Sample records for suspected active tuberculosis

  1. Detection of Mycobacterium tuberculosis directly from sputum specimens & phenotypic drug resistance pattern of M. tuberculosis isolates from suspected tuberculosis patients in Chennai

    PubMed Central

    Therese, K. Lily; Gayathri, R.; Dhanurekha, L.; Sridhar, R.; Meenakshi, N.; Madhavan, H. N.; Manoj, S. Edwin; Vinayagam, A. Kamala

    2012-01-01

    Background & objectives: mRNA is more rapidly destroyed in cells than rRNA or genomic DNA, an assay targeting bacterial mRNA would provide a better guide to mycobacterial viability than amplification tests directed at DNA or rRNA targets. This study was carried out to standardize reverse transcriptase PCR (RT-PCR) targeting 85B gene for the rapid detection of viable Mycobacterium tuberculosis from sputum specimens of suspected TB patients at Chennai, South India and to detect MDR-TB circulating in this population. Methods: Sputum samples from clinically suspected tuberculosis patients (n=301) and 78 controls were included in the study. The sputum samples were collected in sterile diethyl pyrocarbonate (DEPC) treated containers and transported in ice to the laboratory within 2 h to prevent degradation of RNA. RT-PCR targeting 85B gene, mycobacterial culture and phenotypic drug susceptibility testing for the first line drugs streptomycin (S), isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) were performed by BACTEC microMGIT culture system for all the sputum specimens. Results: All the 78 controls were negative for culture and RT-PCR. Among the 301 sputum specimens from patients, 231 (76.8%) were RT-PCR positive and 70 (23.2%) were negative. There were 166 M. tuberculosis isolates, of which 11 (2.9%) were MDR-TB, 33 (8.7%) were polyresistant, 31 (8.2%) were monoresistant and 91 (30.2%) were sensitive to all five first line anti-tuberculous drugs by phenotypic drug susceptibility testing. Monoresistance was higher with Z [20 (20.8%)], followed by S [6 (3%)]. Interpretation & conclusions: RT-PCR targeting 85B gene of M. tuberculosis was a specific, rapid, reliable technique to detect the M. tuberculosis directly from sputum specimens. Our results showed that 2.9 per cent of M. tuberculosis isolates in the study population of Chennai were MDR. PMID:22771612

  2. 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

  3. Trends and Characteristics of HIV Infection among Suspected Tuberculosis Cases in Public Health Centers in Korea: 2001–2013

    PubMed Central

    Kee, Meekyung; Lee, Kyoung-Ho; Lee, Sae-Young; Kang, Chun; Chu, Chaeshin

    2014-01-01

    Objectives The Republic of Korea reports approximately 35,000 new tuberculosis (TB) patients each year, and the number of HIV-infected individuals is steadily increasing. Public health centers (PHCs) conduct TB diagnosis and treatment for risk groups in communities. This study aimed to identify possible trends and characteristics of HIV infection among suspected TB cases in PHCs. Methods Study subjects were suspected TB cases in PHCs who agreed to be tested for HIV from 2001 to 2013. Trends in HIV seroprevalence were assessed through a series of annual cross-sectional analyses. We analyzed suspected TB cases, and HIV-infected individuals among suspected TB cases, by gender, age, nationality, and region. Results The number of suspected tuberculosis cases who took an HIV test in PHCs was approximately 6,000 each year from 2001 to 2013. Among the suspected TB cases who took an HIV test, the number of those aged 20–39 is gradually decreasing, while the number of those aged 50–69 is increasing. During this period, 32 HIV-infected individuals were identified; the majority were men (94%), aged 30–49 (68%), Korean (94%), and residents in a metropolitan area (53%). HIV seroprevalence decreased from 8.2 per 10,000 persons in 2001 to 1.9 per 10,000 persons in 2013. Conclusion This study has identified trends and characteristics of HIV infection among suspected tuberculosis cases in PHCs. This national data provides a basis for public health policy for HIV and tuberculosis infections.

  4. Differential Expression of Host Biomarkers in Saliva and Serum Samples from Individuals with Suspected Pulmonary Tuberculosis

    PubMed Central

    Phalane, Khutso G.; Kriel, Magdalena; Loxton, Andre G.; Menezes, Angela; Stanley, Kim; van der Spuy, Gian D.; Walzl, Gerhard; Chegou, Novel N.

