not the case. There is a need for more studies screening for TB in neonates and observing outcomes, and testing preventative or curative actions. National tuberculosis control programmes (NTPs) should work with antenatal and national HIV programmes in high-burden populations to provide screening at antenatal clinics, or to establish functioning systems whereby pregnant women at high risk can drop in to routine NTP screening stations. PMID:25809768

  11. The role and performance of chest X-ray for the diagnosis of tuberculosis: A cost-effectiveness analysis in Nairobi, Kenya

    Microsoft Academic Search

    MRA van Cleeff; L. E. Kivihya-Ndugga; H. Meme; J. A. Odhiambo; P. R. Klatser

    2005-01-01

    BACKGROUND: The objective of this study was to establish 1) the performance of chest X-ray (CXR) in all suspects of tuberculosis (TB), as well as smear-negative TB suspects and 2) to compare the cost-effectiveness of the routine diagnostic pathway using Ziehl-Neelsen (ZN) sputum microscopy followed by CXR if case of negative sputum result (ZN followed by CXR) with an alternative

  12. Detection of Mycobacterium tuberculosis complex by nested polymerase chain reaction in pulmonary and extrapulmonary specimens* ,**

    PubMed Central

    Furini, Adriana Antônia da Cruz; Pedro, Heloisa da Silveira Paro; Rodrigues, Jean Francisco; Montenegro, Lilian Maria Lapa; Machado, Ricardo Luiz Dantas; Franco, Célia; Schindler, Haiana Charifker; Batista, Ida Maria Foschiani Dias; Rossit, Andrea Regina Baptista

    2013-01-01

    OBJECTIVE: To compare the performance of nested polymerase chain reaction (NPCR) with that of cultures in the detection of the Mycobacterium tuberculosis complex in pulmonary and extrapulmonary specimens. METHODS: We analyzed 20 and 78 pulmonary and extrapulmonary specimens, respectively, of 67 hospitalized patients suspected of having tuberculosis. An automated microbial system was used for the identification of Mycobacterium spp. cultures, and M. tuberculosis IS6110 was used as the target sequence in the NPCR. The kappa statistic was used in order to assess the level of agreement among the results. RESULTS: Among the 67 patients, 6 and 5, respectively, were diagnosed with pulmonary and extrapulmonary tuberculosis, and the NPCR was positive in all of the cases. Among the 98 clinical specimens, smear microscopy, culture, and NPCR were positive in 6.00%, 8.16%, and 13.26%, respectively. Comparing the results of NPCR with those of cultures (the gold standard), we found that NPCR had a sensitivity and specificity of 100% and 83%, respectively, in pulmonary specimens, compared with 83% and 96%, respectively, in extrapulmonary specimens, with good concordance between the tests (kappa, 0.50 and 0.6867, respectively). CONCLUSIONS: Although NPCR proved to be a very useful tool for the detection of M. tuberculosis complex, clinical, epidemiological, and other laboratory data should also be considered in the diagnosis and treatment of pulmonary and extrapulmonary tuberculosis. PMID:24473765

  13. How do we manage and treat a patient with multiple sclerosis at risk of tuberculosis?

    PubMed

    Fragoso, Yara Dadalti; Adoni, Tarso; Anacleto, Andrea; Brooks, Joseph Bruno Bidin; Carvalho, Margarete de Jesus; Claudino, Rinaldo; Damasceno, Alfredo; Ferreira, Maria Lucia Brito; Gama, Paulo Diniz da; Goncalves, Marcus Vinicus Magno; Grzesiuk, Anderson Kuntz; Matta, Andre Palma da Cunha; Parolin, Monica Fiuza Koncke

    2014-11-01

    Tuberculosis continues to be a serious health problem worldwide. The disease continues to be underdiagnosed and not properly treated. In conditions that affect the immune system, such as multiple sclerosis (MS), latent tuberculosis may thrive and reactivate during the use of immunomodulatory and immunosuppressive drugs. Among the best treatment options for patients with latent or active tuberculosis who have MS are IFN-?, glatiramer acetate and mitoxantrone. Drugs leading to a reduced number and/or function of lymphocytes should be avoided or used with caution. Tuberculosis must always be investigated in patients with MS and treated with rigor. PMID:25242167

  14. Regulatory T cells and M. tuberculosis JID 2010:202 (15 August) 533 M A J O R A R T I C L E

    E-print Network

    Kirschner, Denise

    Regulatory T cells and M. tuberculosis · JID 2010:202 (15 August) · 533 M A J O R A R T I C L E CD4+ Regulatory T Cells in a Cynomolgus Macaque Model of Mycobacterium tuberculosis Infection Angela M. Green,1 tuberculosis infection in humans results in either latent infection or active tu- berculosis. We sought

  15. Definition of Mycobacterium tuberculosis Culture Filtrate Proteins by Two-Dimensional Polyacrylamide Gel Electrophoresis, N-Terminal Amino Acid Sequencing, and Electrospray Mass Spectrometry

    Microsoft Academic Search

    MICHAEL G. SONNENBERG; JOHN T. BELISLE

    1997-01-01

    A number of the culture filtrate proteins secreted by Mycobacterium tuberculosis are known to contribute to the immunology of tuberculosis and to possess enzymatic activities associated with pathogenicity. However, a complete analysis of the protein composition of this fraction has been lacking. By using two-dimensional polyacrylamide gel electrophoresis, detailed maps of the culture filtrate proteins of M. tuberculosis H37Rv were

  16. A novel murine cytomegalovirus vaccine vector protects against Mycobacterium tuberculosis.

    PubMed

    Beverley, Peter C L; Ruzsics, Zsolt; Hey, Ariann; Hutchings, Claire; Boos, Simone; Bolinger, Beatrice; Marchi, Emanuele; O'Hara, Geraldine; Klenerman, Paul; Koszinowski, Ulrich H; Tchilian, Elma Z

    2014-09-01

    Tuberculosis remains a global health problem so that a more effective vaccine than bacillus Calmette-Guérin is urgently needed. Cytomegaloviruses persist lifelong in vivo and induce powerful immune and increasing ("inflationary") responses, making them attractive vaccine vectors. We have used an m1-m16-deleted recombinant murine CMV (MCMV) expressing Mycobacterium tuberculosis Ag 85A to show that infection of mice with this recombinant significantly reduces the mycobacterial load after challenge with M. tuberculosis, whereas control empty virus has a lesser effect. Both viruses induce immune responses to H-2(d)-restricted epitopes of MCMV pp89 and M18 Ags characteristic of infection with other MCMVs. A low frequency of 85A-specific memory cells could be revealed by in vivo or in vitro boosting or after challenge with M. tuberculosis. Kinetic analysis of M. tuberculosis growth in the lungs of CMV-infected mice shows early inhibition of M. tuberculosis growth abolished by treatment with NK-depleting anti-asialo ganglio-N-tetraosylceramide Ab. Microarray analysis of the lungs of naive and CMV-infected mice shows increased IL-21 mRNA in infected mice, whereas in vitro NK assays indicate increased levels of NK activity. These data indicate that activation of NK cells by MCMV provides early nonspecific protection against M. tuberculosis, potentiated by a weak 85A-specific T cell response, and they reinforce the view that the innate immune system plays an important role in both natural and vaccine-induced protection against M. tuberculosis. PMID:25070842

  17. [Current epidemiological trend of tuberculosis among foreigners in Japan].

    PubMed

    Yoshiyama, T; Ishikawa, N; Hoshino, H; Ohkado, A

    1999-09-01

    In Japan, the proportion of foreign patients among the total tuberculosis patients is still very small, but their problems in tuberculosis case finding and treatment require intensive control activities as in other low prevalence countries with higher proportion of foreign-born cases. The latest national survey for the foreign tuberculosis patients conducted in 1996 shows the epidemiological status between 1990 and 1993. The number of foreign tuberculosis patients in 1993 was 484, consisting of 1.0% of the total new patients in Japan. The new case rate among foreigners was estimated to be 53 per 100,000 against 38 for whole Japan in 1993. Compared with the figure in the 1993 survey, the number of foreign patients declined from 585 in 1992 to 484 in 1993. However, the number of bacillary positive tuberculosis patients in 1992 was 230 and almost the same as in 1992. The decline or stagnation of total number of tuberculosis patients can be due either to the decrease in the foreign population inflow into Japan (real decline), or partially to the reduction of overdiagnosis in X ray examination and the possible loss of some cases in the 1996 survey method. A manual sorting method from the registration cards was used at each public health center, since there is no item of country of origin in the routine tuberculosis surveillance system, and some cards might have already been displaced by the time of the survey for patients who were excluded from the registry, either cured, died or defaulted. The average treatment completion rate (1991-93) among foreign patients was 51%, which was much lower than the national figure of 81% for the same years. Moreover the rate showed deteriorating trend by year. For more accurate information, the foreigner's data must be taken in the national tuberculosis surveillance system and control activities for foreigners need to be strengthened. PMID:10535280

  18. [Granuloma of epididymis of patient treated with intravesical BCG therapy--complication of BCG therapy or tuberculosis?].

    PubMed

    Micha?owska-Mitczuk, Dorota; Brzezi?ska, Sylwia; Augustynowicz-Kope?, Ewa; Langfort, Renata

    2011-01-01

    We present a case of 72-year old man treated from 2007 for superficial bladder carcinoma. Patient had undergone surgical intervention for transitional cell carcinoma of the bladder, followed by BCG therapy. Two years later enlarged right testis and epididymis was observed. A resection was carried out. Histologic examination revealed in epididymis cauda granulomatous infiltration with eosinophilic necrosis. No bacteriologic tests of resected material were performed. Suspecting BCG infection or TB patient was referred to the Institute of Tuberculosis and Lung Diseases in Warsaw for pulmonary evaluation. Chest X-ray, chest CT scan and bronchoscopy were performed but beside revealing scars in bronchi suggesting a history of TB did not contribute to the diagnosis. Tuberculin skin test was 21 mm. Diagnosis was determinated by spoligotyping which found bacille of Mycobacterium tuberculosis in specimen preserved in paraffin block. Tuberculosis of right epididymis and past pulmonary tuberculosis was diagnosed. Patient was treated with rifampin, isoniazid and pirazynamide. PMID:21678281

  19. Tuberculosis case finding based on symptom screening among immigrants, refugees and asylum seekers in Rome

    PubMed Central

    2013-01-01

    Background In Italy the proportion of cases of tuberculosis in persons originating from high-prevalence countries has been increasing in the last decade. We designed a study to assess adherence to and yield of a tuberculosis screening programme based on symptom screening conducted at primary care centres for regular and irregular immigrants and refugees/asylum seekers. Methods Presence of symptoms suggestive of active tuberculosis was investigated by verbal screening in migrants presenting for any medical condition to 3 free primary care centres in the province of Rome. Individuals reporting at least one symptom were referred to a tuberculosis clinic for diagnostic workup. Results Among 2142 migrants enrolled, 254 (11.9%) reported at least one symptom suggestive of active tuberculosis and 176 were referred to the tuberculosis clinic. Of them, 80 (45.4%) did not present for diagnostic evaluation. Tuberculosis was diagnosed in 7 individuals representing 0.33% of those screened and 7.3% of those evaluated for tuberculosis. Conclusion The overall yield of this intervention was in the range reported for other tuberculosis screening programmes 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. Further evaluation of this approach appears to be warranted. PMID:24053349

  20. Genetic vaccination against tuberculosis

    Microsoft Academic Search

    Douglas B. Lowrie; Celio L. Silvan; Ricardo E. Tascon

    1997-01-01

    New weapons are needed in the fight against tuberculosis. Recent research indicates that a vaccine better than BCG may be within reach. A diverse range of protein antigens can give encouragingly high levels of protective immunity in animal models when administered with adjuvants or as DNA vaccines. Accelerated arrest of bacterial multiplication followed by sustained decline in bacterial numbers are

  1. [Chest tuberculosis imaging].

    PubMed

    Hantous-Zannad, S; Zidi, A; Néji, H; Attia, M; Baccouche, I; Ben Miled-M'rad, K

    2015-01-01

    Tuberculosis is an infectious disease mostly due to Mycobacterium tuberculosis. It is frequent in developing countries and its incidence is rising in developed countries. Lungs are the most involved organs of the chest but other structures can be affected. Imaging is fundamental in the management of the disease. Confirmation of diagnosis can be made only by bacteriologic and/or histologic exams. The first approach of diagnosis is based on clinical symptoms and chest X-ray signs. Radiologic signs depend on patient's age, his immune status and his previous contact with M. tuberculosis. Conventional chest X-ray remains the first-line exam to realize. It can suggest the diagnosis on the appearance and location of the lesions. CT scan is recommended for the positive diagnosis in case of discrepancy between clinical and radiographic signs, as for the diagnosis of parenchymal, vascular, lymph nodes, pleural, parietal or mediastinal complications. It is also essential for the evaluation of parenchyma sequelae. MRI and PET-scan have limited indications. The purpose of this article is to illustrate different radiological forms of chest tuberculosis, its sequelae and complications and to highlight the role of each imaging technique in the patient's management. PMID:24874403

  2. [Tuberculosis: a forgotten challenge].

    PubMed

    Martins, P; Machado, A; Alves, A D; Valente, P; Dias, P G

    1997-01-01

    Tuberculosis continues to be a serious problem in public health even thought eh causative bacillus was discovered over 100 years ago. The authors present a clinical case that illustrates the current concern regarding the disease. The case concerns a child of emigrant parents, who are drug addicts and whose illness has not been fully ascertained. The child was hospitalised at three and an half months with fever, malnutrition, opisthotonos and hepatosplenomegaly. After the diagnosis of disseminated tuberculosis affecting the central nervous system, treatment was started with five antituberculosis drugs and with corticosteroids. Respiration improved favourably, but after 19 days the patient suffered a partial tonic-clonic seizure. Subsequently, hydrocephalus was observed and a shunt was applied. Bacteriological examination of the gastric aspirate showed a strain of Mycobacterium tuberculosis resistant to isoniazid and streptomycin. In the eight month of therapeutics, three antituberculosis drugs were still being administered, the shunt was still present and the patient showed a severe psychomotor retardation. The child belonged to a risk group and presented a serious form of tuberculosis with multidrug-resistance, illustrating that this group of children is particularly vulnerable and reflect transmission of this illness among adults. PMID:9341047

  3. [Surgery for thoracic tuberculosis].

    PubMed

    Kilani, T; Boudaya, M S; Zribi, H; Ouerghi, S; Marghli, A; Mestiri, T; Mezni, F

    2015-01-01

    Tuberculosis is mainly a medical disease. Surgery has been the unique therapeutic tool for a long time before the advent of specific antituberculous drugs, and the role of surgery was then confined to the treatment of the sequelae of tuberculosis and their complications. The resurgence of tuberculosis and the emergence of multidrug-resistant TB combined to immunosuppressed patients represent a new challenge for tuberculosis surgery. Surgery may be indicated for a diagnostic purpose in patients with pulmonary, pleural, mediastinal or thoracic wall involvement, or with a therapeutic purpose (drainage, resection, residual cavity obliteration). Modern imaging techniques and the advent of video-assisted thoracic surgery allowed a new approach of this pathology; the majority of diagnostic interventions and selected cases requiring lung resection can be performed through a mini-invasive approach. Patients proposed for aggressive surgery may be treated with the best results thanks to a good evaluation of the thoracic lesions, of the patients' nutritional, infectious and general status combined with a good coordination between the specialized medical team for an optimal preparation to surgery. PMID:24894967

  4. Interferon-Gamma Release Assay Performance in Pulmonary and Extrapulmonary Tuberculosis

    PubMed Central

    Feng, Yun; Diao, Ni; Shao, Lingyun; Wu, Jing; Zhang, Shu; Jin, Jialin; Wang, Feifei; Weng, Xinhua; Zhang, Ying; Zhang, Wenhong

    2012-01-01

    Background The diagnosis of tuberculosis remains difficult. This study aimed to assess performance of interferon-gamma release assay (IGRA) in diagnosis of active tuberculosis (ATB) with pulmonary and extrapulmonary involvements, and to determine the diagnostic role of IGRA (T-SPOT.TB) and tuberculin skin test (TST) in BCG-vaccinated population. Methods and Findings Two hundred twenty-six ATB suspects were recruited and examined with T-SPOT.TB. Among them, fifty-two and seventy-six subjects were simultaneously tested by TST with 5TU or 1TU of purified protein derivative (PPD). The sensitivity of T-SPOT.TB was 94.7% (71/75), comparable in pulmonary and extrapulmonary disease groups (95.6% vs. 93.3%, P>0.05), while the specificity was 84.10% (90/107) but differed in two groups (69.2% vs. 88.9%, P?=?0.02). Compared to T-SPOT.TB, TST with 5TU-PPD showed less sensitivity (92.3% vs. 56.4%) and specificity (84.6% vs. 61.5%) (both P<0.01); the sensitivity of TST with 1TU-PPD was 27.8%, and despite its specificity identical to T-SPOT.TB (both 82.8%) positive predictive value (PPV) was only 33.3%. By combining T-SPOT.TB with TST (1TU), the specificity rose to 95%, but the PPV stayed unchanged. Conclusions IGRA could function as a powerful immunodiagnostic test to explore pulmonary and extrapulmonary TB, while TST failed to play a reliable or auxiliary role in identifying TB disease and infection in the BCG-vaccinated population. PMID:22427859

  5. Evaluating the usefulness of the ICT tuberculosis test kit for the diagnosis of tuberculosis

    Microsoft Academic Search

    Chulhun Ludgerus Chang; Eun Yup Lee; Han Chul Son; Soon Kew Park

    2000-01-01

    Background—Early diagnosis of tuberculosis is crucial, especially in Korea, where tuberculosis is endemic.Aims—To evaluate the validity of the ICT tuberculosis test (ICT) in early diagnosis of tuberculosis.Methods—Sixty eight patients with tuberculosis were tested; 37 had no history of previous tuberculosis (patient group 1), and 31 had reactivated tuberculosis (patient group 2). The control groups comprised 77 subjects: 25 healthy adults,

  6. [New era in molecular epidemiology of tuberculosis in Japan].

    PubMed

    Takashima, Tetsuya; Iwamoto, Tomotada

    2006-11-01

    Molecular epidemiology of tuberculosis (TB) is a science to study TB transmission dynamics and to enhance our understanding of the epidemiology of TB by utilizing molecular typing methods as an adjunct to classical epidemiological approach. Before the era of molecular epidemiology, it was quite difficult to ascertain the source of the infections since M. tuberculosis is spread by air-borne droplets of respiratory secretions expelled by an infectious person to a susceptible host and it can remain latent as an asymptomatic infection for years. Now a day, our understanding of TB transmission dynamics has been refined by genotyping of M. tuberculosis strains. The methods of molecular epidemiology, especially IS6110 RFLP of M. tuberculosis, were first introduced to outbreak investigations and then gradually been expanded its application to population-based study in Japan. IS6110 RFLP is obviously a powerful tool for strain differentiation of M. tuberculosis but its labor-intensiveness limits the achievable throughput and makes it less useful for long-term prospective studies. Recently, apart from IS6110 RFLP, DNA amplification-based method, i.e., variable number of tandem repeats (VNTR) has appeared as a substitute for or adjunct to the IS6110 RFLP. In this symposium, we have invited four opinion leaders in molecular epidemiology of TB from different fields: Mycobacterium reference center, basic science, clinical practice, and public health practice. We, as the chairpersons of this symposium, hope that this symposium would trigger the development of molecular epidemiological network of TB in Japan. 1. Achievement and problem of molecular epidemiologic study with IS6110-RFLP analyses of tuberculosis in Okinawa: Shinji MAEDA (Mycobacterium Reference Center, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association) The long-term RFLP analyses of tuberculosis in Okinawa showed that endemic M. tuberculosis might be present. This is one of the achievements of our project study. On the other hand, for more effective examination of contact persons, information of molecular epidemiology should be used actively. Therefore because the analysis report needs to be sent back quickly, the PCR-based VNTR method should substitute for the RFLP analysis. 2. Basic knowledge and application of Variable Numbers of Tandem Repeats: Kei NISHIMORI (Department of epidemiology, National Institute of Animal Health) Genomic loci of Variable Numbers of Tandem Repeats (VNTR loci) in Mycobacterium tuberculosis complex and Mycobacterium avium, the history of analysis of VNTR loci, the hypothetical mechanisms of increase or decrease of number of repeats, the structures of the loci, and the necessity of standardizing the VNTR typing were introduced. 3. Clinical application of VNTR: Tomoshige MATSUMOTO, and Hiromi ANO (Department of Clinical Research and Development, Osaka Prefectural Hospital Organization Osaka Prefectural Medical Center for Respiratory and Allergic Diseases) Tuberculosis genotyping was first introduced to outbreak investigations and population-based studies. The advent of Variable Numbers of Tandem Repeats (VNTR) can be applied to clinical fields of not only Mycobacterium tuberculosis but also of Mycobacterium avium. In Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, clinical application of VNTR was first introduced in Japan to determine whether Mycobacterium tuberculosis or avium disease was caused by reactivation or reinfection when relapsed. We showed some examples about usefulness of the clinical application of VNTR. 4. Molecular epidemiology of tuberculosis to improve TB prevention and control activities: Tomotada IWAMOTO (Department of microbiology, Kobe Institute of Health), Riyo FUJIYAMA, Noriko TANAKA, Yasuto KAWAKAMI (Kobe City Public Health Center), Chika SHIRAI (Hyogo-ku Health and Welfare Department, Kobe) M. tuberculosis isolates in Kobe have been characterized as: a) Beijing family strains are highly prevalent (77%), b) two major MIRU profiles in Beijing family were found, one is global

  7. Rapid diagnosis of smear-negative tuberculosis by bronchoalveolar lavage enzyme-linked immunospot

    Microsoft Academic Search

    Claudia Jafari; Martin Ernst; Roland Diel; Ulf Greinert; Barbara Scheuerer; Detlef Kirsten; Kathleen Marienfeld; Ajit Lalvani; Christoph Lange

    2006-01-01

    Rationale: In a large proportion of patients with active pulmonary tuberculosis (pTB), acid-fast bacilli smear results for sputum and bronchial secretions are negative. Detectable growth of Mycobacte- rium tuberculosis (MTB) in cultures takes several weeks and MTB- specific DNA amplification results on sputum and bronchial secre- tions are variable in these patients. Objective: We investigated whether a rapid diagnosis of

  8. Human Exposure following Mycobacterium tuberculosis Infection of Multiple Animal Species in a Metropolitan Zoo

    Microsoft Academic Search

    Peter Oh; Reuben Granich; Jim Scott; Ben Sun; Michael Joseph; Cynthia Stringfield; Susan Thisdell; Jothan Staley; Donna Workman-Malcolm; Lee Borenstein; Eleanor Lehnkering; Patrick Ryan; Jeanne Soukup; Annette Nitta; Jennifer Flood

    From 1997 to 2000, Mycobacterium tuberculosis was diagnosed in two Asian elephants (Elephas maxi- mus), three Rocky Mountain goats (Oreamnos americanus), and one black rhinoceros (Diceros bicornis) in the Los Angeles Zoo. DNA fingerprint patterns suggested recent transmission. An investigation found no active cases of tuberculosis in humans; however, tuberculin skin-test conversions in humans were associ- ated with training elephants

  9. Strain diversity of Mycobacterium tuberculosis isolates from pulmonary tuberculosis patients in Afar pastoral region of Ethiopia.

    PubMed

    Belay, Mulugeta; Ameni, Gobena; Bjune, Gunnar; Couvin, David; Rastogi, Nalin; Abebe, Fekadu

    2014-01-01

    Data on genotypic diversity of Mycobacterium tuberculosis complex (MTBC) is important to understand its epidemiology, human adaptation, clinical phenotypes, and drug resistance. This study aimed to characterize MTBC clinical isolates circulating in a predominantly pastoralist area in Ethiopia, a country where tuberculosis is the second leading cause of mortality. Culture of sputum samples collected from a total of 325 pulmonary TB suspects was done to isolate MTBC. Spoligotyping was used to characterize 105 isolates from culture positive slopes and the result was compared with an international database. Forty-four spoligotype patterns were observed to correspond to 35 shared-types (SITs) containing 96 isolates and 9 orphan patterns; 27 SITs containing 83 isolates matched a preexisting shared-type in the database, whereas 8 SITs (n = 13 isolates) were newly created. A total of 19 SITs containing 80 isolates were clustered within this study (overall clustering of 76.19%). Three dominant lineages (T, CAS, and Manu) accounted for 76.19% of the isolates. SIT149/T3-ETH was one of the two most dominant sublineages. Unlike previous reports, we show that Manu lineage strains not only constitute a dominant lineage, but are also associated with HIV infection in Afar region of Ethiopia. The high level of clustering suggests the presence of recent transmission that should be further studied using additional genotyping markers. PMID:24734230

  10. Framework of behavioral indicators for outcome evaluation of TB health promotion: a Delphi study of TB suspects and Tb patients

    PubMed Central

    2014-01-01

    Background Health promotion for prevention and control of Tuberculosis (TB) is implemented worldwide because of its importance, but few reports have evaluated its impact on behavior due to a lack of standard outcome indicators. The objective of this study was to establish a framework of behavioral indicators for outcome evaluation of TB health promotion among TB suspects and patients. Methods A two-round modified Delphi method involving sixteen TB control experts was used to establish a framework of behavioral indicators for outcome evaluation of TB health promotion targeted at TB suspects and patients. Results Sixteen of seventeen invited experts in TB control (authority score of 0.91 on a 1.0 scale) participated in round 1 survey. All sixteen experts also participated in a second round survey. After two rounds of surveys and several iterations among the experts, there was consensus on a framework of indicators for measuring outcomes of TB health promotion for TB suspects and patients. For TB suspects, the experts reached consensus on 2 domains (“Healthcare seeking behavior” and “Transmission prevention”), 3 subdomains (“Seeking care after onset of TB symptoms”, “Pathways of seeking care” and “Interpersonal contact etiquette”), and 8 indicators (including among others, “Length of patient delay”). For TB patients, consensus was reached on 3 domains (“Adherence to treatment”, “Healthy lifestyle” and “Transmission prevention”), 8 subdomains (including among others, “Adherence to their medication”), and 14 indicators (including “Percentage of patients who adhered to their medication”). Operational definitions and data sources were provided for each indicator. Conclusions The findings of this study provide the basis for debate among international experts on a framework for achieving global consensus on outcome indicators for TB health promotion interventions targeted at TB patients and suspects. Such consensus will help to increase effectiveness of TB health promotion, while ensuring international comparability of outcome data. PMID:24884569

  11. High Prevalence of Multidrug-Resistant Tuberculosis in Georgia

    PubMed Central

    Mdivani, Nino; Zangaladze, Ekaterina; Volkova, Natalia; Kourbatova, Ekaterina; Jibuti, Thea; Shubladze, Natalia; Kutateladze, Tamar; Khechinashvili, George; del Rio, Carlos; Salakaia, Archil; Blumberg, Henry M.

    2009-01-01

    Summary Introduction Tuberculosis (TB) has emerged as a serious public health problem in the country of Georgia. However, there have been little or no data on rates and risk factors for drug resistant TB including multidrug-resistant (MDR)-TB in Georgia. Objective To assess the prevalence and risk factors for drug resistant TB. Methodology A cross-sectional prospective survey of patients with suspected pulmonary TB was carried out at four sentinel sites (Tbilisi, Zugdidi, Kutaisi, and Batumi) in Georgia to in 2001-2004. Results Among 1,422 patients with suspected pulmonary TB, 996 (70.0%) of 1,422 patients were culture positive; 931 (93.5%) of 996 had drug susceptibility testing performed. Overall, 64% of patients (48.3% of new and 85.3% of retreatment cases) had positive cultures for Mycobacterium tuberculosis resistant to ?1 first line antituberculosis drugs. The overall prevalence of MDR-TB was 28.1% (10.5% of newly diagnosed patients and 53.1% of retreatment cases). In multivariate analysis, risk factors for MDR-TB included: being a retreatment case (prevalence ratio [PR]=5.28, 95% CI 3.95-7.07); history of injection drug use (PR=1.59, 95% CI 1.21-2.09); and female gender (PR=1.36, 95% CI 1.12-1.65). Conclusion MDR-TB has emerged as a serious public health problem in Georgia and will greatly impact TB control strategies. PMID:18514008

  12. Cyclic GMP-AMP Synthase Is an Innate Immune DNA Sensor for Mycobacterium tuberculosis.

    PubMed

    Collins, Angela C; Cai, Haocheng; Li, Tuo; Franco, Luis H; Li, Xiao-Dong; Nair, Vidhya R; Scharn, Caitlyn R; Stamm, Chelsea E; Levine, Beth; Chen, Zhijian J; Shiloh, Michael U

    2015-06-10

    Activation of the DNA-dependent cytosolic surveillance pathway in response to Mycobacterium tuberculosis infection stimulates ubiquitin-dependent autophagy and inflammatory cytokine production, and plays an important role in host defense against M. tuberculosis. However, the identity of the host sensor for M. tuberculosis DNA is unknown. Here we show that M. tuberculosis activated cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) in macrophages to produce cGAMP, a second messenger that activates the adaptor protein stimulator of interferon genes (STING) to induce type I interferons and other cytokines. cGAS localized with M. tuberculosis in mouse and human cells and in human tuberculosis lesions. Knockdown or knockout of cGAS in human or mouse macrophages blocked cytokine production and induction of autophagy. Mice deficient in cGAS were more susceptible to lethality caused by infection with M. tuberculosis. These results demonstrate that cGAS is a vital innate immune sensor of M. tuberculosis infection. PMID:26048137

  13. Tuberculosis of spine

    PubMed Central

    Agrawal, Vinod; Patgaonkar, P. R.; Nagariya, S. P.

    2010-01-01

    Tuberculosis of the spine is one of the most common spine pathology in India. Over last 4 decades a lot has changed in the diagnosis, medical treatment and surgical procedures to treat this disorder. Further developments in diagnosis using molecular genetic techniques, more effective antibiotics and more aggressive surgical protocols have become essential with emergence of multidrug resistant TB. Surgical procedures such as single stage anterior and posterior stabilization, extrapleral dorsal spine anterior stabilization and endoscopic thoracoscopic surgeries have reduced the mortality and morbidity of the surgical procedures. is rapidly progressing. It is a challenge to treat MDR-TB Spine with late onset paraplegia and progressive deformity. Physicians must treat tuberculosis of spine on the basis of Culture and sensitivity. PMID:21572628

  14. [Tuberculosis diagnosis in the aged: barriers to accessing health services].

    PubMed

    de Oliveira, Annelissa Andrade Virgínio; de Sá, Lenilde Duarte; Nogueira, Jordana de Almeida; de Andrade, Séfora Luana Evangelista; Palha, Pedro Fredemir; Villa, Tereza Cristina Scatena

    2013-02-01

    This study was performed with the objective to analyze the barriers to diagnosing tuberculosis in the aged and access to health services in the city of João Pessoa, Paraíba, Brazil. This qualitative study included the participation of seven aged women with tuberculosis. Interviews were used for data collection. The empirical material was organized using Atlas.ti 6.0, and analyzed according to the techniques of discourse analysis. The identified barriers related to the access to health services to confirm the diagnosis were: the operating hours of family health units; transferred responsibilities; home visits without controlling communicants; delay of the health service in suspecting the disease and the patient's repeated visits to the health center before being informed about the diagnosis. Despite the identification of common barriers that tuberculosis patients of all ages must deal with, because of the vulnerability of the elderly, health services should implement control actions so as to prevent the disease becoming a common condition in this population. PMID:23515814

  15. 21 CFR 866.3370 - Mycobacterium tuberculosis immunofluorescent reagents.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...2014-04-01 false Mycobacterium tuberculosis immunofluorescent reagents... § 866.3370 Mycobacterium tuberculosis immunofluorescent reagents...Identification. Mycobacterium tuberculosis immunofluorescent...

  16. 21 CFR 866.3370 - Mycobacterium tuberculosis immunofluorescent reagents.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...2011-04-01 false Mycobacterium tuberculosis immunofluorescent reagents... § 866.3370 Mycobacterium tuberculosis immunofluorescent reagents...Identification. Mycobacterium tuberculosis immunofluorescent...

  17. Histopathologic analysis of suspected amiodarone hepatotoxicity.

    PubMed

    Lewis, J H; Mullick, F; Ishak, K G; Ranard, R C; Ragsdale, B; Perse, R M; Rusnock, E J; Wolke, A; Benjamin, S B; Seeff, L B

    1990-01-01

    This analysis of the morphology of suspected amiodarone (AD) liver disease is based on a study of liver specimens from 17 individuals. Changes similar to alcoholic liver injury were commonly seen. Steatosis, both macrovesicular and microvesicular, was the most frequent histopathologic feature. Ballooning of hepatocytes, Mallory bodies, and fibrosis were also common. Other changes included nuclear unrest, acidophilic bodies, foam cells, glycogenated nuclei, and portal inflammation. Characteristic lamellar lysosomal inclusion bodies representing phospholipidosis were found in two of 14 specimens studied ultrastructurally. These changes of pseudoalcoholic hepatitis and/or phospholipidosis were present in liver specimens from asymptomatic, anicteric patients with mild elevations in serum aminotransferase or alkaline phosphatase values with or without hepatomegaly, as well as in patients with clinically overt symptoms of hepatotoxicity. Phospholipidosis appears to be a generalized systemic effect of cationic amphophilic compounds, such as AD. The cytotoxic pseudoalcoholic changes appear to be an independent phenomenon in susceptible patients, whom we speculate may have been unable or less able to metabolize AD through normal pathways. The true incidence of hepatic injury from AD remains to be determined from prospective evaluations of pretreatment and follow-up liver biopsies. PMID:2403975

  18. Metronidazole Therapy in Mice Infected with Tuberculosis

    PubMed Central

    Brooks, Jason V.; Furney, Synthia K.; Orme, Ian M.

    1999-01-01

    The capacity of metronidazole to inhibit the growth of Mycobacterium tuberculosis was tested in in vitro and in vivo mouse models. In vitro addition of metronidazole to cultures of infected bone marrow-derived macrophages had no effect, nor did it increase the reduction in bacterial load due to isoniazid. In vivo, metronidazole did not reduce bacterial numbers in the lungs of aerosol-infected mice during the active stage of the disease, during a phase of containment, or after prolonged isoniazid therapy (Cornell model). A small but significant reduction was seen if metronidazole therapy was given during an established chronic disease state 100 days after aerosol administration. These data indicate that under most conditions M. tuberculosis organisms are not in a metabolic state in which they are susceptible to the action of metronidazole and, hence, that this drug would be of limited clinical value. PMID:10223954

  19. 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-?– 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

  20. Essentials of tuberculosis control for the practising physician. Tuberculosis Committee, Canadian Thoracic Society.

    PubMed Central

    1994-01-01

    OBJECTIVE: To recommend guidelines for the management of tuberculosis (TB), particularly in high-risk groups including poor and homeless people, aboriginal Canadians, immigrants from countries where TB is highly prevalent and people with HIV infection. OPTIONS: Diagnosis, pharmacotherapy, vaccination and chemoprophylaxis. OUTCOMES: Prevention of infection and diagnosis and cure of TB. EVIDENCE: The evidence was gathered in late 1992 from previous guidelines, recommendations by specialist societies and new studies. VALUES: Evidence was categorized into four levels: I, randomized clinical trials of therapeutic interventions or prospective studies of diagnostic strategies; II, case-control studies; III, retrospective descriptive studies; and IV, consensus of the committee members and published statements. The Tuberculosis Committee of the Canadian Thoracic Society comprises experts in TB from across Canada. BENEFITS, HARM AND COSTS: The benefits of early diagnosis and prompt initiation of therapy are well documented. The cost effectiveness of antituberculous therapy in developing countries is well documented. In developed countries chemoprophylaxis has been shown to be cost effective, and directly observed chemotherapy has recently been hypothesized to have economic benefits. RECOMMENDATIONS: In the appropriate clinical setting, particularly when patients are known to be at high risk of TB, clinicians should consider TB, reserve body secretions for mycobacteriologic tests and conduct other investigations such as chest radiography. Furthermore, if TB is strongly suspected or confirmed by appropriate investigation the early initiation of multi-drug therapy, including at least three first-line drugs, is strongly recommended. If drug resistance is suspected a regimen of four to five drugs, including at least two drugs with which the patient has not been treated, should be started. If the strain is found to be resistant to any of the drugs in the regimen appropriate changes should be made. Chemoprophylaxis should be considered especially in contacts with a recent significant reaction to the purified protein derivative (PPD) skin test and in people known to be at risk of reactivated TB infection, particularly those with HIV infection and a significant PPD skin-test result. Vaccination with bacillus Calmette-Guérin should be limited to high-risk groups, particularly aboriginal Canadians living on reserves. VALIDATION: These recommendations are based on a consensus of Canadian experts supported by other specialist societies and reference groups. They have been reviewed by the Standards Committee of the Canadian Thoracic Society. SPONSOR: The Canadian Lung Association and the Tuberculosis Committee of the Canadian Thoracic Society. PMID:8174026

  1. Natural antimicrobial peptides against Mycobacterium tuberculosis.

    PubMed

    Abedinzadeh, Maria; Gaeini, Mahdieh; Sardari, Soroush

    2015-05-01

    TB, caused by Mycobacterium tuberculosis, is one the leading infectious diseases worldwide. There is an urgent need to discover new drugs with unique structures and uncommon mechanisms of action to treat M. tuberculosis and combat antimycobacterial resistance. Naturally occurring compounds contain a wide diversity of chemical structures, displaying a wide range of in vitro potency towards M. tuberculosis. A number of recent studies have shown that natural antimycobacterial peptides can disrupt the function of the mycobacterial cell wall through different modes of action and thereafter interact with intracellular targets, including nucleic acids, enzymes and even organelles. More importantly, the probability of antimycobacterial resistance is low. This review presents several natural antimicrobial peptides isolated from different organism sources, including bacteria, fungi, plants and animals. In addition, the molecular features of these molecules are the subject of much attention. Such peptides have common traits among their chemical features, which may be correlated with their biological activities; hence, different parts of the molecular structures can be modified in order to increase penetration into the target cells. This review also summarizes the available information on the properties of antimycobacterial peptides associated with their biological activities. PMID:25681127

  2. First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity.

    PubMed

    Eng, Wai Soon; Hocková, Dana; Špa?ek, Petr; Janeba, Zlatko; West, Nicholas P; Woods, Kyra; Naesens, Lieve M J; Keough, Dianne T; Guddat, Luke W

    2015-06-11

    Human tuberculosis is a chronic infectious disease affecting millions of lives. Because of emerging resistance to current medications, new therapeutic drugs are needed. One potential new target is hypoxanthine-guanine phosphoribosyltransferase (MtHGPRT), a key enzyme of the purine salvage pathway. Here, newly synthesized acyclic nucleoside phosphonates (ANPs) have been shown to be competitive inhibitors of MtHGPRT with Ki values as low as 0.69 ?M. Prodrugs of these compounds arrest the growth of a virulent strain of M. tuberculosis with MIC50 values as low as 4.5 ?M and possess low cytotoxicity in mammalian cells (CC50 values as high as >300 ?M). In addition, the first crystal structures of MtHGPRT (2.03-2.76 Å resolution) have been determined, three of these in complex with novel ANPs and one with GMP and pyrophosphate. These data provide a solid foundation for the further development of ANPs as selective inhibitors of MtHGPRT and as antituberculosis agents. PMID:25915781

  3. Tuberculosis in children.

    PubMed

    Marais, Ben J

    2014-10-01

    Tuberculosis (TB) is a major, but often unrecognised, cause of disease and death in young children from countries with high TB incidence rates among adults. It is also relevant to paediatricians in low-incidence countries, such as Australia, because of increased international travel, immigration and refugee resettlement. This manuscript provides a brief overview of the global TB disease burden, the natural history of disease in children, and offers guidance on the prevention, diagnosis and treatment of TB in children. PMID:24548085