    2013-01-01

    The diagnosis of tuberculosis remains challenging in individuals with difficulty in providing good quality sputum samples such as children. Host biosignatures of inflammatory markers may be valuable in such cases, especially if they are based on more easily obtainable samples such as saliva. To explore the potential of saliva as an alternative sample in tuberculosis diagnostic/biomarker investigations, we evaluated the levels of 33 host markers in saliva samples from individuals presenting with pulmonary tuberculosis symptoms and compared them to those obtained in serum. Of the 38 individuals included in the study, tuberculosis disease was confirmed in 11 (28.9%) by sputum culture. In both the tuberculosis cases and noncases, the levels of most markers were above the minimum detectable limit in both sample types, but there was no consistent pattern regarding the ratio of markers in serum/saliva. Fractalkine, IL-17, IL-6, IL-9, MIP-1?, CRP, VEGF, and IL-5 levels in saliva and IL-6, IL-2, SAP, and SAA levels in serum were significantly higher in tuberculosis patients (P < 0.05). These preliminary data indicate that there are significant differences in the levels of host markers expressed in saliva in comparison to those expressed in serum and that inflammatory markers in both sample types are potential diagnostic candidates for tuberculosis disease. PMID:24327799

  5. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...department diagnosis of active pulmonary tuberculosis will be accepted unless... Diagnosis of active pulmonary tuberculosis by the medical authorities... Diagnosis of active pulmonary tuberculosis by private...

  6. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...department diagnosis of active pulmonary tuberculosis will be accepted unless... Diagnosis of active pulmonary tuberculosis by the medical authorities... Diagnosis of active pulmonary tuberculosis by private...

  7. Validation of a Clinical-Radiographic Score to Assess the Probability of Pulmonary Tuberculosis in Suspect Patients with Negative Sputum Smears

    PubMed Central

    Soto, Alonso; Solari, Lely; Díaz, Javier; Mantilla, Alberto; Matthys, Francine; van der Stuyft, Patrick

    2011-01-01

    Background Clinical suspects of pulmonary tuberculosis in which the sputum smears are negative for acid fast bacilli represent a diagnostic challenge in resource constrained settings. Our objective was to validate an existing clinical-radiographic score that assessed the probability of smear-negative pulmonary tuberculosis (SNPT) in high incidence settings in Peru. Methodology/Principal Findings We included in two referral hospitals in Lima patients with clinical suspicion of pulmonary tuberculosis and two or more negative sputum smears. Using a published but not externally validated score, patients were classified as having low, intermediate or high probability of pulmonary tuberculosis. The reference standard for the diagnosis of tuberculosis was a positive sputum culture in at least one of 2 liquid (MGIT or Middlebrook 7H9) and 1 solid (Ogawa) media. Prevalence of tuberculosis was calculated in each of the three probability groups. 684 patients were included. 184 (27.8%) had a diagnosis of pulmonary tuberculosis. The score did not perform well in patients with a previous history of pulmonary tuberculosis. In patients without, the prevalence of tuberculosis was 5.1%, 31.7% and 72% in the low, intermediate and high probability group respectively. The area under de ROC curve was 0.76 (95% CI 0.72–0.80) and scores ?6 had a positive LR of 10.9. Conclusions/Significance In smear negative suspects without previous history of tuberculosis, the clinical-radiographic score can be used as a tool to assess the probability of pulmonary tuberculosis and to guide the decision to initiate or defer treatment or to requesting additional tests. PMID:21483690

  8. 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

  9. Activities of the Korean Institute of Tuberculosis

    PubMed Central

    Ryoo, Sungweon; Kim, Hee Jin

    2014-01-01

    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.

  10. Tuberculosis

    NSDL National Science Digital Library

    Patient Education Institute

    This patient education program discusses latent and active tuberculosis infections. It also reviews the symptoms, diagnosis, treatment, and prevention of tuberculosis. This resource is a MedlinePlus Interactive Health Tutorial from the National Library of Medicine, designed and developed by the Patient Education Institute. NOTE: This tutorial requires a special Flash plug-in, version 4 or above. If you do not have Flash, you will be prompted to obtain a free download of the software before you start the tutorial. You will also need an Acrobat Reader, available as a free download, in order to view the Reference Summary.

  11. Identification and Characterization of Non-Tuberculous Mycobacteria Isolated from Tuberculosis Suspects in Southern-Central China

    PubMed Central

    Yu, Xiao-li; Lu, Lian; Chen, Gao-zhan; Liu, Zhi-Guo; Lei, Hang; Song, Yan-zheng; Zhang, Shu-lin