  4. Evaluation of the 2007 WHO guideline to diagnose smear negative tuberculosis in an urban hospital in Ethiopia

    PubMed Central

    2013-01-01

    Background The 2007 World Health Organization (WHO) guideline to diagnose smear-negative tuberculosis (TB) in HIV-prevalent settings was mainly based on expert advice and therefore requires evaluation in real life situations. Methods In 2009, this guideline was introduced at the ALERT hospital in Ethiopia. From October 2009 to January 2011, the accuracy of the guideline was evaluated using Mycobacterium tuberculosis culture positivity as reference standard in HIV positive TB suspects. Results A total of 459 TB suspects were enrolled during the study period; 336 (73.2%) were HIV positive. Acid fast bacilli sputum smear microscopy was done for 74.7% (251/336) HIV positive TB suspects; 94.4% (237/251) were smear negative. A chest X-ray was performed in 92.8% (220/237) and a Mycobacterium tuberculosis culture in 63.7% (151/237). The median TB diagnostic delay for smear negative cases was 3 days (interquartile range 3–4 days). Of the 75 patients diagnosed with smear negative pulmonary TB, 89. 4% (67/75) were diagnosed by chest X-ray, 9.4% (7/75) by culture and 1.3% (1/75) by clinical suspicion only. In 147 smear negative TB suspects Mycobacterium tuberculosis culture and chest X-ray results were available. Among these 147 patients, the sensitivity of the chest X-ray to diagnose smear negative TB in HIV-positive TB suspects was 53.3% (95% CI: 26.7-78.7); the specificity 67.4% (95% CI: 58.7-75.3). Conclusion The 2007 WHO diagnostic algorithm for the diagnosis of smear negative TB is likely to reduce the diagnostic delay and therefore decrease morbidity and mortality of TB in a HIV prevalent settings like Ethiopia. PMID:24020936

  5. Household contact investigation for tuberculosis in Vietnam: study protocol for a cluster randomized controlled trial

    PubMed Central

    2013-01-01

    Background Tuberculosis is an infectious disease that continues to cause considerable morbidity and mortality globally. Only 65% of patients worldwide are currently diagnosed. Contact investigation is a strategy that aims to increase case detection and reduce transmission of tuberculosis, yet there is little evidence to show its effectiveness. Methods/Design We will conduct a cluster randomized controlled trial of contact investigation within the national tuberculosis control program of Vietnam. Household contacts of patients with smear-positive pulmonary tuberculosis will be invited to attend district tuberculosis units for symptom screening, examination, and chest radiography on four occasions over a two-year period. The primary endpoint is clinically confirmed tuberculosis among contacts during the 24 months of follow-up, ascertained using capture-recapture analysis. Microbiologically proven tuberculosis and treatment completion rates among contacts diagnosed with tuberculosis will be secondary endpoints. The incremental cost-effectiveness ratio will be estimated. The study will have 80% power to detect a 50% increase in the primary endpoint in the active intervention arm compared with the control arm. The study will include 8,829 contacts in each of the active screening and control groups, within 70 districts in 8 provinces in Vietnam, in both rural and urban settings. Discussion The effectiveness of contact investigation as a tool for improved tuberculosis case finding has not been established. This cluster randomized trial will provide valuable operational information for national tuberculosis programs in high-prevalence countries, in order to select the most cost-effective strategies to improve tuberculosis case detection. Trial registration The ACT2 study has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN12610000600044). PMID:24138766

  6. Diabetes and immunity to tuberculosis

    PubMed Central

    Martinez, Nuria; Kornfeld, Hardy

    2014-01-01

    Summary The dual burden of tuberculosis and diabetes has attracted much attention in the past decade as diabetes prevalence has increased dramatically in countries already afflicted with a high burden of tuberculosis. The confluence of these two major diseases presents a serious threat to global public health; at the same time it also presents an opportunity to learn more about the key elements of human immunity to tuberculosis that may be relevant to the general population. Some effects of diabetes on innate and adaptive immunity which are potentially relevant to tuberculosis defense have been identified, but have yet to be verified in humans and are unlikely to fully explain the interaction of these two disease states. This review provides an update on the clinical and epidemiological features of tuberculosis in the diabetic population and relates them to recent advances in understanding the mechanistic basis of tuberculosis susceptibility and other complications of diabetes. Issues that merit further investigation, such as geographic host and pathogen differences in the diabetes/tuberculosis interaction, the role of hyperglycemia-induced epigenetic reprogramming in immune dysfunction and the impact of diabetes on lung injury and fibrosis caused by tuberculosis, are highlighted in this review. PMID:24448841

  7. Computed tomography of intracranial tuberculosis

    Microsoft Academic Search

    J. R. Jinkins

    1991-01-01

    The many clinico-radiological manifestations of intracranial tuberculosis have been well documented; however, few long-term retrospective serial studies of large series of patients on therapy have been reported utilizing computed imaging. The computed tomographic appearance, sequential periodic evolution, and final outcome of all patients with cranial tuberculosis seen at this institution in a period of ten years have been evaluated. A

  8. [Pancytopenia and pulmonary tuberculosis. Significance of a hemophagocytic syndrome].

    PubMed

    François, B; Clavel, M; Trimoreau, F; Desachy, A; Slaouti, P; Gastinne, H

    1998-10-01

    Haemophagocytic syndromes or syndromes involving macrophage activation are rare complications of tuberculosis, whether they be pulmonary or polyvisceral. They are characterised by an anomalous increase in the phagocytic power of macrophages with phagocytosis of the formed elements of blood. The clinical biological picture associates a change in the general physical state accompanied by organomegaly, hyperferritinaemia and pancytopenia. Their occurrence is a poor prognostic factor and few treatment seem to check this mechanism. The authors report a rare case of marked macrophage activation syndrome complicating pulmonary tuberculosis in a patient who was HIV negative without an underlying blood disturbance and a favourable outcome. PMID:9834997

  9. Problems in Communicating the Suspect's Rights in Interpreted Police Interviews

    ERIC Educational Resources Information Center

    Nakane, Ikuko

    2007-01-01

    At first glance, communicating a suspect's rights in police interviews appears to be a straightforward task. However, it is more complex than it appears. In particular, for suspects who come from different cultural backgrounds or legal systems and who rely on interpreters in police interviews, ensuring a thorough understanding of their rights and…

  10. Surveillance for fatal suspected adverse drug reactions in the UK

    Microsoft Academic Search

    A Clarkson; I Choonara

    2002-01-01

    Aim: To determine the nature and number of suspected adverse drug reactions (ADRs) associated with fatal outcomes in children reported through the yellow card scheme.Methods: All reports of suspected ADRs with a fatal outcome in children received by the UK Committee on Safety of Medicines through its Yellow Card Scheme from 1964 until December 2000 were reviewed. Reports associated with

  11. Role of Acid pH and Deficient Efflux of Pyrazinoic Acid in Unique Susceptibility of Mycobacterium tuberculosis to Pyrazinamide

    Microsoft Academic Search

    YING ZHANG; ANGELO SCORPIO; HIROSHI NIKAIDO; ZHONGHE SUN

    1999-01-01

    Pyrazinamide (PZA) is an important antituberculosis drug. Unlike most antibacterial agents, PZA, despite its remarkable in vivo activity, has no activity against Mycobacterium tuberculosis in vitro except at an acidic pH. M. tuberculosis is uniquely susceptible to PZA, but other mycobacteria as well as nonmycobacteria are intrinsic- ally resistant. The role of acidic pH in PZA action and the basis

  12. Nitazoxanide Stimulates Autophagy and Inhibits mTORC1 Signaling and Intracellular Proliferation of Mycobacterium tuberculosis

    PubMed Central

    Lam, Karen K. Y.; Zheng, Xingji; Forestieri, Roberto; Balgi, Aruna D.; Nodwell, Matt; Vollett, Sarah; Anderson, Hilary J.; Andersen, Raymond J.; Av-Gay, Yossef; Roberge, Michel

    2012-01-01

    Tuberculosis, caused by Mycobacterium tuberculosis infection, is a major cause of morbidity and mortality in the world today. M. tuberculosis hijacks the phagosome-lysosome trafficking pathway to escape clearance from infected macrophages. There is increasing evidence that manipulation of autophagy, a regulated catabolic trafficking pathway, can enhance killing of M. tuberculosis. Therefore, pharmacological agents that induce autophagy could be important in combating tuberculosis. We report that the antiprotozoal drug nitazoxanide and its active metabolite tizoxanide strongly stimulate autophagy and inhibit signaling by mTORC1, a major negative regulator of autophagy. Analysis of 16 nitazoxanide analogues reveals similar strict structural requirements for activity in autophagosome induction, EGFP-LC3 processing and mTORC1 inhibition. Nitazoxanide can inhibit M. tuberculosis proliferation in vitro. Here we show that it inhibits M. tuberculosis proliferation more potently in infected human THP-1 cells and peripheral monocytes. We identify the human quinone oxidoreductase NQO1 as a nitazoxanide target and propose, based on experiments with cells expressing NQO1 or not, that NQO1 inhibition is partly responsible for mTORC1 inhibition and enhanced autophagy. The dual action of nitazoxanide on both the bacterium and the host cell response to infection may lead to improved tuberculosis treatment. PMID:22589723

  13. Reversal of Mycobacterium tuberculosis Phenotypic Drug Resistance by 2-Aminoimidazole Based Small Molecules

    PubMed Central

    Ackart, David F.; Lindsey, Erick A.; Podell, Brendan K.; Melander, Roberta J.; Basaraba, Randall J.; Melander, Christian

    2014-01-01

    The expression of phenotypic drug resistance or drug tolerance serves as a strategy for Mycobacterium tuberculosis to survive in vivo antimicrobial drug treatment; however the mechanisms are poorly understood. Progress toward a more in depth understanding of in vivo drug tolerance and the discovery of new therapeutic strategies designed specifically to treat drug-tolerant M. tuberculosis are hampered by the lack of appropriate in vitro assays. A library of 2-aminoimidazole based small molecules combined with the anti-tuberculosis drug isoniazid were screened against M. tuberculosis expressing in vitro drug-tolerance as microbial communities attached to an extracellular matrix derived from lysed leukocytes. Based on the ability of nine of ten 2-aminoimidazole compounds to inhibit M. smegmatis biofilm formation and three of ten molecules capable of dispersing established biofilms, two active candidates and one inactive control were tested against drug tolerant M. tuberculosis. The two active compounds restored isoniazid susceptibility as well as reduced the in vitro minimum inhibitory concentrations of isoniazid in a dose-dependent manner. The dispersion of drug tolerant M. tuberculosis with 2-aminoimidazole based small molecules as an adjunct to antimicrobial treatment has the potential to be an effective anti-tuberculosis treatment strategy designed specifically to eradicate drug-tolerant M. tuberculosis. PMID:24478046

  14. Potential Role of Immunodiagnosis for Pulmonary Tuberculosis Using Induced Sputum Cells

    PubMed Central

    Jeon, Doosoo; Lee, Seung Eun; Cho, Woo Hyun; Lee, Byung Hee; Kim, Yun Seong; Lee, Ji-Eun; Son, Eun-Soon; Lee, Ye-Jin; Hong, Min-Sun

    2015-01-01

    Purpose To evaluate the diagnostic utility and predictors for determinate results of an enzyme-linked immunospot assay using induced sputum cells (IS ELISPOT) for a rapid diagnosis of pulmonary tuberculosis (TB). Materials and Methods Subjects suspected of pulmonary TB who had either sputum acid fast bacilli smear-negative or not producing sputum spontaneously were prospectively enrolled. ELISPOT assay was performed using cells from induced sputum. Results A total of 43 subjects, including 25 with TB (TB group) and 18 with non-TB disease (non-TB group) were enrolled. Results of IS ELISPOT were determinate in only 17/43 (39%) subjects, but all of determinate results were consistent with the final diagnosis. Of the 43 sputum samples, 11 (26%) were inadequate to perform IS ELISPOT. Of 32 adequate sputum samples, the proportion of determinate results was significantly higher in the TB group (75%, 15/20) than in the non-TB group (17%, 2/12) (p=0.002). The status of active TB was a unique predictor but smear positivity was not a significant predictor for determinate results. In addition, sensitivity of IS ELISPOT (75%, 9/12) in smear negative TB was higher than that of TB-polymerase chain reaction (25%, 3/12). Conclusion IS ELISPOT showed relatively high diagnostic value and accuracy in the TB group, independent of smear positivity. IS ELISPOT may provide additional diagnostic yield for microbiological tools in the rapid diagnosis of smear-negative TB. PMID:25683979

  15. Evaluation of mtp40 genomic fragment amplification for specific detection of Mycobacterium tuberculosis in clinical specimens.

    PubMed Central

    Herrera, E A; Segovia, M

    1996-01-01

    A PCR assay based on the species-specific mtp40 genomic fragment was developed for the specific detection and identification of Mycobacterium tuberculosis in different uncultured clinical specimens. The aim of the study was to evaluate the clinical applicability of this target DNA in comparison with those of conventional microbiological methods and to compare the results obtained with those obtained after amplification with the IS6110 repetitive element. Discrepant results were interpreted in conjunction with the patients' clinical data, medical histories, and response to therapy. A total of 172 specimens from 162 patients with respiratory symptoms were tested, 101 specimens were obtained from 92 patients clinically suspected of having tuberculosis, and 71 specimens were obtained from 70 patients without known mycobacterial infection. The results of our study suggest that PCR amplification with the mtp40 genomic fragment provides a highly sensitive and specific technique for the detection of M. tuberculosis strains in clinical samples. It allows for the differentiation between M. tuberculosis and other related mycobacteria, including M. bovis, and is more specific than the IS6110 target. For these and other reasons, we propose that the mtp40 assay is a possible alternative for the specific direct detection of M. tuberculosis in clinical laboratories. PMID:8727885

  16. Methionine Aminopeptidases from Mycobacterium tuberculosis as Novel Antimycobacterial Targets

    PubMed Central

    Olaleye, Omonike; Raghunand, Tirumalai R.; Bhat, Shridhar; He, Jian; Tyagi, Sandeep; Lamichhane, Gyanu; Gu, Peihua; Zhou, Jiangbing; Zhang, Ying; Grosset, Jacques; Bishai, William R.; Liu, Jun O.

    2011-01-01

    Methionine aminopeptidase (MetAP) is a metalloprotease that removes the N-terminal methionine during protein synthesis. To assess the importance of the two MetAPs in M. tuberculosis, we overexpressed and purified each of the MetAPs to near homogeneity and showed that both were active as MetAP enzymes in vitro. We screened a library of 175,000 compounds against MtMetAP1c and identified 2, 3-dichloro-1, 4-napthoquinone class of compounds as inhibitors of both MtMetAPs. It was found that the MtMetAP inhibitors were active against replicating and aged non-growing M. tuberculosis. Overexpression of either MtMetAP1a or MtMetAP1c in M. tuberculosis conferred resistance of bacterial cells to the inhibitors. Moreover, knockdown of MtMetAP1a, but not MtMetAP1c, resulted in decreased viability of M. tuberculosis. These results suggest that MtMetAP1a is a promising target for developing anti-tuberculosis agents. PMID:20142044

  17. Do not chase the suspect. Stay calm and try to observe the direction of the suspect's escape. If

    E-print Network

    Eustice, Ryan

    type of hair hat (color, type) glasses tie tattoos coat complexion shirt scars/marks pants's escape. If the suspect has a vehicle, note the type, color, and license plate number if possible. Also-1131 Business Office 763-3434 SUSPECT DESCRIPTION FACIAL APPEARANCE color make year body style (2dr, 4dr, etc

  18. The tuberculosis epidemic. Scientific challenges and opportunities.

    PubMed

    Ginsberg, A M

    1998-01-01

    One in every three people on Earth is believed to be infected with Mycobacterium tuberculosis, leading to seven to eight million cases of active tuberculosis (TB) per year and approximately three million deaths annually. this epidemic, like those of most infectious diseases, creates scientific challenges and opportunities as it raises the demand for public health solutions. The currently available weapons for fighting TB are inadequate. The ultimate goal of biomedical TB research is to lessen the public health burden of this disease by developing improved diagnostic, therapeutic, and intervention strategies. Achieving this goal requires a base of knowledge about the biology of M. tuberculosis and related mycobacteria, their interactions with human and animal hosts, and the nature of an effective host-protective immune response. TB researchers are applying this accumulating base of knowledge to developing rapid, easy-to-use diagnostic assays appropriate for low-as well as high-income countries, improving the current complicated therapeutic regimen, identifying potential new drugs to combat multidrug-resistant TB, and creating more effective vaccines. PMID:9719813

  19. DevR (DosR) mimetic peptides impair transcriptional regulation and survival of Mycobacterium tuberculosis under hypoxia by inhibiting the autokinase activity of DevS sensor kinase

    PubMed Central

    2014-01-01

    Background Two-component systems have emerged as compelling targets for antibacterial drug design for a number of reasons including the distinct histidine phosphorylation property of their constituent sensor kinases. The DevR-DevS/DosT two component system of Mycobacterium tuberculosis (M. tb) is essential for survival under hypoxia, a stress associated with dormancy development in vivo. In the present study a combinatorial peptide phage display library was screened for DevS histidine kinase interacting peptides with the aim of isolating inhibitors of DevR-DevS signaling. Results DevS binding peptides were identified from a phage display library after three rounds of panning using DevS as bait. The peptides showed sequence similarity with conserved residues in the N-terminal domain of DevR and suggested that they may represent interacting surfaces between DevS and DevR. Two DevR mimetic peptides were found to specifically inhibit DevR-dependent transcriptional activity and restrict the hypoxic survival of M. tb. The mechanism of peptide action is majorly attributed to an inhibition of DevS autokinase activity. Conclusions These findings demonstrate that DevR mimetic peptides impede DevS activation and that intercepting DevS activation at an early step in the signaling cascade impairs M. tb survival in a hypoxia persistence model. PMID:25048654

  20. Highly structured genetic diversity of the Mycobacterium tuberculosis population in

    E-print Network

    Choisy, Marc

    Highly structured genetic diversity of the Mycobacterium tuberculosis population in Djibouti S, Djibouti Ville, Djibouti Abstract Djibouti is an East African country with a high tuberculosis incidence with pulmonary tuberculosis (TB) were included. Genetic characterization of Mycobacterium tuberculosis, using

  1. What steps do we need to take to improve diagnosis of tuberculosis in children?

    PubMed

    Venturini, Elisabetta; Remaschi, Giulia; Berti, Elettra; Montagnani, Carlotta; Galli, Luisa; de Martino, Maurizio; Chiappini, Elena

    2015-07-01

    Tuberculosis still represents a big global public health challenge. The diagnosis of tuberculosis and the differentiation between active and latent tuberculosis remain difficult, particularly in childhood, because of the lack of a gold standard test for diagnosis. In the last decade, novel diagnostic assays have been developed. Among immunologic tests, new assays based on the measurement of different cytokines released by specific T cells in response to Mycobacterium tuberculosis antigens, other than INF-?, have been investigated. Promising results rely on nucleic acid amplification techniques, also able to detect drugs resistance. Innovative research fields studied the modifications of CD27 expression in T cells as well as different host gene expression in response to M. tuberculosis. Further studies are needed to assess the diagnostic value and the accuracy of these new assays. PMID:25938981

  2. Antibiotics. Targeting DnaN for tuberculosis therapy using novel griselimycins.

    PubMed

    Kling, Angela; Lukat, Peer; Almeida, Deepak V; Bauer, Armin; Fontaine, Evelyne; Sordello, Sylvie; Zaburannyi, Nestor; Herrmann, Jennifer; Wenzel, Silke C; König, Claudia; Ammerman, Nicole C; Barrio, María Belén; Borchers, Kai; Bordon-Pallier, Florence; Brönstrup, Mark; Courtemanche, Gilles; Gerlitz, Martin; Geslin, Michel; Hammann, Peter; Heinz, Dirk W; Hoffmann, Holger; Klieber, Sylvie; Kohlmann, Markus; Kurz, Michael; Lair, Christine; Matter, Hans; Nuermberger, Eric; Tyagi, Sandeep; Fraisse, Laurent; Grosset, Jacques H; Lagrange, Sophie; Müller, Rolf

    2015-06-01

    The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification. PMID:26045430

  3. Selected results of the tuberculosis control program in the Czech Republic.

    PubMed

    Príkazský, V; Kubín, M; Pikhartová, J

    1999-08-01

    There are probably several causes why steady decrease of tuberculosis incidence stopped. The aim of our work was to investigate a possible relation of tuberculosis incidence in smaller administrative areas with several social and economic characteristics. The individual data were taken from the Information System of Bacillary Tuberculosis, based on laboratory reporting network. Tuberculosis incidence dropped to 19.8/100,000 in 1987 and since then it fluctuates around that level. The levels in districts ranged from 1.9 to 45.6 in 1997. The social status, overcrowding, air pollution and unemployment rates are weakly correlated with tuberculosis incidence. These unfavourable values of social, economical and ecological indicators are linked with more industrialised parts of the country. Age and gender analysis shows that male population aged from 40-60 is the most affected population with higher rates of smear positive pulmonary TB. These rates are positively linked with a size of the municipality, in larger towns higher number of those cases are detected. Contrary to that, relatively higher rates of pulmonary tuberculosis are in elderly women in smaller municipalities. There is a suspicion about important role of relative poverty in the epidemiology of tuberculosis in the Czech Republic. The results indicate that we should concentrate our effort to reduce the incidence of tuberculosis mainly in economically active male population. PMID:10499141

  4. NOD2 and Toll-Like Receptors Are Nonredundant Recognition Systems of Mycobacterium tuberculosis

    PubMed Central

    2005-01-01

    Infection with Mycobacterium tuberculosis is one of the leading causes of death worldwide. Recognition of M. tuberculosis by pattern recognition receptors is crucial for activation of both innate and adaptive immune responses. In the present study, we demonstrate that nucleotide-binding oligomerization domain 2 (NOD2) and Toll-like receptors (TLRs) are two nonredundant recognition mechanisms of M. tuberculosis. CHO cell lines transfected with human TLR2 or TLR4 were responsive to M. tuberculosis. TLR2 knock-out mice displayed more than 50% defective cytokine production after stimulation with mycobacteria, whereas TLR4-defective mice also released 30% less cytokines compared to controls. Similarly, HEK293T cells transfected with NOD2 responded to stimulation with M. tuberculosis. The important role of NOD2 for the recognition of M. tuberculosis was demonstrated in mononuclear cells of individuals homozygous for the 3020insC NOD2 mutation, who showed an 80% defective cytokine response after stimulation with M. tuberculosis. Finally, the mycobacterial TLR2 ligand 19-kDa lipoprotein and the NOD2 ligand muramyl dipeptide synergized for the induction of cytokines, and this synergism was lost in cells defective in either TLR2 or NOD2. Together, these results demonstrate that NOD2 and TLR pathways are nonredundant recognition mechanisms of M. tuberculosis that synergize for the induction of proinflammatory cytokines. PMID:16322770

  5. Molecular Epidemiology, Drug Susceptibility and Economic Aspects of Tuberculosis in Mubende District, Uganda

    PubMed Central

    Muwonge, Adrian; Malama, Sydney; Johansen, Tone B.; Kankya, Clovice; Biffa, Demelash; Ssengooba, Willy; Godfroid, Jacques; Djønne, Berit; Skjerve, Eystein

    2013-01-01

    Background Tuberculosis (TB) remains a global public health problem whose effects have major impact in developing countries like Uganda. This study aimed at investigating genotypic characteristics and drug resistance profiles of Mycobacterium tuberculosis isolated from suspected TB patients. Furthermore, risk factors and economic burdens that could affect the current control strategies were studied. Methods TB suspected patients were examined in a cross-sectional study at the Mubende regional referral hospital between February and July 2011. A questionnaire was administered to each patient to obtain information associated with TB prevalence. Isolates of M. tuberculosis recovered during sampling were examined for drug resistance to first line anti-TB drugs using the BACTEC-MGIT960TMsystem. All isolates were further characterized using deletion analysis, spoligotyping and MIRU-VNTR analysis. Data were analyzed using different software; MIRU-VNTR plus, SITVITWEB, BioNumerics and multivariable regression models. Results M. tuberculosis was isolated from 74 out of 344 patients, 48 of these were co-infected with HIV. Results from the questionnaire showed that previously treated TB, co-infection with HIV, cigarette smoking, and overcrowding were risk factors associated with TB, while high medical related transport bills were identified as an economic burden. Out of the 67 isolates that gave interpretable results, 23 different spoligopatterns were detected, nine of which were novel patterns. T2 with the sub types Uganda-I and Uganda-II was the most predominant lineage detected. Antibiotic resistance was detected in 19% and multidrug resistance was detected in 3% of the isolates. Conclusion The study detected M. tuberculosis from 21% of examined TB patients, 62% of whom were also HIV positive. There is a heterogeneous pool of genotypes that circulate in this area, with the T2 lineage being the most predominant. High medical related transport bills and drug resistance could undermine the usefulness of the current TB strategic interventions. PMID:23741382

  6. Safe Re-administration of Tumor Necrosis Factor-alpha (TNF?) Inhibitors in Patients with Rheumatoid Arthritis or Ankylosing Spondylitis Who Developed Active Tuberculosis on Previous Anti-TNF? Therapy

    PubMed Central

    Suh, Young Sun; Kwok, Seung-ki; Ju, Ji Hyeon; Park, Kyung-Su; Park, Sung-Hwan

    2014-01-01

    There is no consensus on whether it is safe to re-administer tumor necrosis factor-alpha (TNF?) inhibitors in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) flared after withdrawal of TNF? inhibitors due to active tuberculosis (TB). We evaluated the safety of restarting anti-TNF? therapy in patients with TNF?-associated TB. We used data of 1,012 patients with RA or AS treated with TNF? inhibitors at Seoul St. Mary's Hospital between January 2003 and July 2013 to identify patients who developed active TB. Demographic and clinical data including the results of tuberculin skin tests (TST) and interferon-? releasing assays (IGRA) were collected. Fifteen patients developed active TB. Five cases were occurred in RA and 10 cases in AS. Nine of 15 patients had a negative TST or IGRA and 6 TST-positive patients had received prophylaxis prior to initiating anti-TNF? therapy. All patients discontinued TNF? inhibitors with starting the treatment of TB. Eight patients were re-administered TNF? inhibitors due to disease flares and promptly improved without recurrence of TB. TNF? inhibitors could be safely resumed after starting anti-TB regimen in patients with RA or AS. PMID:24431903

  7. Tuberculosis: Past, Present and Future

    PubMed Central

    Paine, A. L.; Hershfield, Earl S.

    1979-01-01

    Observation and statistics are offered on treatment of tuberculosis in sanatoria during the lifespan of those institutions with special reference to one where the first author's medical life was mainly spent as patient, physician, surgeon and superintendent. Despite the rapid decrease in morbidity and mortality of tuberculosis, the change in direction, and the change in treatment programs, vigilance is still required. It is only because of the commitment of those involved over the many years in the treatment of tuberculosis that we are now at this enviable position. Imagesp[57]-ap56-a PMID:21301581

  8. Concomitant acromioclavicular and miliary tuberculosis

    PubMed Central

    Agathangelidis, Filon; Boutsiadis, Achilleas; Fouka, Evangelia; Karataglis, Dimitrios

    2013-01-01

    A 48-year-old man was being treated unsuccessfully for miliary tuberculosis for 5?months until he presented with acromioclavicular joint swelling. Imaging of the shoulder revealed destruction of the acromioclavicular joint and the patient was brought to the operating theatre and underwent the excision of the distal end of the clavicle, synovectomy and drainage of the abscess. Surgery was followed by prompt clinical, functional and radiological improvement. Histopathology confirmed the diagnosis of acromioclavicular tuberculosis. Resistance to appropriate antituberculous treatment in patients with miliary tuberculosis can sometimes be a result of undiagnosed extrapulmonary site of infection. PMID:23813516

  9. New vaccines against tuberculosis.

    PubMed

    Mark Doherty, T

    2004-07-01

    In September 2000, recognizing the effect of communicable diseases as obstacles to development in poorer countries, the European Commission assembled a special round table on 'accelerated action targeted at major communicable diseases within the context of poverty reduction'. The three major communicable diseases discussed were tuberculosis (TB), malaria and HIV. One outcome of this discussion was a workshop examining issues related to the fight against TB in Africa, which took place in Gorée, Sénégal, in May 2001. The timing was propitious, as new vaccines for TB (recombinant MVA and BCG, and adjuvanated recombinant fusion proteins or peptide constructs), are just beginning to enter human clinical trials. All but the last of these have shown promise in animal models, up to and including non-human primates, and all are strongly immunogenic and apparently safe. Humans trials for safety and efficacy are thus the logical next step. This review summarizes recent advances in tuberculosis vaccine development, with a special emphasis on issues raised at the Gorée meeting about testing and deploying new generation vaccines in TB-endemic areas such as Africa. PMID:15228493

  10. Educating workers about tuberculosis.

    PubMed

    Watson, L H; Rosen, J D

    1994-01-01

    At a state penitentiary, workers are told that the communicable disease unit is a safe environment in which to work due to the negative air pressure in the isolation rooms and the improved ventilation system. However, nobody is trained to monitor the system or understands the role of negative air pressure, and isolation room doors are occasionally left open. As a result, workers are reluctant to work in the unit. At a soup kitchen, workers refuse to serve people with HIV due to fear of tuberculosis transmission. They have heard that people infected with HIV are likely to have TB and, therefore, to protect themselves, they feel the soup kitchen should not serve people with HIV. In a large, urban social service agency, workers buy masks and begin wearing them to work when they hear a coworker has tuberculosis. Pictures of them in the newspaper instigate a string of similar actions in other agencies. Emergency room workers in a city hospital have been told they are not at increased risk of contracting TB, because they do not have prolonged contact with infectious patients. However, when they discover that several coworkers tested positive on PPD screening tests, they go to their union demanding action. PMID:7878495

  11. Mycobacterium tuberculosis arabinomannan–protein conjugates protect against tuberculosis

    Microsoft Academic Search

    Beston Hamasur; Melles Haile; Andrzej Pawlowski; Ulf Schröder; Ann Williams; Graham Hatch; Graham Hall; Philip Marsh; Gunilla Källenius; Stefan B. Svenson

    2003-01-01

    Lipoarabinomannan (LAM) is a major structural surface component of mycobacteria. Arabinomannan (AM) oligosaccharides derived from LAM of Mycobacterium tuberculosis H37Rv were isolated and covalently conjugated to tetanus toxoid (TT) or to short-term culture filtrate proteins (antigen 85B (Ag85B) or a 75kDa protein) from M. tuberculosis strain Harlingen. The different AM oligosaccharide (AMOs)–protein conjugate vaccine candidates proved to be highly immunogenic,

  12. Inflammatory pseudotumour of the spleen associated with splenic tuberculosis

    PubMed Central

    Prieto-Nieto, Maria Isabel; Pérez-Robledo, Juan Pedro; Díaz-San Andrés, Beatriz; Nistal, Manuel; Rodríguez-Montes, José Antonio

    2014-01-01

    Inflammatory pseudotumor (IPT) of the spleen is an uncommon entity with an uncertain aetiology. Inflammatory pseudotumors present diagnostic difficulties because the clinical and radiological findings tend to suggest a malignancy. The symptoms include weight loss, fever, and abdominal pain. Most cases of splenic IPT present solitary relatively large well circumscribed masses on imaging. The diagnosis in the majority of the cases is made after histopathologic study of splenectomy specimens. The IPTs that occur in the spleen and liver are typically associated with Epstein-Barr virus. Thirty-seven percent of all new cases of active tuberculosis infection are extrapulmonary tuberculosis and tuberculous lymphadenitis the most commonly occurring form of extrapulmonary tuberculosis. We report the case of an inflammatory pseudotumor of the spleen associated with splenic tuberculous lymphadenitis in a 50-year-old female patient who was preoperatively diagnosed with a malignant spleen tumour based on her history of breast of carcinoma. PMID:25548610

  13. In Vitro Activities of Fourteen Antimicrobial Agents Against Drug Susceptible and Resistant Clinical Isolates of Mycobacterium tuberculosis and Comparative Intracellular Activities Against the Virulent H37Rv Strain in Human Macrophages

    Microsoft Academic Search

    Nalin Rastogi; Valérie Labrousse; Khye Seng Goh

    1996-01-01

    .   Minimal inhibitory concentrations (MICs) of 14 first and second-line antituberculous drugs against drug-susceptible and drug-resistant\\u000a clinical isolates of Mycobacterium tuberculosis (including the multiple drug-resistant or MDR-TB isolates), as well as the type strain H37Rv, were determined radiometrically\\u000a by the Bactec 460-TB methodols. MICs (?g\\/ml) of all the fourteen drugs were within an extremely narrow range in case of susceptible

  14. Targeting the chromosome partitioning protein ParA in tuberculosis drug discovery

    PubMed Central

    Nisa, Shahista; Blokpoel, Marian C. J.; Robertson, Brian D.; Tyndall, Joel D. A.; Lun, Shichun; Bishai, William R.; O'Toole, Ronan

    2010-01-01

    Objective To identify inhibitors of the essential chromosome partitioning protein ParA that are active against Mycobacterium tuberculosis. Methods Antisense expression of the parA orthologue MSMEG_6939 was induced on the Mycobacterium smegmatis background. Screening of synthetic chemical libraries was performed to identify compounds with higher anti-mycobacterial activity in the presence of parA antisense. Differentially active compounds were validated for specific inhibition of purified ParA protein from M. tuberculosis (Rv3918c). ParA inhibitors were then characterized for their activity towards M. tuberculosis in vitro. Results Under a number of culture conditions, parA antisense expression in M. smegmatis resulted in reduced growth. This effect on growth provided a basis for the detection of compounds that increased susceptibility to expression of parA antisense. Two compounds identified from library screening, phenoxybenzamine and octoclothepin, also inhibited the in vitro ATPase activity of ParA from M. tuberculosis. Structural in silico analyses predict that phenoxybenzamine and octoclothepin undergo interactions compatible with the active site of ParA. Octoclothepin exhibited significant bacteriostatic activity towards M. tuberculosis. Conclusions Our data support the use of whole-cell differential antisense screens for the discovery of inhibitors of specific anti-tubercular drug targets. Using this approach, we have identified an inhibitor of purified ParA and whole cells of M. tuberculosis. PMID:20810423

  15. A comment on the suspected solar neutrino -- solar activity connection

    NASA Technical Reports Server (NTRS)

    Wilson, Robert M.

    1994-01-01

    Recently, it has been proposed that there exists a highly statistically significant (at greater than or equal to 98% level of confidence) relationship between Ar-37 production rate (namely, solar neutrinos) and the Ap geomagnetic index (namely, solar particles), based on the chi-square goodness-of-fit test and correlation analysis, for the interval 1970-1990. While a relationship between the two parameters, indeed, seems to be discernible, the strength of the relationship has been overstated. Instead of being significant at the afore-mentioned level of confidence, the relationship is found to be significant at only greater than or equal to 95% level of confidence, based on Yates' modification to the chi-square test for 2 x 2 contingency tables. Likewise, while correlation analysis yields a value of r = 0.2691, it is important to note that such a value suggests that only about 7% of the variance can be 'explained' by the inferred correlation and that the remaining 93% of the variance must be attributed to other sources.

  16. Bovine tuberculosis at a cattle-small ruminant-human interface in Meskan, Gurage region, Central Ethiopia

    PubMed Central

    2011-01-01

    Background Bovine tuberculosis (BTB) is endemic in Ethiopian cattle. The aim of this study was to assess BTB prevalence at an intensive contact interface in Meskan Woreda (district) in cattle, small ruminants and suspected TB-lymphadenitis (TBLN) human patients. Methods The comparative intradermal test (CIDT) was carried out for all animals involved in the cross-sectional study and results interpreted using a > 4 mm and a > 2 mm cut-off. One PPD positive goat was slaughtered and lymph nodes subjected to culture and molecular typing. In the same villages, people with lymphadenitis were subjected to clinical examination. Fine needle aspirates (FNA) were taken from suspected TBLN and analyzed by smear microscopy and molecular typing. Results A total of 1214 cattle and 406 small ruminants were tested for BTB. In cattle, overall individual prevalence (> 2 mm cut-off) was 6.8% (CI: 5.4-8.5%) with 100% herd prevalence. Only three small ruminants (2 sheep and 1 goat) were reactors. The overall individual prevalence in small ruminants (> 2 mm cut-off) was 0.4% (CI: 0.03-5.1%) with 25% herd prevalence. Cattle from owners with PPD positive small ruminants were all PPD negative. 83% of the owners kept their sheep and goats inside their house at night and 5% drank regularly goat milk. FNAs were taken from 33 TBLN suspected cases out of a total of 127 screened individuals with lymph node swellings. Based on cytology results, 12 were confirmed TBLN cases. Nine out of 33 cultures were AFB positive. Culture positive samples were subjected to molecular typing and they all yielded M. tuberculosis. M. tuberculosis was also isolated from the goat that was slaughtered. Conclusions This study highlighted a low BTB prevalence in sheep and goats despite intensive contact with cattle reactors. TBLN in humans was caused entirely by M. tuberculosis, the human pathogen. M. tuberculosis seems to circulate also in livestock but their role at the interface is unknown. PMID:22085784

  17. SUSPECTS: enabling fast and effective prioritization of positional candidates. 

    E-print Network

    Adie, Euan A; Evans, K.; Porteous, David; Pickard, B.; Adams, Richard R

    2006-03-01

    SUSPECTS is a web-based server which combines annotation and sequence-based approaches to prioritize disease candidate genes in large regions of interest. It uses multiple lines of evidence to rank genes quickly and ...

  18. Suspect confession of child sexual abuse to investigators.

    PubMed

    Lippert, Tonya; Cross, Theodore P; Jones, Lisa; Walsh, Wendy

    2010-05-01

    Increasing the number of suspects who give true confessions of sexual abuse serves justice and reduces the burden of the criminal justice process on child victims. With data from four communities, this study examined confession rates and predictors of confession of child sexual abuse over the course of criminal investigations (final N = 282). Overall, 30% of suspects confessed partially or fully to the crime. This rate was consistent across the communities and is very similar to the rates of suspect confession of child sexual abuse found by previous research, although lower than that from a study focused on a community with a vigorous practice of polygraph testing. In a multivariate analysis, confession was more likely when suspects were younger and when more evidence of abuse was available, particularly child disclosure and corroborative evidence. These results suggest the difficulty of obtaining confession but also the value of methods that facilitate child disclosure and seek corroborative evidence, for increasing the odds of confession. PMID:20410024

  19. COMMUNITY ALERT INCIDENT: Two Bike Theft Suspects Arrested

    E-print Network

    Barrett, Jeffrey A.

    COMMUNITY ALERT INCIDENT: Two Bike Theft Suspects Arrested DETAILS: On Wednesday morning, December. The community is encouraged to visit http://police.uci.edu/safety/publications/Bicycle.pdf for more information

  20. The Journal of Immunology Differential Risk of Tuberculosis Reactivation among

    E-print Network

    Kirschner, Denise

    The Journal of Immunology Differential Risk of Tuberculosis Reactivation among Anti-TNF Therapies specific host factors that, if augmented, would improve granuloma function during anti-TNF therapy. Our bacterial growth (4, 5, 7­10). TNF, a pleiotropic cytokine produced by infected and activated macro- phages

  1. [Treatment of extrapulmonary tuberculosis and complicated forms of pulmonary tuberculosis].