    2014-01-01

    The incidence of non-tuberculous mycobacteria (NTM)-related death has increased globally recently. To obtain information of the species and characterization of pathogens involved in NTM pulmonary infection in Southern-central China, we identified 160 non-tuberculous infection cases from 3995 acid-fast bacilli (AFB)-positive tuberculous suspects. We then randomly selected 101 non-tuberculous patients, isolated bacteria from their sputa and genotyped the pathogens using the 16S rRNA gene and 16S-23S rRNA internal transcribed spacer sequences. M. intracellulare (32.67%, 33/101), M. abscessus (32.67%, 33/101) and M. fortuitum (7.92%, 8/101) are identified in these isolates. Surprisingly, non-mycobacteria including Gordonia (8.91%, 9/101), Nocardia (5.94%, 6/101) and Tsukamurella (0.99%, 1/101) are also discovered, and the case of Tsukamurella pulmonis infection is first discovered in Southern-central China. Moreover, species of M. mucogenicum group, M. chubuense, M. kansasii, M. gastri, M. avium, M. porcinum and M. smegmatis are identified. In addition, nine immune compromised cases (8.91%, 9/101), including type two diabetes mellitus and HIV/AIDS are found to be infected with non-tuberculous bacteria. This study revealed the distribution and characteristics of non-tuberculous AFB pathogen infection occurred in Southern-central China, and suggested that physicians should be alert of the emerging of NTM and non-mycobacteria infection in AFB positive cases and take caution when choosing chemotherapy for tuberculosis-like pulmonary infections. Generally, this study may help with the development of new strategy for the diagnosis and treatment of mycobacterial infection. PMID:25463697

  12. 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...

  13. 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...

  14. 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...

  15. Treatment of tuberculosis: use of active pharmaceuticals.

    PubMed

    Samad, Abdus; Sultana, Yasmin; Akhter, Md S; Aqil, Mohammad

    2008-01-01

    Tuberculosis (TB) is a highly infectious disease caused by several species of mycobacteria. Multi drug resistant strains of mycobacteria leading to the increase of patient world wide. There is an urgent need for new effective antimicrobial agent to replace those currently in use because of highly toxic. Screening methods available for discovering new chemical entities active against the resistant strains are detailed. The plant origin antimicrobial agents are the valuable anti tubercular drugs. The present review of patent stated several findings from an extensive literature search of semi synthetic, synthetic and natural plants that have been assessed for the antimicrobial activity over 20 years. An attempt has been made to summarize the information in order to highlight those chemical entities and plant species which are of worthy for further investigation as leads to the drug developments. Over 150 chemical entities of semi synthetic and synthetic and over 350 plant species from wide range of families containing various chemical classes of compounds have been cited here which are worthy for the researchers and the industrialist concerned to tuberculosis. The present review includes some patents relevant to the treatment of tuberculosis. PMID:18221184

  16. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...2011-07-01 false Pulmonary tuberculosis shown by X-ray in active...Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active...direct service connection for pulmonary tuberculosis. When under...

  17. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...2010-07-01 false Pulmonary tuberculosis shown by X-ray in active...Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active...direct service connection for pulmonary tuberculosis. When under...

  18. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 2014-07-01 false Pulmonary tuberculosis shown by X-ray in active service...Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active service...direct service connection for pulmonary tuberculosis. When under...

  19. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 2013-07-01 false Pulmonary tuberculosis shown by X-ray in active service...Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active service...direct service connection for pulmonary tuberculosis. When under...

  20. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 2012-07-01 false Pulmonary tuberculosis shown by X-ray in active service...Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active service...direct service connection for pulmonary tuberculosis. When under...

  1. Tuberculosis

    MedlinePLUS

    ... Dynamic Stretching A Guy's Guide to Body Image Tuberculosis KidsHealth > Teens > Infections > Bacterial & Viral Infections > Tuberculosis Print ... Prevention Treatment Duration When to Call the Doctor TB Basics Tuberculosis (also known as "TB") is a ...

  2. Tuberculosis

    MedlinePLUS

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

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

    E-print Network

    Sali, Andrej

    Target Prediction for an Open Access Set of Compounds Active against Mycobacterium tuberculosis tuberculosis, the causative agent of tuberculosis (TB), infects an estimated two billion people worldwide. The screen revealed 776 compounds with significant activity against the M. tuberculosis H37Rv strain

  4. 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

  5. Use of PCR-based Mycobacterium tuberculosis genotyping to prioritize tuberculosis outbreak control activities.

    PubMed

    Ashworth, Maegan; Horan, Kathleen L; Freeman, Robert; Oren, Eyal; Narita, Masahiro; Cangelosi, Gerard A

    2008-03-01

    Genotypic analysis of Mycobacterium tuberculosis isolates is increasingly applied in direct support of tuberculosis outbreak control activities. This is facilitated by PCR-based strain typing methods that enable the genotypic characterization of samples containing small numbers of M. tuberculosis cells. By using DNA extracted directly from primary diagnostic cultures, PCR-based methods were applied to a tuberculosis outbreak investigation and to surveillance in King County, Washington. In the outbreak investigation, five epidemiologically linked M. tuberculosis isolates had a unique pattern at mycobacterial interspersed repeating unit (MIRU) loci 10 and 23 when the pattern was compared to the patterns in a local MIRU locus database. In order to quickly identify new cases involving this strain (termed SBRI10), targeted genotyping at these two loci was performed with cultures from epidemiologically associated tuberculosis cases. Isolates with the characteristic genotypes at loci 10 and 23 were further analyzed by use of a 12-locus MIRU panel and by repetitive-unit-sequence-based PCR (rep-PCR). Between May 2004 and January 2005, 82 cases were screened, of which 14 were identified for further analysis and 13 were confirmed to be infected with SBRI10. Between September 2005 and August 2006, surveillance universal genotyping was performed by using the 12-locus MIRU panel with DNA from primary diagnostic enrichment cultures. A total of 161 samples were submitted for analysis, and 156 were successfully typed. Fifty-one cases formed 18 presumptive clusters by MIRU locus typing. Of these, 30 cases were confirmed to be members of 11 clusters by rep-PCR. Presumptive genotypic data were available rapidly, sometimes within 2 weeks of diagnosis. In this fashion, PCR-based genotyping provided data that can be used to prioritize disease control activities. PMID:18174293