    PubMed

    2008-09-01

    Tuberculosis is one of the most important health problems worldwide. In developed countries there is an increased number of cases due to different reasons. The most likely determinant cause is from immigrants coming from high endemic areas. This phenomenon is a direct cause of the increase in extrapulmonary and complicated pulmonary forms of tuberculosis. There are only a few controlled clinical trials evaluating therapies for extrapulmonary tuberculosis. Consequently, documented evidence is scarce, particularly in paediatrics. The majority of therapeutic recommendations are based on series of cases or expert opinions, with a lack of uniformity provided by the different consensus of the main scientific societies. The main objective of this fourth consensus by the Tuberculosis Study Group of the Spanish Society of Paediatric Infectious Diseases (Sociedad Española de Infectología Pediátrica, SEIP) is to perform a thorough revision of the data obtained from scientific literature, in order to establish recommendations for the treatment of extrapulmonary tuberculosis and complicated forms of pulmonary tuberculosis, adapted to the characteristics and drugs available in Spain. PMID:18775275

  2. Nosocomial Outbreak of Multidrug-Resistant Tuberculosis Caused by a Strain of Mycobacterium tuberculosis W-Beijing Family in St. Petersburg, Russia

    Microsoft Academic Search

    O. Narvskaya; T. Otten; E. Limeschenko; N. Sapozhnikova; O. Graschenkova; L. Steklova; A. Nikonova; M. L. Filipenko; I. Mokrousov; B. Vyshnevskiy

    2002-01-01

    .   A molecular epidemiologic study of 35 Mycobacterium tuberculosis isolates from 19 patients was conducted to define a nosocomial outbreak of multidrug-resistant tuberculosis in St. Petersburg,\\u000a Russia. IS6110-restriction fragment length polymorphism (RFLP) fingerprinting, together with investigations to detect mutations conferring\\u000a drug resistance, revealed relationships between the isolates and links between the cases. Three patients and a nurse exposed\\u000a to active

  3. Targeting dormant bacilli to fight tuberculosis.

    PubMed

    Fattorini, Lanfranco; Piccaro, Giovanni; Mustazzolu, Alessandro; Giannoni, Federico

    2013-01-01

    Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which kills about 2 million people annually. Furthermore, 2 billion people worldwide are latently infected with this organism, with 10% of them reactivating to active TB due to re-growth of nonreplicating (dormant) Mtb residing in their tissues. Because of the huge reservoir of latent TB it is important to find novel drugs/drug combinations killing dormant bacilli (microaerophiles, anaerobes and drug-tolerant persisters) surviving for decades in a wide spectrum of granulomatous lesions in the lungs of TB patients. Antibiotic treatment of drug-susceptible TB requires administration of isoniazid, rifampin, pyrazinamide, ethambutol for 2 months, followed by isoniazid and rifampin for 4 months. To avoid reactivation of dormant Mtb to active pulmonary TB, up to 9 months of treatment with isoniazid is required. Therefore, a strategy to eliminate dormant bacilli needs to be developed to shorten therapy of active and latent TB and reduce the reservoir of people with latent TB. Finding drugs with high rate of penetration into the caseous granulomas and understanding the biology of dormant bacilli and in particular of persister cells, phenotypically resistant to antibiotics, will be essential to eradicate Mtb from humans. In recent years unprecedented efforts have been done in TB drug discovery, aimed at identifying novel drugs and drug combinations killing both actively replicating and nonreplicating Mtb in vitro, in animal models and in clinical trials in humans. PMID:24363887

  4. Tuberculosis care: an evaluability study

    PubMed Central

    Coelho, Ardigleusa Alves; Martiniano, Cláudia Santos; Brito, Ewerton Willian Gomes; Negrão, Oswaldo Gomes Corrêa; Arcêncio, Ricardo Alexandre; Uchôa, Severina Alice da Costa

    2014-01-01

    OBJECTIVE: to verify whether the tuberculosis control program (TCP) is evaluable and to examine the feasibility of building an evaluation model in apriority municipality for the control of tuberculosis. METHOD: this evaluability study was conducted in a municipality in northeastern Brazil. For data collection, documental analysis and interviews with key informants were performed. For indicator validation, the nominal group technique was adopted. RESULTS: the details of TCP were described, and both the logical model and the classification framework for indicators were developed and agreed up on, with the goal of characterizing the structural elements of the program, defining the structure and process indicators, and formulating the evaluation questions. CONCLUSION: TCP is evaluable. Based on logical operational analysis, it was possible to evaluate the adequacy of the program goals for the control of tuberculosis. Therefore, the performance of a summative evaluation is recommended, with a focus on the analysis of the effects of tuberculosis control interventions on decreasing morbidity and mortality. PMID:25493675

  5. Tuberculosis in Hispanics/Latinos

    MedlinePLUS

    ... the African-American Community Summit Background Slideset Slideset Text version Websites Children Correctional Facilities Table of Contents ... Tuberculosis Laboratory Aggregate Reports Slide Sets Core Curriculum Text- only version Self-Study Modules Module 1 (text ...

  6. Tuberculosis Information for International Travelers

    MedlinePLUS

    ... the African-American Community Summit Background Slideset Slideset Text version Websites Children Correctional Facilities Table of Contents ... Tuberculosis Laboratory Aggregate Reports Slide Sets Core Curriculum Text- only version Self-Study Modules Module 1 (text ...

  7. Tuberculosis presenting as epitrochlear lymphadenitis.

    PubMed

    Crum, Nancy F

    2003-01-01

    Epitrochlear lymphadenitis is an uncommon presentation of extrapulmonary tuberculosis in an immunocompetent host. This case report describes the third case in the literature and provides a review of the literature. PMID:14723371

  8. Interviewing strategically to elicit admissions from guilty suspects.

    PubMed

    Tekin, Serra; Granhag, Pär Anders; Strömwall, Leif; Giolla, Erik Mac; Vrij, Aldert; Hartwig, Maria

    2015-06-01

    In this article we introduce a novel interviewing tactic to elicit admissions from guilty suspects. By influencing the suspects' perception of the amount of evidence the interviewer holds against them, we aimed to shift the suspects' counterinterrogation strategies from less to more forthcoming. The proposed tactic (SUE-Confrontation) is a development of the Strategic Use of Evidence (SUE) framework and aims to affect the suspects' perception by confronting them with statement-evidence inconsistencies. Participants (N = 90) were asked to perform several mock criminal tasks before being interviewed using 1 of 3 interview techniques: (a) SUE-Confrontation, (b) Early Disclosure of Evidence, or (c) No Disclosure of Evidence. As predicted, the SUE-Confrontation interview generated more statement-evidence inconsistencies from suspects than the Early Disclosure interview. Importantly, suspects in the SUE-Confrontation condition (vs. Early and No disclosure conditions) admitted more self-incriminating information and also perceived the interviewer to have had more information about the critical phase of the crime (the phase where the interviewer lacked evidence). The findings show the adaptability of the SUE-technique and how it may be used as a tool for eliciting admissions. (PsycINFO Database Record PMID:25844517

  9. Suspect aggression and victim resistance in multiple perpetrator rapes.

    PubMed

    Woodhams, Jessica; Cooke, Claire

    2013-11-01

    Several research studies have reported an elevated level of aggression in rapes committed by multiple perpetrators compared to rapes committed by lone suspects. Several factors that have been linked to elevated aggression in generic samples of rape were examined for the first time with a sample of multiple perpetrator rapes. Factors that might be associated with victim resistance were also investigated. Victim and offender characteristics, as well as the behaviors displayed by victims and offenders, were extracted from the police files of 89 multiple perpetrator stranger rapes perpetrated against female victims in the United Kingdom. These behaviors were rated for their level of suspect (non-sexual) aggression and victim resistance, respectively. Degree of victim resistance was significantly and positively associated with suspect aggression. Older victims were the recipients of significantly higher levels of suspect aggression. Victims who were incapacitated from drugs and/or alcohol were less likely to be the recipients of suspect aggression. Group leaders displayed more aggression towards the victim than the followers in the groups. The number of perpetrators was significantly related to the degree of resistance displayed by the victim with offences perpetrated by fewer suspects being characterized by more victim resistance. Research regarding cognitive appraisal during criminal interactions and the respective roles of offenders is referred to in considering these relationships. PMID:23740469

  10. Mediastinal Lymphadenopathy: Melioidosis Mimicking Tuberculosis

    PubMed Central

    Chan, Hiang Ping; Yip, Hwee Seng

    2015-01-01

    Melioidosis has protean manifestations and often mimics other disease processes. We present a case of a gentleman presenting with chronic cough whose initial radiographic findings of a cavitatory lung lesion and mediastinal lymphadenopathy were suggestive of tuberculosis. This case highlights the important role that bronchoscopy and endobronchial ultrasound can play in the diagnosis of melioidosis in patients presenting with mediastinal lymphadenopathy whose initial microbiological findings from sputum are negative for tuberculosis.

  11. Mediastinal Lymphadenopathy: Melioidosis Mimicking Tuberculosis.

    PubMed

    Chan, Hiang Ping; Yip, Hwee Seng

    2015-06-01

    Melioidosis has protean manifestations and often mimics other disease processes. We present a case of a gentleman presenting with chronic cough whose initial radiographic findings of a cavitatory lung lesion and mediastinal lymphadenopathy were suggestive of tuberculosis. This case highlights the important role that bronchoscopy and endobronchial ultrasound can play in the diagnosis of melioidosis in patients presenting with mediastinal lymphadenopathy whose initial microbiological findings from sputum are negative for tuberculosis. PMID:26060421

  12. Positive skin and serologic test results of diagnostic assays for bovine tuberculosis and subsequent isolation of Mycobacterium interjectum in a pygmy hippopotamus (Hexaprotodon liberiensis).

    PubMed

    Bouts, Tim; Vordermeier, Martin; Flach, Edmund; Routh, Andrew

    2009-09-01

    A 20-yr-old male pygmy hippopotamus (Hexaprotodon liberiensis), weighing 250 kg, arrived at Zoological Society London Whipsnade Zoo (United Kingdom) from a captive collection in Portugal. A quarantine health check was performed including a comparative intradermal tuberculosis (IDTB) test. Assessment of the comparative IDTB test at 72 hr revealed a strong positive reaction at the bovine site. Serum was tested with a rapid immunochromatographic assay (TB STAT-PAK) and was positive for tuberculosis antibodies. The tuberculosis tests were repeated 6 wk later with the same positive test outcome. In addition, a broncho-alveolar lavage (BAL) was submitted for mycobacterial culture. The positive IDTB test and TB STAT-PAK results were supported by multiantigen print immunoassay (MAPIA). Based on these results, the animal was suspected to be infected with Mycobacterium tuberculosis complex organisms and was euthanized. No gross or histologic signs of tuberculosis were found at postmortem examination. Mycobacterium interjectum was cultured from the BAL but not from necropsy samples. The antigens used in the TB STAT-PAK and MAPIA tests are reportedly specific for the M. tuberculosis complex, and so it is possible this animal presented with a latent case of tuberculosis or had a previous tuberculosis infection that resolved prior to testing. Cross-reactions with nontuberculous mycobacteria have been described with TB STAT-PAK and MAPIA tests. However, Western blotting analysis using serum from this animal did not recognize M. interjectum proteins of equivalent size to the M. tuberculosis-Mycobacterium bovis proteins recognized in the MAPIA. Thus, antigenic cross-reactivity with M. interjectum can be deemed less likely, but other nontuberculous mycobacterial proteins cannot be ruled out. It is therefore possible that false-positive reactions were obtained. These results highlight the difficulty of diagnosing tuberculosis in the absence of pathology and the presence of nontuberculous mycobacteria. PMID:19746870

  13. Efficient Ex Vivo Stimulation of Mycobacterium tuberculosis-Specific T Cells by Genetically Detoxified Bordetella pertussis Adenylate Cyclase Antigen Toxoids

    Microsoft Academic Search

    Katalin A. Wilkinson; Marcela Simsova; Elisabeth Scholvinck; Peter Sebo; Claude Leclerc; H. Martin Vordermeier; Stuart J. Dickson; Jillian R. Brown; Robert N. Davidson; Geoffrey Pasvol; Michael Levin; Robert J. Wilkinson

    2005-01-01

    Mycobacterium tuberculosis is a significant threat to global health. Mycobacterium bovis BCG vaccine provides only partial protection, and the skin test reagent used to aid diagnosis of both active and latent tuberculosis, purified protein derivative (PPD), lacks specificity and sensitivity. The use of genetically detoxified Bordetella pertussis adenylate cyclase toxin (CyaA) as a delivery system for two immunodominant proteins of

  14. Comparative evaluation of intranasal and subcutaneous route of immunization for development of mucosal vaccine against experimental tuberculosis

    Microsoft Academic Search

    Pramod K. Giri; Suraj B. Sable; Indu Verma; Gopal K. Khuller

    2005-01-01

    Activation of mucosal immunity in the respiratory tract is crucial for protection against respiratory infections. Whether the intranasal route of vaccination imparts better protection against pulmonary tuberculosis than that of subcutaneous vaccination remains a debatable issue. In this study, we have investigated the effect of the routes of immunization on the induction of immunoprotection against experimental tuberculosis employing mycobacterial culture

  15. Analysis of the Shotgun Expression Library of the Mycobacterium tuberculosis Genome for Immunodominant Polypeptides: Potential Use in Serodiagnosis

    PubMed Central

    Bisen, Prakash S.; Garg, Sanjay K.; Tiwari, Ram P.; Tagore, P. Ravindra Nath; Chandra, Ramesh; Karnik, Rucha; Thaker, Nimesh; Desai, Nirav; Ghosh, P. K.; Fraziano, Maurizio; Colizzi, Vittorio

    2003-01-01

    A recombinant DNA strategy was applied to analyze and screen the shotgun expression library from a clinically confirmed local virulent isolate of Mycobacterium tuberculosis with sera from tuberculosis patients, which led to expression and purification of highly immunoreactive and specific mycobacterial antigens expressed during the course of active disease which could be of diagnostic significance. An enzyme-linked immunoassay for diagnosis of tuberculosis was devised by using a shotgun immunoexpression library in the ?gt11 vector. DNA from a virulent M. tuberculosis patient isolate (TBW-33) confirmed with the BACTEC 460 system was sheared and expressed to generate shotgun polypeptides. ?-Galactosidase fusion proteins capable of demarcating active tuberculosis infections from Mycobacterium bovis BCG-vaccinated healthy subjects or people harboring environmental mycobacteria were selected by comparative immunoreactivity studies. Promising mycobacterial DNA cassettes were subcloned and expressed into the glutathione S-transferase (GST) fusion vector pGEX-5X-1 with a strong tac promoter and were expressed in Escherichia coli BL21. These fusion proteins were severed at a built-in factor Xa recognition site to separate the GST tags and were utilized in an indirect enzyme-linked immunoassay for serodiagnosis of patients with active tuberculosis. The system offered a clear demarcation between BCG-vaccinated healthy subjects and patients with active tuberculosis and proved to be effective in detecting pulmonary as well as extrapulmonary tuberculosis, with an overall sensitivity of 84.33% and an overall specificity of 93.62%. PMID:14607866

  16. Synthesis and evaluation of SQ109 analogues as potential anti-tuberculosis candidates.

    PubMed

    Onajole, Oluseye K; Govender, Patrick; van Helden, Paul D; Kruger, Hendrik G; Maguire, Glenn E M; Wiid, Ian; Govender, Thavendran

    2010-05-01

    As part of an ongoing project to develop highly potent anti-tuberculosis therapeutics, six SQ109 derivatives were synthesized and screened in vitro for their anti-tuberculosis activity against the ATCC strain H37Rv and the extensively drug-resistant clinical strain XDR 173. Compound 16 with an extended alkene chain was the most active against both strains of Mycobacterium tuberculosis within a MIC range of 0.5-0.25 microM. Compound 12 and SQ109 were potent within a MIC range of 1-0.5 microM, whilst compound 18 displayed an activity within the MIC range of 0.5-2 microM against both Mycobacterium tuberculosis strains. PMID:20149497

  17. Tuberculosis origin: The Neolithic scenario.

    PubMed

    Hershkovitz, Israel; Donoghue, Helen D; Minnikin, David E; May, Hila; Lee, Oona Y-C; Feldman, Michal; Galili, Ehud; Spigelman, Mark; Rothschild, Bruce M; Bar-Gal, Gila Kahila

    2015-06-01

    This paper follows the dramatic changes in scientific research during the last 20 years regarding the relationship between the Mycobacterium tuberculosis complex and its hosts - bovids and/or humans. Once the M. tuberculosis and Mycobacterium bovis genomes were sequenced, it became obvious that the old story of M. bovis evolving into the human pathogen should be reversed, as M. tuberculosis is more ancestral than M. bovis. Nevertheless, the timescale and geographical origin remained an enigma. In the current study human and cattle bone samples were examined for evidence of tuberculosis from the site of Atlit-Yam in the Eastern Mediterranean, dating from 9250 to 8160 (calibrated) years ago. Strict precautions were used to prevent contamination in the DNA analysis, and independent centers used to confirm authenticity of findings. DNA from five M. tuberculosis genetic loci was detected and had characteristics consistent with extant genetic lineages. High performance liquid chromatography was used as an independent method of verification and it directly detected mycolic acid lipid biomarkers, specific for the M. tuberculosis complex. These, together with pathological changes detected in some of the bones, confirm the presence of the disease in the Levantine populations during the Pre-pottery Neolithic C period, more than 8000 years ago. PMID:25726364

  18. 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 elevated mutation rates during tuberculosis latency in humans, unlike the situation in rhesus macaques. PMID:24618815

  19. Increase in the Number of Tuberculosis Cases Treated following Tuberculin Skin Testing in First-Year Schoolchildren in Madagascar

    PubMed Central

    Ratovoson, Rila; Raharimanga, Voamalala; Rakotosamimanana, Niaina; Ravaloson, B.; Ratsitorahina, Maherisosa; Randremanana, Rindra; Ramarokoto, Herimanana; Rajatonirina, Soatiana; Rasolofo, Voahangy; Richard, Vincent

    2014-01-01

    Background Tuberculosis continues to cause unacceptably high levels of disease and death worldwide. Active preventive strategies are required to improve tuberculosis control and to increase the number of cases treated in developing countries. The aim of this study was to evaluate the utility of the tuberculin skin test (TST) in first-year schoolchildren as a means of increasing the number of tuberculosis cases detected through the screening of close contacts. Methods All members of the households of 90 schoolchildren assigned to three groups on the basis of TST category (?5 mm, [5–15)mm, ?15 mm) were screened for sputum smear-positive pulmonary tuberculosis. The percentage detection of tuberculosis in close contacts was compared between TST categories. Results We identified 433 close contacts of the 90 schoolchildren, who were then evaluated for tuberculosis. We identified 11 cases of pulmonary tuberculosis among the close contacts (7 already on treatment and 4 previously undiagnosed): 0 in TST category ?5 mm, 3 in TST category [5–15) mm and 8 in TST category ?15 mm). This approach increased the detection of tuberculosis cases by a factor of 1.6 in first-year schoolchildren of the TST ?5 mm group. Conclusion TST in first-year schoolchildren is a potentially effective method for improving the detection of tuberculosis in close contacts. PMID:24743554

  20. INHIBITOR STUDIES ON MYCOBACTERIUM TUBERCULOSIS MALATE SYNTHASE 

    E-print Network

    Owen, Joshua

    2008-08-03

    The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) has intensified efforts to discover novel drugs for tuberculosis (TB) treatment. Targeting the persistent state of Mtb, a condition in which Mtb is resistant...

  1. A case of isolated splenic tuberculosis

    PubMed Central

    Basa, Johanna V.; Singh, Lilly; Jaoude, Wassim Abi; Sugiyama, Gainosuke

    2014-01-01

    There are few cases of isolated splenic tuberculosis reported in the literature internationally, and nearly none from western medical centers. The incidence of tuberculosis has declined in the United States since the 1950s, with 11,585 reported cases in 2009, 21% of which were exclusively extrapulmonary. Splenic tuberculosis occurs mostly as part of miliary tuberculosis in immunocompromised patients. Isolated splenic tuberculosis is extremely rare, particularly in the immunocompetent patient. Patients susceptible to acquiring splenic tuberculosis usually have one of the following risk factors: immunosuppression, preceding pyogenic infections, splenic abnormalities, prior trauma to the spleen, sickle cell disease and other hemopathies, and in the immunocompetent patient another body site infected by M. tuberculosis. In this report we present the case of a young immunocompetent male with no other significant past medical history with isolated splenic tuberculosis. PMID:25667987

  2. Pulmonary Tuberculosis in a Patient with Cystic Fibrosis

    PubMed Central

    Patil, Naveen; Marco, Asween; Montales, Maria Theresa; Bhaskar, Nutan; Mittadodla, Penchala; Mukasa, Leonard N.

    2015-01-01

    Context: Mycobacterium tuberculosis (MTB) infection is rarely seen in cystic fibrosis (CF) patients. Case Report: We report a 24-year-old CF patient with fever, cough, hemoptysis, and weight loss of 1week duration prior to admission. Past sputum cultures grew methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. The patient was treated with broad spectrum antibiotics based on previous culture data, but failed to improve. Chest radiograph and computed tomography (CT) chest revealed chronic collapse of the anterior subsegment of right upper lobe and multiple bilateral cavitary lesions which were worse compared to prior films. MTB was suspected and was confirmed by positive acid-fast bacilli (AFB) smears and cultures. After receiving first-line antituberculous drugs, the patient's condition markedly improved. Conclusion: MTB is an infrequent finding, but considered a potential pathogen in CF patients, and may lead to serious pulmonary complications if there is a delay in diagnosis and treatment.

  3. Validity of Suspected Alcohol and Drug Violations in Aviation Employees

    PubMed Central

    Li, Guohua; Brady, Joanne E.; DiMaggio, Charles; Baker, Susan P.; Rebok, George W.

    2012-01-01

    Introduction In the United States, transportation employees who are suspected of using alcohol and drugs are subject to reasonable-cause testing. This study aims to assess the validity of suspected alcohol and drug violations in aviation employees. Methods Using reasonable-cause testing and random testing data from the Federal Aviation Administration for the years 1995 through 2005, we calculated the positive predictive value (PPV) and positive likelihood ratio (LR+) of suspected alcohol and drug violations. The true status of violations was based on testing results, with an alcohol violation being defined as a blood alcohol concentration of ?40 mg/dL and a drug violation as a test positive for marijuana, cocaine, amphetamines, phencyclidine, or opiates. Results During the 11-year study period, a total of 2,284 alcohol tests and 2,015 drug tests were performed under the reasonable-cause testing program. The PPV was 37.7% [95% confidence interval (CI), 35.7–39.7%] for suspected alcohol violations and 12.6% (95% CI, 11.2–14.1%) for suspected drug violations. Random testing revealed an overall prevalence of 0.09% (601/649,796) for alcohol violations and 0.6% (7,211/1,130,922) for drug violations. The LR+ was 653.6 (95% CI, 581.7–734.3) for suspected alcohol violations and 22.5 (95% CI, 19.6–25.7) for suspected drug violations. Discussion The discriminative power of reasonable-cause testing suggests that, despite its limited positive predictive value, physical and behavioral observation represents an efficient screening method for detecting alcohol and drug violations. The limited positive predictive value of reasonable-cause testing in aviation employees is due in part to the very low prevalence of alcohol and drug violations. PMID:20712820

  4. Polymerase chain reaction targeting insertion sequence for the diagnosis of extrapulmonary tuberculosis

    PubMed Central

    Makeshkumar, V.; Madhavan, Radha; Narayanan, Sujatha

    2014-01-01

    Background & objectives: Diagnosis of extrapulmonary tuberculosis (EPTB) is difficult using conventional diagnostic methods. This study was conducted to evaluate the use of polymerase chain reaction (PCR) in diagnosis of definitive and probable extrapulmonary tuberculosis patients, and to assess the performance of insertion sequence (IS) 6110 based PCR assay as compared to conventional culture by Lowenstein-Jensen (LJ) method for the diagnosis of EPTB. Methods: A total of 178 non repeated clinical specimens were collected from clinically suspected extrapulmonary tuberculosis patients. The specimens included 59 ascitic fluid, 54 pleural fluid, 25 cerebrospinal fluid (CSF), 12 fine needle aspiration (FNA), 8 urine, 7 pus, 6 synovial fluid, 2 skin tissue, one pericardial fluid, one liver abscess, one pancreatic cyst fluid, one omental biopsy and one semen sample. All these clinical samples were subjected to Ziehl-Neelsen staining (ZN) for acid fast bacilli (AFB) and culture on LJ medium. PCR was performed by targeting 123bp fragment of insertion sequence IS6110 of Mycobacterium tuberculosis (MTB). Results: Of the 178 specimens, 10 (5.61%) were ZN smear positive for AFB, six (3.37%) were L-J culture positive from 10 AFB smear positive cases and 48 (26.96%) were PCR IS 6110 positive for M. tuberculosis. Interpretation & conclusions: PCR using IS6110 primer was able to pick up more EPTB patients compared to conventional L-J culture method for detection of M. tuberculosis. False positive PCR IS6110 in three CSF samples may be due to latent TB infection which was limitation in this study. PMID:24604051

  5. Z-100, extracted from Mycobacterium tuberculosis strain Aoyama B, promotes TNF-? production via nucleotide-binding oligomerization domain containing 2 (Nod2)-dependent NF-?B activation in RAW264.7 cells.

    PubMed

    Katsunuma, Kokichi; Yoshinaga, Koji; Ohira, Yuta; Eta, Runa; Sato, Takanori; Horii, Takayuki; Tanaka, Takao; Takei, Mineo; Seto, Koichi

    2015-03-01

    Macrophages are a major component of the innate immune system, and the cytokines they secrete are involved in antitumor responses. Z-100 is obtained from hot-water extract of human-type Mycobacterium tuberculosis strain Aoyama B and activates the innate immune response. However, while Z-100 is known to modulate macrophage activity, the mechanism behind this modulation is not fully understood. We evaluated the effects of Z-100 on the murine macrophage cell line RAW264.7. Tumor necrosis factor-alpha (TNF-?) production from RAW264.7 cells was strongly induced by Z-100 and interferon-gamma (IFN-?) stimulation but only weakly induced by Z-100 alone. Quantitative gene expression analysis showed that nucleotide-binding oligomerization domain containing 2 (Nod2) expression was up-regulated by IFN-? treatment in RAW264.7 cells while Z-100-induced TNF-? production was attenuated by Nod2 gene silencing. Further, componential analysis demonstrated that muramic acid and amino acids distinctive of muramyl dipeptide (MDP) were contained within Z-100 and Z-100Fr I, the low-molecular-weight fraction containing components <3 kDa in size. In addition, Z-100Fr I enhanced TNF-? production in RAW264.7 cells and promoted NOD2-dependent nuclear factor-kappa B (NF-?B) activation in murine NOD2-expressing SEAP reporter HEK293 (HEK-Blue-mNOD2) cells. Taken together, these results suggest that Z-100 contains MDP-like molecules and augments NF-?B signaling via the direct activation of Nod2 in macrophages, which might be one mechanism driving the innate immune responses induced by Z-100 in cancer immunotherapy. PMID:25499802

  6. Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

    PubMed Central

    Black, Philippa A.; Warren, Robin M.; Louw, Gail E.; van Helden, Paul D.; Victor, Thomas C.

    2014-01-01

    The inherent drug susceptibility of microorganisms is determined by multiple factors, including growth state, the rate of drug diffusion into and out of the cell, and the intrinsic vulnerability of drug targets with regard to the corresponding antimicrobial agent. Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a significant source of global morbidity and mortality, further exacerbated by its ability to readily evolve drug resistance. It is well accepted that drug resistance in M. tuberculosis is driven by the acquisition of chromosomal mutations in genes encoding drug targets/promoter regions; however, a comprehensive description of the molecular mechanisms that fuel drug resistance in the clinical setting is currently lacking. In this context, there is a growing body of evidence suggesting that active extrusion of drugs from the cell is critical for drug tolerance. M. tuberculosis encodes representatives of a diverse range of multidrug transporters, many of which are dependent on the proton motive force (PMF) or the availability of ATP. This suggests that energy metabolism and ATP production through the PMF, which is established by the electron transport chain (ETC), are critical in determining the drug susceptibility of M. tuberculosis. In this review, we detail advances in the study of the mycobacterial ETC and highlight drugs that target various components of the ETC. We provide an overview of some of the efflux pumps present in M. tuberculosis and their association, if any, with drug transport and concomitant effects on drug resistance. The implications of inhibiting drug extrusion, through the use of efflux pump inhibitors, are also discussed. PMID:24614376

  7. 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

  8. Oropharyngeal tuberculosis causing severe odynophagia and dysphagia

    Microsoft Academic Search

    Rahmet Caylan; Kemalettin Aydin

    2002-01-01

    Oropharyngeal tuberculosis is a rare disease and is usually secondary to laryngeal involvement in pulmonary tuberculosis.\\u000a The major symptom in such patients is sore throat. Here, we report a case of tuberculosis of the posterior oropharyngeal wall\\u000a without laryngeal involvement and causing severe dysphagia and odynophagia without esophageal or mediastinal involvement.\\u000a The unusual presentation of extrapulmonary tuberculosis is emphasized, and

  9. Miliary tuberculosis and adult respiratory distress syndrome

    Microsoft Academic Search

    A. Roglan Piqueras; L. Marruecos; A. Artigas; C. Rodriguez

    1987-01-01

    Although, miliary tuberculosis is an unusual cause of severe acute respiratory failure, we describe nine patients with miliary tuberculosis who developed adult respiratory distress syndrome. This complication occurred in seven patients despite treatment with antituberculous drugs. In two patients who developed the syndrome, miliary tuberculosis was diagnosed only at postmortem. The presence of pulmonary hypertension in all cases and disseminated

  10. Crystal structure of the enoyl-ACP reductase of Mycobacterium tuberculosis (InhA) in the apo-form and in complex with the active metabolite of isoniazid pre-formed by a biomimetic approach.

    PubMed

    Chollet, Aurélien; Mourey, Lionel; Lherbet, Christian; Delbot, Alexandra; Julien, Sylviane; Baltas, Michel; Bernadou, Jean; Pratviel, Geneviève; Maveyraud, Laurent; Bernardes-Génisson, Vania

    2015-06-01

    InhA is an enoyl-ACP reductase of Mycobacterium tuberculosis implicated in the biosynthesis of mycolic acids, essential constituents of the mycobacterial cell wall. To date, this enzyme is considered as a promising target for the discovery of novel antitubercular drugs. In this work, we describe the first crystal structure of the apo form of the wild-type InhA at 1.80Å resolution as well as the crystal structure of InhA in complex with the synthetic metabolite of the antitubercular drug isoniazid refined to 1.40Å. This metabolite, synthesized in the absence of InhA, is able to displace and replace the cofactor NADH in the enzyme active site. This work provides a unique opportunity to enlighten the structural adaptation of apo-InhA to the binding of the NADH cofactor or of the isoniazid adduct. In addition, a differential scanning fluorimetry study of InhA, in the apo-form as well as in the presence of NAD(+), NADH and INH-NADH was performed showing that binding of the INH-NADH adduct had a strong stabilizing effect. PMID:25891098

  11. Synthesis, crystal structures and characterization of late first row transition metal complexes derived from benzothiazole core: anti-tuberculosis activity and special emphasis on DNA binding and cleavage property.

    PubMed

    Netalkar, Priya P; Netalkar, Sandeep P; Budagumpi, Srinivasa; Revankar, Vidyanand K

    2014-05-22

    Air and moisture stable coordination compounds of late first row transition metals, viz. Co(II), Ni(II), Cu(II) and Zn(II), with a newly designed ligand, 2-(2-benzo[d]thiazol-2-yl)hydrazono)propan-1-ol (LH), were prepared and successfully characterized using various spectro-analytical techniques. The molecular structures of the ligand and nickel complex were unambiguously determined by single-crystal X-ray diffraction method. The [Ni(LH)2]Cl2.3H2O complex is stabilized by intermolecular CH?? stacking interactions between the methyl hydrogen and the C18 atom of the phenyl ring (C11-H11B?C18) forming 1D zig-zag chain structure. Both, the ligand and its copper complex, were electrochemically active in the working potential range, showing quasi-reversible redox system. The interactions of all the compounds with calf thymus DNA have been comprehensively investigated using electronic absorption spectroscopy, viscosity, electrochemistry and thermal denaturation studies. The cleavage reaction on pBR322 DNA has been monitored by agarose gel electrophoresis. The results showed that the ligand can bind to CT-DNA through partial intercalation, whereas the complexes bind electrostatically. Further, [Ni(LH)2]Cl2.3H2O and [CuLCl(H2O)2] complexes in the series have high binding and cleavage affinity towards pBR322 DNA. Additionally, all the compounds were screened for anti-tuberculosis activity. All the complexes revealed an MIC value of 0.8 ?g/mL, which is almost 8 times active than standard used (Streptomycin, 6.25 ?g/mL). PMID:24721314

  12. Tobacco exposure and susceptibility to tuberculosis: is there a smoking gun?

    PubMed

    Chan, Edward D; Kinney, William H; Honda, Jennifer R; Bishwakarma, Raju; Gangavelli, Avani; Mya, Jenny; Bai, Xiyuan; Ordway, Diane J

    2014-12-01

    In many regions of the world, there is a great overlap between the prevalence of cigarette smoke exposure and tuberculosis. Despite the large body of epidemiologic evidence that tobacco smoke exposure is associated with increased tuberculosis infection, active disease, severity of disease, and mortality from tuberculosis, these studies cannot distinguish whether the mechanism is principally through direct impairment of anti-tuberculosis immunity by cigarette smoke or due to potential confounders that increase risk for tuberculosis and are commonly associated with smoking--such as poverty, malnutrition, and crowded living conditions. While there are several in vivo murine and in vitro macrophage studies showing cigarette smoke impairs control of tuberculous infection, little is known of the molecular and cellular mechanisms by which this impairment occurs. Herein, we highlight the key findings of these studies. Additionally, we review key immune cells that play critical roles in host-defense or pathogenesis of tuberculosis and generate a hypothesis-driven discussion of the possible mechanisms by which cigarette smoke impairs or enhances their functions, respectively, ultimately resulting in compromised immunity against tuberculosis. PMID:25305002

  13. [New diagnosis methods of tuberculosis].

    PubMed

    Slim-Saidi, L; Mehiri-Zeghal, E; Ghariani, A; Tritar, F

    2015-01-01

    Bacteriological diagnosis of tuberculosis has benefited in recent years from many technological advances to improve rapidity and sensitivity of the techniques. Thus, new LED fluorescence microscopes are in the process of replacing the optical microscopes and the Ziehl-Neelsen technique, making the examination more precise, faster and easier. The manual and automatic liquid culture has improved Lowenstein-Jensen culture and helped shorten antibiotic sensitivity test, allowing appropriate management of patients. The development and standardization of molecular biology methods led to the rapid detection and identification of mycobacterium directly in clinical samples but also of resistance genes for early diagnosis of MDR-TB and dealing with them quickly. However, the performance of these techniques does not sufficiently cover the diagnosis of smear-negative tuberculosis, extrapulmonary forms, children- and immune-compromised tuberculosis where sensitivity is limited. The diagnosis of latent tuberculosis is reinforced by the in vitro release testing of gamma interferon overcoming the lack of specificity of the tuberculin skin test. Despite considerable progress, more amelioration is still needed to improve these techniques in order to extend them to the paucibacillary tuberculosis and to facilitate their access to low-resource countries. PMID:25754128

  14. Pancreatic Tuberculosis or Autoimmune Pancreatitis

    PubMed Central

    Saif, Muhammad Wasif

    2014-01-01

    Introduction. Isolated pancreatic and peripancreatic tuberculosis is a challenging diagnosis due to its rarity and variable presentation. Pancreatic tuberculosis can mimic pancreatic carcinoma. Similarly, autoimmune pancreatitis can appear as a focal lesion resembling pancreatic malignancy. Endoscopic ultrasound-guided fine needle aspiration provides an effective tool for differentiating between benign and malignant pancreatic lesions. The immune processes involved in immunoglobulin G4 related systemic diseases and tuberculosis appear to have some similarities. Case Report. We report a case of a 59-year-old Southeast Asian male who presented with fever, weight loss, and obstructive jaundice. CT scan revealed pancreatic mass and enlarged peripancreatic lymph nodes. Endoscopic ultrasound-guided fine needle aspiration confirmed the presence of mycobacterium tuberculosis. Patient also had high immunoglobulin G4 levels suggestive of autoimmune pancreatitis. He was started on antituberculosis medications and steroids. Clinically, he responded to treatment. Follow-up imaging showed findings suggestive of chronic pancreatitis. Discussion. Pancreatic tuberculosis and autoimmune pancreatitis can mimic pancreatic malignancy. Accurate diagnosis is imperative as unnecessary surgical intervention can be avoided. Endoscopic ultrasound-guided fine needle aspiration seems to be the diagnostic test of choice for pancreatic masses. Long-term follow-up is warranted in cases of chronic pancreatitis. PMID:24839445

  15. Pancreatic tuberculosis or autoimmune pancreatitis.

    PubMed

    Salahuddin, Ayesha; Saif, Muhammad Wasif

    2014-01-01

    Introduction. Isolated pancreatic and peripancreatic tuberculosis is a challenging diagnosis due to its rarity and variable presentation. Pancreatic tuberculosis can mimic pancreatic carcinoma. Similarly, autoimmune pancreatitis can appear as a focal lesion resembling pancreatic malignancy. Endoscopic ultrasound-guided fine needle aspiration provides an effective tool for differentiating between benign and malignant pancreatic lesions. The immune processes involved in immunoglobulin G4 related systemic diseases and tuberculosis appear to have some similarities. Case Report. We report a case of a 59-year-old Southeast Asian male who presented with fever, weight loss, and obstructive jaundice. CT scan revealed pancreatic mass and enlarged peripancreatic lymph nodes. Endoscopic ultrasound-guided fine needle aspiration confirmed the presence of mycobacterium tuberculosis. Patient also had high immunoglobulin G4 levels suggestive of autoimmune pancreatitis. He was started on antituberculosis medications and steroids. Clinically, he responded to treatment. Follow-up imaging showed findings suggestive of chronic pancreatitis. Discussion. Pancreatic tuberculosis and autoimmune pancreatitis can mimic pancreatic malignancy. Accurate diagnosis is imperative as unnecessary surgical intervention can be avoided. Endoscopic ultrasound-guided fine needle aspiration seems to be the diagnostic test of choice for pancreatic masses. Long-term follow-up is warranted in cases of chronic pancreatitis. PMID:24839445

  16. Structure–Function Analysis of the Acyl Carrier Protein Synthase (AcpS) from Mycobacterium tuberculosis

    Microsoft Academic Search

    Orly Dym; Shira Albeck; Yoav Peleg; Alon Schwarz; Zippora Shakked; Yigal Burstein; Oren Zimhony

    2009-01-01

    We have solved the crystal structure of the acyl carrier protein synthase (AcpS) from Mycobacterium tuberculosis (Mtb) at 1.95 Å resolution. AcpS, a 4-phosphopantetheinyl transferase, activates two distinct acyl carrier proteins (ACPs) that are present in fatty acid synthase (FAS) systems FAS-I and FAS-II, the ACP-I domain and the mycobacterial ACP-II protein (ACPM), respectively. Mtb, the causal agent of tuberculosis (TB),

  17. Human exposure following Mycobacterium tuberculosis infection of multiple animal species in a Metropolitan Zoo.

    PubMed

    Oh, Peter; Granich, Reuben; Scott, Jim; Sun, Ben; Joseph, Michael; Stringfield, Cynthia; Thisdell, Susan; Staley, Jothan; Workman-Malcolm, Donna; Borenstein, Lee; Lehnkering, Eleanor; Ryan, Patrick; Soukup, Jeanne; Nitta, Annette; Flood, Jennifer

    2002-11-01

    From 1997 to 2000, Mycobacterium tuberculosis was diagnosed in two Asian elephants (Elephas maximus), three Rocky Mountain goats (Oreamnos americanus), and one black rhinoceros (Diceros bicornis) in the Los Angeles Zoo. DNA fingerprint patterns suggested recent transmission. An investigation found no active cases of tuberculosis in humans; however, tuberculin skin-test conversions in humans were associated with training elephants and attending an elephant necropsy. PMID:12453358

  18. Human Exposure following Mycobacterium tuberculosis Infection of Multiple Animal Species in a Metropolitan Zoo

    PubMed Central

    Oh, Peter; Granich, Reuben; Scott, Jim; Sun, Ben; Joseph, Michael; Stringfield, Cynthia; Thisdell, Susan; Staley, Jothan; Workman-Malcolm, Donna; Borenstein, Lee; Lehnkering, Eleanor; Ryan, Patrick; Soukup, Jeanne; Nitta, Annette

    2002-01-01

    From 1997 to 2000, Mycobacterium tuberculosis was diagnosed in two Asian elephants (Elephas maximus), three Rocky Mountain goats (Oreamnos americanus), and one black rhinoceros (Diceros bicornis) in the Los Angeles Zoo. DNA fingerprint patterns suggested recent transmission. An investigation found no active cases of tuberculosis in humans; however, tuberculin skin-test conversions in humans were associated with training elephants and attending an elephant necropsy. PMID:12453358

  19. Streptomycin-starved Mycobacterium tuberculosis 18b, a drug discovery tool for latent tuberculosis.

    PubMed

    Zhang, Ming; Sala, Claudia; Hartkoorn, Ruben C; Dhar, Neeraj; Mendoza-Losana, Alfonso; Cole, Stewart T

    2012-11-01

    Mycobacterium tuberculosis 18b, a streptomycin (STR)-dependent mutant that enters a viable but nonreplicating state in the absence of STR, has been developed as a simple model for drug testing against dormant bacilli. Here, we further evaluated the STR-starved 18b (SS18b) model both in vitro and in vivo by comparing the behavior of 22 approved and experimental tuberculosis drugs. Using the resazurin reduction microplate assay (REMA), rifampin (RIF), rifapentine (RPT), TMC207, clofazimine (CFM), and linezolid (LIN) were found to be active against SS18b in vitro, and their bactericidal activity was confirmed by determining the number of CFU. A latent 18b infection was established in mice, and some of the above-mentioned drugs were used for treatment, either alone or in combination with RIF. RIF, RPT, TMC207, CFM, and pyrazinamide (PZA) were all active in vivo, while cell wall inhibitors were not. A comparative kinetic study of rifamycin efficacy was then undertaken, and the results indicated that RPT clears latent 18b infection in mice faster than RIF. Intrigued by the opposing responses of live and dormant 18b cells to cell wall inhibitors, we conducted a systematic analysis of 14 such inhibitors using REMA. This uncovered an SS18b signature (CWPRED) that accurately predicted the activities of cell wall inhibitors and performed well in a blind study. CWPRED will be useful for establishing the mode of action of compounds with unknown targets, while the SS18b system should facilitate the discovery of drugs for treating latent tuberculosis. PMID:22926567

  20. [Choroidal tuberculosis: reports of 3 cases].