  6. Spooky Suspects

    ERIC Educational Resources Information Center

    Pacifici, Lara

    2011-01-01

    This activity presents an option for covering biology content while engaging students in an investigation that highlights the spirit of Halloween. Students are engaged in the story line and have fun trying to solve the mystery kidnapping by using science skills to examine the evidence and eliminate some ghoulish suspects. (Contains 1 figure.)

  7. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...2010-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 ...Diseases § 3.378 Changes from activity in pulmonary tuberculosis pension cases. A permanent...

  8. 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 ...Diseases § 3.378 Changes from activity in pulmonary tuberculosis pension cases. A permanent...

  9. 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...

  10. 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...

  11. 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...

  12. Pathogen-derived biomarkers for active tuberculosis diagnosis

    PubMed Central

    Tucci, Paula; González-Sapienza, Gualberto; Marin, Monica

    2014-01-01

    Tuberculosis (TB) is an infectious disease caused by members of Mycobacterium tuberculosis complex. Despite the availability of effective treatments, TB remains a major public health concern in most low and middle-income countries, representing worldwide the second leading cause of death from an infectious disease. Inadequate case detection and failures to classify the disease status hamper proper TB control. The limitations of the conventional diagnostic methods have encouraged much research activities in this field, but there is still an urgent need for an accurate point of care test for active TB diagnosis. A rapid, precise, and inexpensive TB diagnostic test would allow an earlier implementation of an appropriate treatment and the reduction of disease transmission. Pathogen-derived molecules present in clinical specimens of affected patients are being validated for that purpose. This short review aims to summarize the available data regarding biomarkers derived from M. tuberculosis, and their current usage in active TB diagnosis. PMID:25368609

  13. Patient and provider delay in tuberculosis suspects from communities with a high HIV prevalence in South Africa: A cross-sectional study

    PubMed Central

    Meintjes, Graeme; Schoeman, Hennie; Morroni, Chelsea; Wilson, Douglas; Maartens, Gary

    2008-01-01

    Background Delay in the diagnosis of tuberculosis (TB) results in excess morbidity and mortality, particularly among HIV-infected individuals. This study was conducted at a secondary level hospital serving communities with a high HIV prevalence in Cape Town, South Africa. The aim was to describe patient and provider delay in the diagnosis of TB in patients with suspected TB requiring admission, and to determine the risk factors for this delay and the consequences. Methods A cross-sectional study was conducted. Patients admitted who were TB suspects were interviewed using a structured questionnaire to assess history of their symptoms and health seeking behaviour. Data regarding TB diagnosis and outcome were obtained from the medical records. Bivariate associations were described using student's T-tests (for means), chi-square tests (for proportions), and Wilcoxon rank-sum tests (for medians). Linear regression models were used for multivariate analysis. Results One hundred twenty-five (125) patients were interviewed. In 104 TB was diagnosed and these were included in the analysis. Seventy of 83 (84%) tested were HIV-infected. Provider delay (median = 30 days, interquartile range (IQR) = 10.3–60) was double that of patient delay (median = 14 days, IQR = 7–30). Patients had a median of 3 contacts with formal health care services before referral. Factors independently associated with longer patient delay were male gender, cough and first health care visit being to public sector clinic (compared with private general practitioner). Patient delay ? 14 days was associated with increased need for transfer to a TB hospital. Provider delay ? 30 days was associated with increased mortality. Conclusion Delay in TB diagnosis was more attributable to provider than patient delay, and provider delay was associated with increased mortality. Interventions to expedite TB diagnosis in primary care need to be developed and evaluated in this setting. PMID:18501019

  14. Tuberculosis

    MedlinePLUS

    ... PEPFARâ??s Global Fund to Fight AIDS, Tuberculosis and Malaria funds health initiatives and strengthens health systems worldwide ... secure better health outcomes for HIV, TB and malaria. Read about the Global Fund on the AIDS. ...

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

    PubMed Central

    2010-01-01

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

  16. Tuberculosis.

    PubMed

    Garcia-Monco, Juan Carlos

    2014-01-01

    Tuberculosis remains a serious health problem worldwide, particularly affecting the poorest in both high-income and developing countries. It was declared a global emergency by the World Health Organization in 1993. Central nervous system (CNS) tuberculosis is caused by mycobacteria belonging to the Mycobacterium tuberculosis complex, and is acquired through inhalation of aerosolized droplet nuclei. Meningitis represents the most frequent and severe form of CNS tuberculosis. Parenchymal CNS involvement can occur in the form of tuberculoma or, more rarely, abscess. Also, damage of the spinal cord, roots, and spine can occur in the form of spinal meningitis, radiculomyelitis, spondylitis, or spinal cord infarction. Diagnosis remains a challenge due to the slow growth of the organisms and the low yield of cerebrospinal fluid cultures, as well as the frequent absence of evidence of infection elsewhere. This results in frequent empirical therapy, based on a combination of four drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) for 2 months, followed by 10 additional months with two drugs (isoniazid and rifampicin) to a total duration of 12 months. Shorter regimens have also been successful, but there have been few controlled trials in patients with extrapulmonary disease. Corticoid therapy seems to be associated with a reduced risk of death, and is usually indicated. Evidence of multidrug resistance requires variable combinations of first- and second-line drugs; fortunately, resistance does not seem to represent a serious threat for CNS tuberculosis at present, but still requires the utmost vigilance. PMID:24365432

  17. Tuberculosis.

    PubMed

    Maartens, Gary; Wilkinson, Robert J

    2007-12-15

    Tuberculosis is still a leading cause of death in low-income and middle-income countries, especially those of sub-Saharan Africa where tuberculosis is an epidemic because of the increased susceptibility conferred by HIV infection. The effectiveness of the Bacille Calmette Guérin (BCG) vaccine is partial, and that of treatment of latent tuberculosis is unclear in high-incidence settings. The routine diagnostic methods that are used in many parts of the world are still very similar to those used 100 years ago. Multidrug treatment, within the context of structured, directly observed therapy, is a cost-effective control strategy. Nevertheless, the duration of treatment needed reduces its effectiveness, as does the emergence of multidrug-resistant and extensively drug-resistant disease; the latter has recently become widespread. The rapid expansion of basic, clinical, and operational research, in addition to increasing knowledge of tuberculosis, is providing new diagnostic, treatment, and preventive measures. The challenge is to apply these advances to the populations most at risk. The development of a comprehensive worldwide plan to stop tuberculosis might facilitate this process by coordinating the work of health agencies. However, massive effort, political will, and resources are needed for this plan to succeed. PMID:17719083

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

    PubMed Central

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

    2014-01-01

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

  19. Combined use of Mycobacterium tuberculosis-specific CD4 and CD8 T-cell responses is a powerful diagnostic tool of active tuberculosis.

    PubMed

    Rozot, Virginie; Patrizia, Amelio; Vigano, Selena; Mazza-Stalder, Jesica; Idrizi, Elita; Day, Cheryl L; Perreau, Matthieu; Lazor-Blanchet, Catherine; Ohmiti, Khalid; Goletti, Delia; Bart, Pierre-Alexandre; Hanekom, Willem; Scriba, Thomas J; Nicod, Laurent; Pantaleo, Giuseppe; Harari, Alexandre

    2015-02-01

    Immune-based assays are promising tools to help to formulate diagnosis of active tuberculosis. A multiparameter flow cytometry assay assessing T-cell responses specific to Mycobacterium tuberculosis and the combination of both CD4 and CD8 T-cell responses accurately discriminated between active tuberculosis and latent infection. PMID:25362202

  20. Effect of pyrazinamidase activity on pyrazinamide resistance in Mycobacterium tuberculosis.

    PubMed

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

    2009-03-01

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

  1. LAG3 Expression in Active Mycobacterium tuberculosis Infections.

    PubMed

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

    2015-03-01

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

  2. Revisiting Anti-tuberculosis Activity of Pyrazinamide in Mice

    PubMed Central

    Almeida, Deepak V.; Tyagi, Sandeep; Li, Si-Yang; Wallengren, Kristina; Pym, Alexander S.; Ammerman, Nicole C.; Bishai, William R.; Grosset, Jacques H.