    PubMed

    Baha Ali, T; Benhaddou, R; Hajj, I; Khoumiri, R; Guelzim, H; Moutaouakil, A

    2009-01-01

    Tuberculosis is a chronic infection with a high incidence in Morocco. Ocular involvement is rare. We report three cases of choroidal tuberculosis. Case no 1: A 24-year-old female with tuberculous meningitis, multifocal choroiditis in the right eye and choroidal granuloma in the left eye. Case no 2: A 22-year-old female with multifocal tuberculosis. The ocular examination showed a choroidal granuloma. Case no 3: A 25-year-old male with HIV infection and miliary tuberculosis. Ocular involvement consisted in a choroidal granuloma. Ocular involvement in tuberculosis is uncommon. Choroidal granuloma is a characteristic manifestation. PMID:20108570

  1. Mycobacterium tuberculosis nuoG Is a Virulence Gene That Inhibits Apoptosis of Infected Host Cells

    PubMed Central

    Velmurugan, Kamalakannan; Chen, Bing; Miller, Jessica L; Azogue, Sharon; Gurses, Serdar; Hsu, Tsungda; Glickman, Michael; Jacobs, William R; Porcelli, Steven A; Briken, Volker

    2007-01-01

    The survival and persistence of Mycobacterium tuberculosis depends on its capacity to manipulate multiple host defense pathways, including the ability to actively inhibit the death by apoptosis of infected host cells. The genetic basis for this anti-apoptotic activity and its implication for mycobacterial virulence have not been demonstrated or elucidated. Using a novel gain-of-function genetic screen, we demonstrated that inhibition of infection-induced apoptosis of macrophages is controlled by multiple genetic loci in M. tuberculosis. Characterization of one of these loci in detail revealed that the anti-apoptosis activity was attributable to the type I NADH-dehydrogenase of M. tuberculosis, and was mainly due to the subunit of this multicomponent complex encoded by the nuoG gene. Expression of M. tuberculosis nuoG in nonpathogenic mycobacteria endowed them with the ability to inhibit apoptosis of infected human or mouse macrophages, and increased their virulence in a SCID mouse model. Conversely, deletion of nuoG in M. tuberculosis ablated its ability to inhibit macrophage apoptosis and significantly reduced its virulence in mice. These results identify a key component of the genetic basis for an important virulence trait of M. tuberculosis and support a direct causal relationship between virulence of pathogenic mycobacteria and their ability to inhibit macrophage apoptosis. PMID:17658950

  2. Revised device labeling for the Cepheid Xpert MTB/RIF assay for detecting Mycobacterium tuberculosis.

    PubMed

    2015-02-27

    The Food and Drug Administration (FDA) has cleared the Xpert MTB/RIF Assay (Cepheid; Sunnyvale, California) with an expanded intended use that includes testing of either one or two sputum specimens as an alternative to examination of serial acid-fast stained sputum smears to aid in the decision of whether continued airborne infection isolation (AII) is warranted for patients with suspected pulmonary tuberculosis. This change reflects the outcome of a recent multicenter international study demonstrating that negative Xpert MTB/RIF Assay results from either one or two sputum specimens are highly predictive of the results of two or three negative acid-fast sputum smears. PMID:25719683

  3. Tracheobronchial Tuberculosis Without Lung Involvement

    PubMed Central

    Campos, Jeronimo; Ernst, Glenda; Borsini, Eduardo; Garcia, Artemio; Blasco, Miguel; Bosio, Martin; Salvado, Alejandro

    2015-01-01

    Endotracheal tuberculosis (ETTB) is an infrequent form of tuberculosis whose major feature is the infection of the tracheobronchial tree by Mycobacterium tuberculosis. This case presents a 73-year-old man admitted to our hospital with fatigue, weakness, dry cough and weight loss. His chest X-ray was normal but the high resolution computed tomography (HRCT) showed normal parenchyma images with mediastinal and hilar lymphadenopathy. There was inflammation of the tracheal wall and infiltrates in pavement epithelium; however, the tracheal biopsy for acid-fast bacilli was negative. He was finally diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of the lymph nodes. Four drugs were prescribed and symptoms improved. EBUS-TBNA contributed to prompt diagnosis. The patient was treated and evolved without complications, such as tracheal stenosis. PMID:26124914

  4. Tracheobronchial Tuberculosis Without Lung Involvement.

    PubMed

    Campos, Jeronimo; Ernst, Glenda; Borsini, Eduardo; Garcia, Artemio; Blasco, Miguel; Bosio, Martin; Salvado, Alejandro

    2015-08-01

    Endotracheal tuberculosis (ETTB) is an infrequent form of tuberculosis whose major feature is the infection of the tracheobronchial tree by Mycobacterium tuberculosis. This case presents a 73-year-old man admitted to our hospital with fatigue, weakness, dry cough and weight loss. His chest X-ray was normal but the high resolution computed tomography (HRCT) showed normal parenchyma images with mediastinal and hilar lymphadenopathy. There was inflammation of the tracheal wall and infiltrates in pavement epithelium; however, the tracheal biopsy for acid-fast bacilli was negative. He was finally diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of the lymph nodes. Four drugs were prescribed and symptoms improved. EBUS-TBNA contributed to prompt diagnosis. The patient was treated and evolved without complications, such as tracheal stenosis. PMID:26124914

  5. Chapter Nine: Logic Clue Game (continued) Suspects, Weapons, and Scenes of the Crime

    E-print Network

    Morton, Dena - Department of Mathematics and Computer Science, Xavier University

    Chapter Nine: Logic ­ Clue Game (continued) Suspects, Weapons, and Scenes of the Crime The following is a list of the possible suspects, murder weapons, and murder scenes. There are six suspects, six weapons, and nine rooms. Suspects: Mr. Green, Colonel Mustard, Mrs. Peacock, Professor Plum, Miss Scarlet

  6. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase

    PubMed Central

    Ferrajolo, Carmen; Capuano, Annalisa; Verhamme, Katia M C; Schuemie, Martijn; Rossi, Francesco; Stricker, Bruno H; Sturkenboom, Miriam C J M

    2010-01-01

    AIM To identify which drugs are associated with reports of suspected hepatic injury in children and adolescents. METHODS Using a worldwide pharmacovigilance database, VigiBase, we conducted a case/non-case study on suspected adverse drug reactions (ADRs) occurring in the population <18 years old. Cases were all the records with hepatic ADRs and non-cases were all the other ADR records. Records regarding topically administered drugs were excluded from both groups. The association between drug and suspected hepatic ADRs was calculated using the reporting odds ratio (ROR) as a measure of disproportionality while adjusting for gender, country, reporter and calendar year. Sub-analyses were performed within therapeutic class and by excluding vaccination-related reports to reduce confounding. RESULTS Overall, 6595 (1%) out of 624 673 ADR records in children and adolescents concerned hepatic injury. Most of the reported hepatic injuries concerned children 12–17 years of age. Drugs that were most frequently reported as suspected cause and were associated with hepatic injury comprised paracetamol, valproic acid, carbamazepine, methotrexate, minocycline, zidovudine, pemoline, ceftriaxone, bosentan, ciclosporin, atomoxetine, olanzapine, basiliximab, erythromycin and voriconazole. The association between hepatotoxicity and all these drugs, except for basiliximab, is already known. CONCLUSIONS Drug-induced hepatic injury is infrequently reported (only 1% of total) as a suspected ADR in children and adolescents. The drugs associated with reported hepatotoxicity (paracetamol, antiepileptic and anti-tuberculosis agents) are known to be hepatotoxic in adults as well, but age related changes in associations were observed. VigiBase is useful as a start to plan further drug safety studies in children. PMID:21039766

  7. Tuberculosis in Children

    PubMed Central

    Esposito, Susanna; Tagliabue, Claudia; Bosis, Samantha

    2013-01-01

    Tuberculosis (TB) in children is a neglected aspect of the TB epidemic despite it constituting 20% or more of all TB cases in many countries with high TB incidence. Childhood TB is a direct consequence of adult TB but remains overshadowed by adult TB because it is usually smear-negative. Infants and young children are more likely to develop life-threatening forms of TB than older children and adults due to their immature immune systems. Therefore, prompt diagnoses are extremely important although difficult since clinical and radiological signs of TB can be non-specific and variable in children. Despite undeniable advances in identifying definite, probable, or possible TB markers, pediatricians still face many problems when diagnosing TB diagnosis. Moreover, curing TB can be difficult when treatment is delayed and when multi-drug resistant (MDR) pathogens are the cause of the disease. In these cases, the prognosis in children is particularly poor because MDR-TB treatment and treatment duration remain unclear. New studies of diagnostic tests and optimal treatment in children are urgently needed with the final goal of developing an effective anti-TB vaccine. PMID:24363879

  8. Tuberculosis after renal transplantation.

    PubMed

    Kaaroud, H; Beji, S; Boubaker, K; Abderrahim, E; Ben Hamida, F; Ben Abdallah, T; El Younsi, F; Ben Moussa, F; Kheder, A

    2007-05-01

    Tuberculosis (TB) remains a major public health problem in our country. Its diagnosis in immunodeficient patients is difficult. In this retrospective study, we analyzed the prevalence, clinical presentation, and outcome of TB after renal transplantation (RT) in our Tunisian team's experience. Among 359 renal transplant recipients, 9 (2.5%) developed TB at 49.6 months (range, 3-156 months) after RT. There were 7 men and 2 women of mean age 37.8 years (range, 15-53 years). The organs involved included lymph nodes in 1 case; lung in 5 cases; genitourinary system in 1 case; rachis in 1 case; pleural in 1 case; and both pulmonary and urinary systems in 1 case. The diagnosis was bacteriologic in 6 cases; histologic in 1 case; and 2 patients had a high index of suspicion. All patients were treated with a combination of rifampicin, isoniazide, pyrazinamide, and ethambutal. Recurrence of TB infection was noted in 3 cases with multiple localizations: lymph node, muscle abscess, meningitis, genitourinary system, rachis, and lung. Two patients died. In conclusion, among renal transplant patients, extrapulmonary involvement and recurrence of TB were frequent. PMID:17524877

  9. Transcription factor regulatory network for early lung immune response to tuberculosis in mice.

    PubMed

    Yaqubi, Moein; Mohammadnia, Abdulshakour; Fallahi, Hossein

    2015-08-01

    Numerous transcription factors (TFs) have been suggested to have a role in Mycobacterium tuberculosis infection; however, the TFs involved in the early immune response of lung cells remains to be fully elucidated. The present study aimed to identify TFs which may have a role in the early immune response to tuberculosis and the gene regulatory networks in which they are involved. Gene expression data obtained from microarray analysis of the early lung immune response to tuberculosis (Gene Expression Omnibus; accession no. GSE23014) was integrated with data for TF binding sites and protein?protein interactions in order to construct a TF regulatory network. The role of TFs in protein complexes, active modules, topology of the network and regulation of immune processes were investigated. The results demonstrated that the constructed gene regulatory network harbored 1,270 differentially expressed (DE) genes with 4,070 regulatory and protein?protein interactions. In addition, it was revealed that 17 DE TFs were involved in the positive regulation of numerous immunological and biological processes, including T cell activation, T cell proliferation and tuberculosis?associated gene expression, in the constructed regulatory network. Signal transducer and activator of transcription 4, interferon regulatory factor 8, spleen focus-forming virus proviral integration 1, enhancer of zeste homolog 2 and kruppel?like factor 4 were predicted to be the primary TFs regulating the DE genes during early lung infection by M. tuberculosis, as determined through various analyses of the gene regulatory network. In conclusion, the present study identified novel TFs involved in the early response to M. tuberculosis infection, which may enhance current understanding of the molecular mechanism underlying tuberculosis infection and introduced potential targets for novel tuberculosis therapies. PMID:25955085

  10. Resources for controlling tuberculosis in Malawi.

    PubMed Central

    Harries, A. D.; Kwanjana, J. H.; Hargreaves, N. J.; Van Gorkom, J.; Salaniponi, F. M.

    2001-01-01

    OBJECTIVE: To document resources for controlling tuberculosis (TB) in Malawi. METHODS: We performed a countrywide study of all 43 hospitals (3 central, 22 district and 18 mission) which register and treat patients with TB. To collect data for 1998 on the TB-related workload, diagnostic facilities, programme staff and treatment facilities, we used laboratory, radiographic and TB registers, conducted interviews and visited hospital facilities. FINDINGS: The data show that in 1998, 88,257 TB suspects/patients contributed approximately 230,000 sputum specimens for smear microscopy, 55,667 chest X-rays were performed and 23,285 patients were registered for TB treatment. There were 86 trained laboratory personnel, 44 radiographers and 83 TB programme staff. Of these, about 40% had periods of illness during 1998. Approximately 20% of the microscopes and X-ray machines were broken. Some 16% of the hospital beds were designated for TB patients in special wards, but even so, the occupancy of beds in TB wards exceeded 100%. Although stocks of anti-TB drugs were good, there was a shortage of full-time TB ward nurses and 50% of district hospitals conducted no TB ward rounds. In general, there was a shortage of facilities for managing associated HIV-related disease; central hospitals, in particular, were underresourced. CONCLUSION: Malawi needs better planning to utilize its manpower and should consider cross-training hospital personnel. The equipment needs regular maintenance, and more attention should be paid to HIV-related illness. The policies of decentralizing resources to the periphery and increasing diagnostic and case-holding resources for central hospitals should be continued. PMID:11357212

  11. Towards a new tuberculosis drug: pyridomycin – nature's isoniazid

    PubMed Central

    Hartkoorn, Ruben C; Sala, Claudia; Neres, João; Pojer, Florence; Magnet, Sophie; Mukherjee, Raju; Uplekar, Swapna; Boy-Röttger, Stefanie; Altmann, Karl-Heinz; Cole, Stewart T

    2012-01-01

    Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti-tuberculosis agents. Here, we describe pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin-resistant mutants of Mycobacterium tuberculosis, whole-genome sequencing and genetic validation, we identified the NADH-dependent enoyl- (Acyl-Carrier-Protein) reductase InhA as the principal target and demonstrate that pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH-binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid-resistant clinical isolates remain fully susceptible to pyridomycin, thus opening new avenues for drug development. PMID:22987724

  12. Towards a new tuberculosis drug: pyridomycin - nature's isoniazid.

    PubMed

    Hartkoorn, Ruben C; Sala, Claudia; Neres, João; Pojer, Florence; Magnet, Sophie; Mukherjee, Raju; Uplekar, Swapna; Boy-Röttger, Stefanie; Altmann, Karl-Heinz; Cole, Stewart T

    2012-10-01

    Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti-tuberculosis agents. Here, we describe pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin-resistant mutants of Mycobacterium tuberculosis, whole-genome sequencing and genetic validation, we identified the NADH-dependent enoyl- (Acyl-Carrier-Protein) reductase InhA as the principal target and demonstrate that pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH-binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid-resistant clinical isolates remain fully susceptible to pyridomycin, thus opening new avenues for drug development. ?See accompanying article http://dx.doi.org/10.1002/emmm.201201811. PMID:22987724

  13. In Vitro and In Vivo Efficacy of ?-Lactams against Replicating and Slowly Growing/Nonreplicating Mycobacterium tuberculosis

    PubMed Central

    Dinesh, Neela; Shandil, Radha; Ramachandran, Vasanthi; Sharma, Sreevalli; Bhattacharjee, Deepa; Ganguly, Samit; Reddy, Jitendar; Ahuja, Vijaykamal; Panduga, Vijender; Parab, Manish; Vishwas, K. G.; Kumar, Naveen; Balganesh, Meenakshi; Balasubramanian, V.

    2013-01-01

    Beta-lactams, in combination with beta-lactamase inhibitors, are reported to have activity against Mycobacterium tuberculosis bacteria growing in broth, as well as inside the human macrophage. We tested representative beta-lactams belonging to 3 different classes for activity against replicating M. tuberculosis in broth and nonreplicating M. tuberculosis under hypoxia, as well as against streptomycin-starved M. tuberculosis strain 18b (ss18b) in the presence or absence of clavulanate. Most of the combinations showed bactericidal activity against replicating M. tuberculosis, with up to 200-fold improvement in potency in the presence of clavulanate. None of the combinations, including those containing meropenem, imipenem, and faropenem, killed M. tuberculosis under hypoxia. However, faropenem- and meropenem-containing combinations killed strain ss18b moderately. We tested the bactericidal activities of meropenem-clavulanate and amoxicillin-clavulanate combinations in the acute and chronic aerosol infection models of tuberculosis in BALB/c mice. Based on pharmacokinetic/pharmacodynamic indexes reported for beta-lactams against other bacterial pathogens, a cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%TMIC) of 20 to 40% was achieved in mice using a suitable dosing regimen. Both combinations showed marginal reduction in lung CFU compared to the late controls in the acute model, whereas both were inactive in the chronic model. PMID:23507276

  14. Radial velocities of cD suspects in poor clusters

    Microsoft Academic Search

    J. C. Thomas; D. Batchelor

    1978-01-01

    Radial velocities are derived for 12 suspected members of the cD poor clusters of galaxies listed by Morgan, Kayser, and White (1975) and designated MKW 1S, MKW 1, MKW 2, and MKW 4. A comparison of the intrinsic brightnesses of the dominant galaxies indicates that the dominant galaxies in MKW 1 and MKW 2, and possibly MKW 1S, should be

  15. 48 CFR 1403.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...a) Reports on suspected violations of antitrust laws as required by FAR 3.303 shall be prepared by the CO, reviewed by the SOL, and submitted by the HCA directly to the Attorney General, Department of Justice. A copy of this submission must also...

  16. 48 CFR 1403.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...a) Reports on suspected violations of antitrust laws as required by FAR 3.303 shall be prepared by the CO, reviewed by the SOL, and submitted by the HCA directly to the Attorney General, Department of Justice. A copy of this submission must also...

  17. Differential Diagnosis of Children with Suspected Childhood Apraxia of Speech

    ERIC Educational Resources Information Center

    Murray, Elizabeth; McCabe, Patricia; Heard, Robert; Ballard, Kirrie J.

    2015-01-01

    Purpose: The gold standard for diagnosing childhood apraxia of speech (CAS) is expert judgment of perceptual features. The aim of this study was to identify a set of objective measures that differentiate CAS from other speech disorders. Method: Seventy-two children (4-12 years of age) diagnosed with suspected CAS by community speech-language…

  18. WHAT TO DO IF YOU SUSPECT BED BUGS IN

    E-print Network

    Ferrara, Katherine W.

    WHAT TO DO IF YOU SUSPECT BED BUGS IN YOUR ROOM 1. Notify your RA and the area service desk of your in to your room For Student Housing Residents STUDENT HOUSING BED BUGS Information On Notify your area SEEING AN INCREASE IN BEDBUGS? Bed bugs were nearly eradicated in the United States after World War II

  19. Family Pedigrees of Children with Suspected Childhood Apraxia of Speech

    ERIC Educational Resources Information Center

    Lewis, Barbara A.; Freebairn, Lisa A.; Hansen, Amy; Taylor, H. Gerry; Iyengar, Sudha; Shriberg, Lawrence D.