    2014-01-01

    The mechanism of action of pyrazinamide, a key sterilizing drug in the treatment of tuberculosis, remains elusive; pyrazinamide is a pro-drug that requires activation by a bacterial-encoded enzyme, and its activity is most apparent on non-replicating Mycobacterium tuberculosis. Recently, it has been suggested that pyrazinamide might exert also some host-directed effect in addition to its antimicrobial activity. To address this possibility, three sequential experiments were conducted in immune-competent BALB/c and in immune-deficient, athymic nude mice. In the first experiment, BALB/c mice infected with M. bovis, which is naturally resistant to pyrazinamide because it is unable to activate the drug, were treated with standard drug regimens with and without pyrazinamide to specifically detect a host-directed effect. As no effect was observed, pyrazinamide activity was compared in M. tuberculosis-infected BALB/c and nude mice to determine whether the effect of pyrazinamide would be reduced in the immune deficient mice. As pyrazinamide did not appear to have any affect in the nude mice, a third experiment was performed in which rifampin was replaced with rifapentine (a similar drug with a longer half-life) to permanently suppress mycobacterial growth. In these experimental conditions, the antimicrobial effect of pyrazinamide was clear. Therefore, the results of our studies rule out a significant host-directed effect of pyrazinamide in the TB infected host. PMID:25525563

  3. Activity of levofloxacin in a murine model of tuberculosis.

    PubMed Central

    Klemens, S P; Sharpe, C A; Rogge, M C; Cynamon, M H

    1994-01-01

    The activity of levofloxacin (LEV) was evaluated in a murine model of tuberculosis. Approximately 10(7) viable Mycobacterium tuberculosis ATCC 35801 were given intravenously to 4-week-old female outbred mice. In a dose-response study, treatment with LEV at 100, 200, and 400 mg/kg of body weight was started 1 day after infection and was given daily for 28 days. Viable cell counts were determined from homogenates of spleens and lungs. A dose-related reduction in organism cell counts in organs was noted for LEV. The activities of LEV at 100, 200, and 300 mg/kg were compared with those of first-line antituberculosis agents. Both isoniazid and rifampin were more active than LEV. There was no difference in activity between LEV and either ethambutol or pyrazinamide against splenic organisms. The activities of ethambutol and LEV at the two higher doses were comparable against lung organisms. LEV at 300 mg/kg was more active than pyrazinamide against lung organisms. The activity of LEV was compared with those of two other quinolones, ofloxacin and sparfloxacin. LEV at 200 mg/kg had more than twofold greater activity than ofloxacin at the same dose. Sparfloxacin at 100 mg/kg was more active than LEV at 200 mg/kg; however, the activities of sparfloxacin at 50 mg/kg and LEV at 200 mg/kg were comparable. The promising activity of LEV in M. tuberculosis-infected mice suggests that it is a good candidate for clinical development as a new antituberculosis agent. PMID:7979275

  4. Soluble urokinase plasminogen activator receptor levels in tuberculosis patients at high risk for multidrug resistance.

    PubMed

    Mardining Raras, Tri Yudani; Astuti, Triwahju; Noor Chozin, Iin

    2012-01-01

    The soluble urokinase plasminogen activator receptor (suPAR) has been shown to be a strong prognostic biomarker for tuberculosis (TB). In the present study, the profiles of plasma suPAR levels in pulmonary TB patients at high risk for multidrug resistance were analyzed and compared with those in multidrug resistant (MDR)-TB patients. Forty patients were prospectively included, consisting of 10 MDR-TB patients and 30 TB patients at high risk for MDR, underwent clinical assesment. Plasma suPAR levels were measured using ELISA (SUPARnostic, Denmark) and bacterial cultures were performed in addition to drug susceptibility tests. All patients of suspected MDR-TB group demonstrated significantly higher suPAR levels compared with the healthy TB-negative group (1.79?ng/mL). Among the three groups at high risk for MDR-TB, only the relapse group (7.87?ng/mL) demonstrated suPAR levels comparable with those of MDR-TB patients (7.67?ng/mL). suPAR levels in the two-month negative acid-fast bacilli conversion group (9.29 ng/mL) were higher than positive control, whereas levels in the group consisting of therapy failure patients (5.32?ng/mL) were lower. Our results strongly suggest that suPAR levels enable rapid screening of suspected MDR-TB patients, but cannot differentiate between groups. PMID:23304490

  5. Effect of Standard Tuberculosis Treatment on Plasma Cytokine Levels in Patients with Active Pulmonary Tuberculosis

    PubMed Central

    Riou, Catherine; Perez Peixoto, Blas; Roberts, Lindi; Ronacher, Katharina; Walzl, Gerhard; Manca, Claudia; Rustomjee, Roxana; Mthiyane, Thuli; Fallows, Dorothy