    2004-01-01

    Forty-two children (29 boys and 13 girls), ages 3-10 years, were referred from the caseloads of clinical speech-language pathologists for suspected childhood apraxia of speech (CAS). According to results from tests of speech and oral motor skills, 22 children met criteria for CAS, including a severely limited consonant and vowel repertoire,…

  20. Appropriateness of Diagnostic Management and Outcomes of Suspected Pulmonary Embolism

    Microsoft Academic Search

    Pierre-Marie Roy; Guy Meyer; Bruno Vielle; Catherine Le Gall; Franck Verschuren; Francoise Carpentier; Philippe Leveau; Alain Furber

    2006-01-01

    Background: International guidelines include several strategies for diagnosing pulmonary embolism with confidence, but little is known about how these guidelines are implemented in routine practice. Objective: To evaluate the appropriateness of diagnostic manage- ment of suspected pulmonary embolism and the relationship be- tween diagnostic criteria and outcome. Design: Prospective cohort study with a 3-month follow-up. Setting: 116 emergency departments in

  1. Suspected photosensitisation in lambs grazing birdsfoot trefoil (Lotus corniculatus)

    Microsoft Academic Search

    K. J. Stafford; D. M. West; M. R. Alley; G. C. Waghorn

    1995-01-01

    Suspected photosensitisation occurred in three groups of lambs grazing birdsfoot trefoil (Lotus corniculatus C.V. Grasslands Goldie). In one group, sucking lambs aged about 10 weeks, grazing birdsfoot trefoil, developed skin lesions while lambs of a similar age and from the same flock grazing lucerne (Medicago sativa) or a mixed sward of both species showed no signs of photosensitisation. Affected lambs

  2. Correlates and Suspected Causes of Obesity in Children

    ERIC Educational Resources Information Center

    Crothers, Laura M.; Kehle, Thomas J.; Bray, Melissa A.; Theodore, Lea A.

    2009-01-01

    The correlates and suspected causes of the intractable condition obesity are complex and involve environmental and heritable, psychological and physical variables. Overall, the factors associated with and possible causes of it are not clearly understood. Although there exists some ambiguity in the research regarding the degree of happiness in…

  3. Lineup Composition, Suspect Position, and the Sequential Lineup Advantage

    ERIC Educational Resources Information Center

    Carlson, Curt A.; Gronlund, Scott D.; Clark, Steven E.

    2008-01-01

    N. M. Steblay, J. Dysart, S. Fulero, and R. C. L. Lindsay (2001) argued that sequential lineups reduce the likelihood of mistaken eyewitness identification. Experiment 1 replicated the design of R. C. L. Lindsay and G. L. Wells (1985), the first study to show the sequential lineup advantage. However, the innocent suspect was chosen at a lower rate…

  4. Nucleic Acid Amplification Testing in Suspected Child Sexual Abuse

    Microsoft Academic Search

    Debra Esernio-Jenssen; Marilyn Barnes

    2011-01-01

    The American Academy of Pediatrics recommends that site-specific cultures be obtained, when indicated, for sexually victimized children. Nucleic acid amplification testing is a highly sensitive and specific methodology for identifying sexually transmitted infections. Nucleic acid amplification tests are also less invasive than culture, and this may provide an efficacious alternative for children suspected of being sexually abused.

  5. Prehospital use of analgesia for suspected extremity fractures

    Microsoft Academic Search

    Lynn J. White; Joseph D. Cooper; Rita M. Chambers; Richard E. Gradisek

    2000-01-01

    Introduction. Pain and its control have been studied extensively in the emergency department. Numerous studies indicate that inadequate treatment of pain is common, despite the availability of myriad analgesics. It has been suggested that oligoanesthesia is also a common practice in the prehospital setting. Objective. To assess the use of prehospital analgesia in patients with suspected extremity fracture. Methods. Emergency

  6. Reporting and Investigating Suspected Noncompliance in Animal Research

    E-print Network

    Shahriar, Selim

    Page 1 Reporting and Investigating Suspected Noncompliance in Animal Research Policy Statement An important component in fulfilling the research mission of Northwestern University is the use of animals in research. The University must ensure that all research animals are used responsibly and in compliance

  7. MmPPOX Inhibits Mycobacterium tuberculosis Lipolytic Enzymes Belonging to the Hormone-Sensitive Lipase Family and Alters Mycobacterial Growth

    PubMed Central

    Delorme, Vincent; Diomandé, Sadia V.; Dedieu, Luc; Cavalier, Jean-François; Carrière, Frédéric; Kremer, Laurent; Leclaire, Julien; Fotiadu, Frédéric; Canaan, Stéphane

    2012-01-01

    Lipid metabolism plays an important role during the lifetime of Mycobacterium tuberculosis, the causative agent of tuberculosis. Although M. tuberculosis possesses numerous lipolytic enzymes, very few have been characterized yet at a biochemical/pharmacological level. This study was devoted to the M. tuberculosis lipolytic enzymes belonging to the Hormone-Sensitive Lipase (HSL) family, which encompasses twelve serine hydrolases closely related to the human HSL. Among them, nine were expressed, purified and biochemically characterized using a broad range of substrates. In vitro enzymatic inhibition studies using the recombinant HSL proteins, combined with mass spectrometry analyses, revealed the potent inhibitory activity of an oxadiazolone compound, named MmPPOX. In addition, we provide evidence that MmPPOX alters mycobacterial growth. Overall, these findings suggest that the M. tuberculosis HSL family displays important metabolic functions, thus opening the way to further investigations linking the involvement of these enzymes in mycobacterial growth. PMID:23029536

  8. Tuberculosis: An Inorganic Medicinal Chemistry Perspective.

    PubMed

    Viganor, Livia; Skerry, Ciaran; McCann, Malachy; Devereux, Michael

    2015-01-01

    Tuberculosis (TB) which is caused by the resilient pathogen Mycobacterium tuberculosis (MTB) has re-emerged to become a leading public health problem in the world. The growing number of multi-drug resistant MTB strains and the more recently emerging problem with the extensively drug resistant strains of the pathogen are greatly undermining conventional anti-TB therapeutic strategies which are lengthy and expose patients to toxicity and other unwanted side effects. The search for new anti-TB drugs essentially involves either the repurposing of existing organic drugs which are now off patent and already FDA approved, the synthesis of modified analogues of existing organic drugs, with the aim of shortening and improving drug treatment for the disease, or the search for novel structures that offer the possibility of new mechanisms of action against the mycobacterium. Inorganic medicinal chemistry offers an alternative to organic drugs through opportunities for the design of therapeutics that target different biochemical pathways. The incorporation of metal ions into the molecular structure of a potential drug offers the medicinal chemist an opportunity to exploit structural diversity, have access to various oxidation states of the metal and also offer the possibility of enhancing the activity of an established organic drug through its coordination to the metal centre. In this review, we summarize what is currently known about the antitubercular capability of metal complexes, their mechanisms of action and speculate on their potential applications in the clinic. PMID:25850770

  9. The ongoing challenge of latent tuberculosis

    PubMed Central

    Esmail, H.; Barry, C. E.; Young, D. B.; Wilkinson, R. J.

    2014-01-01

    The global health community has set itself the task of eliminating tuberculosis (TB) as a public health problem by 2050. Although progress has been made in global TB control, the current decline in incidence of 2% yr?1 is far from the rate needed to achieve this. If we are to succeed in this endeavour, new strategies to reduce the reservoir of latently infected persons (from which new cases arise) would be advantageous. However, ascertainment of the extent and risk posed by this group is poor. The current diagnostics tests (tuberculin skin test and interferon-gamma release assays) poorly predict who will develop active disease and the therapeutic options available are not optimal for the scale of the intervention that may be required. In this article, we outline a basis for our current understanding of latent TB and highlight areas where innovation leading to development of novel diagnostic tests, drug regimens and vaccines may assist progress. We argue that the pool of individuals at high risk of progression may be significantly smaller than the 2.33 billion thought to be immune sensitized by Mycobacterium tuberculosis and that identifying and targeting this group will be an important strategy in the road to elimination. PMID:24821923

  10. Macrophages in Tuberculosis: Friend or Foe

    PubMed Central

    Guirado, Evelyn; Schlesinger, Larry S.; Kaplan, Gilla

    2013-01-01

    Tuberculosis (TB) remains one of the greatest threats to human health. The causative bacterium, Mycobacterium tuberculosis (Mtb) is acquired by the respiratory route. It is exquisitely human-adapted and a prototypic intracellular pathogen of macrophages, with alveolar macrophages (AMs) being the primary conduit of infection and disease. The outcome of primary infection is most often a latently infected healthy human host, in whom the bacteria are held in check by the host immune response. Such individuals can develop active TB later in life with impairment in the immune system. In contrast, in a minority of infected individuals, the host immune response fails to control the growth of bacilli, and progressive granulomatous disease develops, facilitating spread of the bacilli via infectious aerosols coughed out into the environment and inhaled by new hosts. The molecular details of the Mtb-macrophage interaction continue to be elucidated. However, it is clear that a number of complex processes are involved at the different stages of infection that may benefit either the bacterium or the host. Macrophages demonstrate tremendous phenotypic heterogeneity and functional plasticity which, depending on the site and stage of infection, facilitate the diverse outcomes. Moreover, host responses vary depending on the specific characteristics of the infecting Mtb strain. In this chapter, we describe a contemporary view of the behavior of AMs and their interaction with various Mtb strains in generating unique immunologic lung specific responses. PMID:23864058

  11. New tuberculosis therapeutics: a growing pipeline.

    PubMed

    Spigelman, Melvin K

    2007-08-15

    Novel chemotherapeutic drugs are needed to improve tuberculosis (TB) control, especially in the developing world. Given the magnitude of the problem and the resources available in countries that have the highest burden of disease, the present standards of care for the treatment of drug-susceptible TB, drug-resistant TB, TB/human immunodeficiency virus (HIV) coinfection, and latent TB infection are all unsatisfactory. Because no truly novel compounds for the treatment of TB have been discovered in the past 40 years, the recent enhanced activity in the research and development of new TB drugs is extremely encouraging. Seven compounds are presently in clinical development specifically for the treatment of TB. Other known antibiotic compound families are being investigated preclinically, in an attempt to identify new antimicrobial drugs with specific antituberculous activity. In addition, novel targets have been identified and are the subject of efforts to validate their potential usefulness in the treatment of TB. PMID:17624823

  12. Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections.

    PubMed

    Amaral, Leonard; Viveiros, Miguel

    2012-05-01

    Thioridazine (TDZ) in combination with antibiotics to which extensively drug-resistant Mycobacterium tuberculosis (XDR-TB) is initially resistant yields a cure. This is due to the fact that TDZ enhances the killing of intracellular M. tuberculosis by non-killing macrophages, inhibits the genetic expression of efflux pumps of M. tuberculosis that extrude antibiotics prior to reaching their intended targets, and inhibits the activity of existing efflux pumps that contribute to the multidrug-resistant phenotype of M. tuberculosis. The combination of these effects of TDZ probably contributes to the successful recent cures of XDR-TB cases when the phenothiazine TDZ is used in combination with antibiotics to which the patient with XDR-TB was initially unresponsive. PMID:22445204

  13. Collectin CL-LK Is a Novel Soluble Pattern Recognition Receptor for Mycobacterium tuberculosis

    PubMed Central

    Hansen, Søren; Rasolofo, Voahangy; Henriksen, Maiken Lumby; Mori, Kenichiro; Ohtani, Katsuki; Duval, Carine; Mercier, Ingrid; Bénard, Alan; Nigou, Jérome; Hudrisier, Denis; Wakamiya, Nobutaka; Neyrolles, Olivier

    2015-01-01

    Understanding the molecular components of immune recognition of the tuberculosis (TB) bacillus, Mycobacterium tuberculosis, can help designing novel strategies to combat TB. Here, we identify collectin CL-LK as a novel soluble C-type lectin able to bind M. tuberculosis, and characterize mycobacterial mannose-capped lipoarabinomannan as a primary ligand for CL-LK. Mice deficient in CL-K1, one of the CL-LK subunits, do not display altered susceptibility to M. tuberculosis. However, we found that the amount of CL-LK in the serum of patients with active TB is reduced, compared to that in controls, and correlates inversely to the magnitude of the immune response to the pathogen. These findings indicate that CL-LK might be of interest for future diagnostic and treatment monitoring purposes. PMID:26173080

  14. Computerized tomography detects pulmonary lesions in children with normal radiographs diagnosed to have tuberculosis.

    PubMed

    Swaminathan, Soumya; Raghavan, Aarti; Datta, Manjula; Paramasivan, C N; Saravanan, K C

    2005-03-01

    This report is based on observations during the conduct of a larger study to develop diagnostic criteria for childhood tuberculosis (TB). Of 201 children confirmed to have pulmonary or lymph node TB, 84 had normal chest radiographs. Computerized tomography (CT) of the chest was performed in nine of them, seven of whom had normal chest radiographs while two had visible calcification. Eight of the nine children had definitive lesions detected by computerized tomography of the chest. While five children had primarily hilar lymph node enlargement, three had pulmonary parenchymal lesions. The use of more sensitive diagnostic tests like computed tomography helps to detect tuberculosis lesions not otherwise visualized on chest radiographs. This report highlights the difficulty in excluding active tuberculosis in children. More studies are required on the role of CT scans in the diagnosis of tuberculosis in children. PMID:15817975

  15. Evaluation of Methods for Testing the Susceptibility of Clinical Mycobacterium tuberculosis Isolates to Pyrazinamide

    PubMed Central

    Cui, Zhenling; Wang, Jie; Lu, Junmei; Huang, Xiaochen; Zheng, Ruijuan

    2013-01-01

    Pyrazinamide (PZA) is a first-line antituberculosis (anti-TB) drug capable of killing nonreplicating, persistent Mycobacterium tuberculosis. However, reliable testing of the susceptibility of M. tuberculosis to PZA is challenging. Using 432 clinical M. tuberculosis isolates, we compared the performances of five methods for the determination of M. tuberculosis susceptibility to PZA: the MGIT 960 system, the molecular drug susceptibility test (mDST), the pyrazinamidase (PZase) activity assay, the resazurin microtiter assay (REMA), and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction test. The sensitivities of the MGIT 960 system, the PZase activity assay, the mDST, the REMA, and the MTT assay were 98.8%, 88.8%, 90.5%, 98.8%, and 98.2%, respectively. The sensitivities of the PZase activity assay and the mDST were lower than those of the other three methods (P < 0.05). The specificities of the MGIT 960 system, the PZase activity assay, the mDST, the REMA and the MTT assays were 99.2%, 98.9%, 90.9%, 98.5%, and 100%, respectively. The specificity of the mDST was lower than those of the other four methods (P < 0.05). In conclusion, the MGIT 960 system, the MTT assay, and the REMA are superior to the PZase activity assay and the mDST in determining the susceptibility of M. tuberculosis to PZA. The MTT assay and the REMA might serve as alternative methods for clinical laboratories without access to the MGIT 960 system. For rapid testing in well-equipped laboratories, the mDST might be the best choice, particularly for small quantities of M. tuberculosis. The PZase activity assay has no obvious advantage in the assessment of M. tuberculosis susceptibility to PZA, as it is less accurate and requires larger quantities of bacteria. PMID:23390285

  16. The roles of microRNAs on tuberculosis infection: meaning or myth?

    PubMed

    Harapan, Harapan; Fitra, Fitra; Ichsan, Ichsan; Mulyadi, Mulyadi; Miotto, Paolo; Hasan, Nabeeh A; Calado, Marta; Cirillo, Daniela M

    2013-11-01

    The central proteins for protection against tuberculosis are attributed to interferon-?, tumor necrosis factor-?, interleukin (IL)-6 and IL-1?, while IL-10 primarily suppresses anti-mycobacterial responses. Several studies found alteration of expression profile of genes involved in anti-mycobacterial responses in macrophages and natural killer (NK) cells from active and latent tuberculosis and from tuberculosis and healthy controls. This alteration of cellular composition might be regulated by microRNAs (miRNAs). Albeit only 1% of the genomic transcripts in mammalian cells encode miRNA, they are predicted to control the activity of more than 60% of all protein-coding genes and they have a huge influence in pathogenesis theory, diagnosis and treatment approach to some diseases. Several miRNAs have been found to regulate T cell differentiation and function and have critical role in regulating the innate function of macrophages, dendritic cells and NK cells. Here, we have reviewed the role of miRNAs implicated in tuberculosis infection, especially related to their new roles in the molecular pathology of tuberculosis immunology and as new targets for future tuberculosis diagnostics. PMID:24025365

  17. Mycobacterium tuberculosis modulates macrophage lipid-sensing nuclear receptors PPAR? and TR4 for survival.

    PubMed

    Mahajan, Sahil; Dkhar, H Kitdorlang; Chandra, Vemika; Dave, Sandeep; Nanduri, Ravikanth; Janmeja, Ashok Kumar; Agrewala, Javed N; Gupta, Pawan

    2012-06-01

    Mycobacterium tuberculosis-macrophage interactions are key to pathogenesis and clearance of these bacteria. Although interactions between M. tuberculosis-associated lipids and TLRs, non-TLRs, and opsonic receptors have been investigated, interactions of these lipids and infected macrophage lipid repertoire with lipid-sensing nuclear receptors expressed in macrophages have not been addressed. In this study, we report that M. tuberculosis-macrophage lipids can interact with host peroxisome proliferator-activated receptor ? and testicular receptor 4 to ensure survival of the pathogen by modulating macrophage function. These two lipid-sensing nuclear receptors create a foamy niche within macrophage by modulating oxidized low-density lipoprotein receptor CD36, phagolysosomal maturation block by induction of IL-10, and a blunted innate response by alternative polarization of the macrophages, which leads to survival of M. tuberculosis. These results also suggest possible heterologous ligands for peroxisome proliferator-activated receptor ? and testicular receptor 4 and are suggestive of adaptive or coevolution of the host and pathogen. Relative mRNA expression levels of these receptors in PBMCs derived from clinical samples convincingly implicate them in tuberculosis susceptibility. These observations expose a novel paradigm in the pathogenesis of M. tuberculosis amenable for pharmacological modulation. PMID:22544925

  18. Truman State University Student Health Center Tuberculosis Screening Form

    E-print Network

    Gering, Jon C.

    Truman State University Student Health Center Tuberculosis Screening Form Name been exposed to Tuberculosis since your last TB skin test? Yes No If yes, when and where did the exposure occur? ________________________________________ Have you ever been treated for Tuberculosis? Yes

  19. Is Adipose Tissue a Place for Mycobacterium tuberculosis Persistence?

    E-print Network

    Paris-Sud XI, Université de

    Is Adipose Tissue a Place for Mycobacterium tuberculosis Persistence? Olivier Neyrolles1 of Electron Microscopy, Institut Pasteur, Paris, France Background. Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), has the ability to persist in its human host for exceptionally long

  20. Mechanistic and Bioinformatic Investigation of a Conserved Active Site Helix in ?-Isopropylmalate Synthase from Mycobacterium tuberculosis, a Member of the DRE-TIM Metallolyase Superfamily

    PubMed Central

    2015-01-01

    The characterization of functionally diverse enzyme superfamilies provides the opportunity to identify evolutionarily conserved catalytic strategies, as well as amino acid substitutions responsible for the evolution of new functions or specificities. Isopropylmalate synthase (IPMS) belongs to the DRE-TIM metallolyase superfamily. Members of this superfamily share common active site elements, including a conserved active site helix and an HXH divalent metal binding motif, associated with stabilization of a common enolate anion intermediate. These common elements are overlaid by variations in active site architecture resulting in the evolution of a diverse set of reactions that include condensation, lyase/aldolase, and carboxyl transfer activities. Here, using IPMS, an integrated biochemical and bioinformatics approach has been utilized to investigate the catalytic role of residues on an active site helix that is conserved across the superfamily. The construction of a sequence similarity network for the DRE-TIM metallolyase superfamily allows for the biochemical results obtained with IPMS variants to be compared across superfamily members and within other condensation-catalyzing enzymes related to IPMS. A comparison of our results with previous biochemical data indicates an active site arginine residue (R80 in IPMS) is strictly required for activity across the superfamily, suggesting that it plays a key role in catalysis, most likely through enolate stabilization. In contrast, differential results obtained from substitution of the C-terminal residue of the helix (Q84 in IPMS) suggest that this residue plays a role in reaction specificity within the superfamily. PMID:24720347