    2012-01-01

    Background Sputum Mycobacterium tuberculosis (Mtb) culture is commonly used to assess response to antibiotic treatment in individuals with pulmonary tuberculosis (TB). Such techniques are constrained by the slow growth rate of Mtb, and more sensitive methods to monitor Mtb clearance are needed. The goal of this study was to evaluate changes in plasma cytokines in patients undergoing treatment for TB as a means of identifying candidate host markers associated with microbiologic response to therapy. Methods Twenty-four plasma cytokines/chemokines were measured in 42 individuals diagnosed with active pulmonary TB, 52% were HIV co-infected. Individuals, undergoing a 26-week standard TB treatment, were followed longitudinally over 18 months and measurements were associated with HIV status and rates of sputum culture conversion. Results Plasma concentrations of interferon-inducible protein-10 (IP-10) and vascular endothelial growth factor (VEGF) were significantly reduced upon TB treatment, regardless of HIV status. By the end of treatment, IP-10 concentrations were significantly lower in HIV negative individuals when compared to HIV-positive individuals (p?=?0.02). Moreover, in HIV negative patients, plasma VEGF concentrations, measured as early as 2-weeks post TB treatment initiation, positively correlated with the time of sputum conversion (p?=?0.0017). No significant changes were observed in other studied immune mediators. Conclusions These data suggest that VEGF plasma concentration, measured during early TB treatment, could represent a surrogate marker to monitor sputum culture conversion in HIV uninfected individuals. PMID:22606304

  6. 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.

  7. Mycobacterium tuberculosis activates the DNA-dependent cytosolic surveillance pathway within macrophages

    PubMed Central

    Manzanillo, Paolo S.; Shiloh, Michael U.; Portnoy, Daniel A.; Cox, Jeffery S.

    2013-01-01

    Summary Cytosolic bacterial pathogens activate the cytosolic surveillance pathway (CSP) and induce innate immune responses, but how the host detects vacuolar pathogens like Mycobacterium tuberculosis is poorly understood. We show that M. tuberculosis also initiates the CSP upon macrophage infection via limited perforation of the phagosome membrane mediated by the ESX-1 secretion system. Although the bacterium remains within the phagosome, this permeabilization results in phagosomal and cytoplasmic mixing and allows extracellular mycobacterial DNA to access host cytosolic receptors, thus blurring the distinction between “vacuolar” and “cytosolic” pathogens. Activation of cytosolic receptors induces signaling through the STING/TBK1/IRF3 axis, resulting in IFN-? production. Surprisingly, IRF3?/? mice, which cannot respond to cytosolic DNA, are resistant to long-term M. tuberculosis infection, suggesting that the CSP promotes M. tuberculosis infection. Thus, cytosolic sensing of mycobacterial DNA plays a key role in M. tuberculosis pathogenesis and likely contributes to the high type I IFN signature in tuberculosis. PMID:22607800

  8. 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

  9. Bactericidal Activities of Commonly Used Antiseptics against Multidrug-Resistant Mycobacterium tuberculosis

    Microsoft Academic Search

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

    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,

  10. A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis

    Microsoft Academic Search

    Koen Andries; Peter Verhasselt; Jerome Guillemont; Hinrich W. H. Göhlmann; Jean-Marc Neefs; Hans Winkler; Jef Van Gestel; Philip Timmerman; Min Zhu; Ennis Lee; Peter Williams; Didier de Chaffoy; Emma Huitric; Sven Hoffner; Emmanuelle Cambau; Chantal Truffot-Pernot; Nacer Lounis; Vincent Jarlier

    2005-01-01

    The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug\\/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at

  11. Identification of potential Mycobacterium tuberculosis topoisomerase I inhibitors: A study against active, dormant and resistant tuberculosis.

    PubMed

    Sridevi, Jonnalagadda Padma; Suryadevara, Priyanka; Janupally, Renuka; Sridhar, Jogula; Soni, Vijay; Anantaraju, Hasitha Shilpa; Yogeeswari, Perumal; Sriram, Dharmarajan

    2015-05-25

    Mycobacterium tuberculosis (Mtb) topoisomerase I (Topo I), involved in the relaxation of negatively supercoiled DNA, plays an important role in the viability of pathogen Mtb. Being one of the most significant enzymes; it also takes part in crucial biological pathways such as transcription and replication of the pathogen. The present study aims at the development of Mtb Topo I 3D protein structure which in turn was employed for the virtual screening of compound libraries in a process of identification of a hit molecule. The identified hit, hydroxycamptothecin, was active at 6.25?M which was further derivatized synthetically into fifteen novel analogues. Among these, four compounds (3b, 3g, 3h and 3l) emerged to be active displaying IC50 values ranging from 2.9 to 9.3?M against Mtb Topo I and were non-cytotoxic at 25?M. These four compounds also proved their efficacy when tested against active, dormant and resistant forms of Mtb. The most potent inhibitor 3b was screened for in vivo anti-mycobacterial activity using zebrafish model and was found to be more effective when compared to first line anti-tubercular drugs, isoniazid and rifampicin. The binding affinity of this compound towards Mtb Topo I was analyzed by differential scanning fluorimetry which resulted in a positive shift in melting temperature when compared to the native protein thereby proving its stabilization effect over protein. PMID:25769524

  12. Mefloquine and Its Enantiomers Are Active against Mycobacterium tuberculosis In Vitro and in Macrophages

    PubMed Central

    Bermudez, Luiz E.; Meek, Laura

    2014-01-01

    Objective. Tuberculosis is a serious problem of public health. The increase on the number of clinical cases of tuberculosis infected with multidrug resistant (MDR) M. tuberculosis calls for the development of novel therapy. Design. We investigated the effect of mefloquine and two enantiomers, (+)erythro-mefloquine and (+)threo-mefloquine against M. tuberculosis strains in the environment resembling the aspects of the granuloma environment and in macrophages. Results. The results suggest that mefloquine (racemic mixture) and (+)erythro-mefloquine have bactericidal activity against M. tuberculosis strains both in acidic, low oxygen tension and in macrophages. The activity, however, was impaired under increased osmolarity. Conclusion. Identification of the target for mefloquine in the pathogen will allow for the development of novel drugs with antituberculosis activity. PMID:25580293

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

    PubMed Central

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

    2012-01-01

    Characterizing host immune responses to molecular targets of Mycobacterium tuberculosis is essential to develop effective immunodiagnostics and better vaccines. We investigated the immune response against a large series of M. tuberculosis antigens, including 5 classical and 64 nonclassical (39 DosR regulon-encoded, 4 resuscitation-promoting factor [RPF], and 21 reactivation-associated) antigens in active-pulmonary-tuberculosis (TB) patients. Whole blood from TB patients (n = 34) was stimulated in vitro with M. tuberculosis antigens. Gamma interferon (IFN-?) was measured after 7 days of stimulation, using an enzyme-linked immunosorbent assay (ELISA). The majority of the study participants responded to the classical M. tuberculosis antigens TB10.4 (84.8%), early secreted antigenic target-6 kDa (ESAT-6)/CFP-10 (70.6%), and purified protein derivative (PPD) (55.9%). However, only 26.5% and 24.2% responded to HSP65 and Ag85A/B, respectively. Of the 64 nonclassical antigens, 23 (33.3%) were immunogenic (IFN-? levels, >62 pg/ml) and 8 were strong inducers of IFN-? (IFN-? levels, ?100 pg/ml). The RPF antigens were the most immunogenic. In addition, we observed distinct cytokine expression profiles in response to several M. tuberculosis antigens by multiplex immunoassay. Tumor necrosis factor alpha (TNF-?), interleukin 10 (IL-10), and IL-6 were commonly detected at high levels after stimulation with 4/15 latency antigens (Rv0081, Rv2006, Rv2629, and Rv1733c) and were found especially in supernatants of the three strong IFN-? inducers (Rv2629, Rv1009, and Rv2389c). IL-8, IL-6, and IL-17 were exclusively detected after stimulation with Rv0574c, Rv2630, Rv1998, Rv054c, and Rv2028c. In conclusion, in active-pulmonary-TB patients, we identified 23 new immunogenic M. tuberculosis antigens. The distinct expression levels of IFN-?, TNF-?, IL-6, and IL-10 in response to specific subsets of M. tuberculosis antigens may be promising for the development of immunodiagnostics. PMID:23015647

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

    PubMed Central

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

    2015-01-01

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

  15. 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...

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

    PubMed Central

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

    2014-01-01

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

  17. Phosphorylation of Mitogen-Activated Protein Kinases Contributes to Interferon ? Production in Response to Mycobacterium tuberculosis

    PubMed Central

    Pasquinelli, Virginia; Rovetta, Ana I.; Alvarez, Ivana B.; Jurado, Javier O.; Musella, Rosa M.; Palmero, Domingo J.; Malbrán, Alejandro; Samten, Buka; Barnes, Peter F.; García, Verónica E.

    2013-01-01

    Immune control of Mycobacterium tuberculosis depends on interferon ? (IFN-?)–producing CD4+ lymphocytes. Previous studies have shown that T cells from patients with tuberculosis produce less IFN-?, compared with healthy donors, in response to mycobacterial antigens, although IFN-? responses to mitogens are preserved. In this work, we found that M. tuberculosis–induced IFN-? production by human T cells correlated with phosphorylation of the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38. Moreover, the majority of IFN-?–producing T cells expressed signaling lymphocyte activation molecule (SLAM), and SLAM activation further increased ERK phosphorylation. Interestingly, patients with tuberculosis had delayed activation of ERK and p38, and this was most marked in patients with the poorest IFN-? responses (ie, low responders). Besides, SLAM signaling failed to phosphorylate ERK in low responders. Our findings suggest that activation of p38 and ERK, in part through SLAM, mediates T-cell IFN-? production in response to M. tuberculosis, a pathway that is defective in patients with tuberculosis. PMID:23125442

  18. 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

  19. Mycobacterium tuberculosis Alters the Metalloprotease Activity of the COP9 Signalosome

    PubMed Central

    Babrak, Lmar; Rose, Sasha J.; Everman, Jamie

    2014-01-01

    ABSTRACT Inhibition of apoptotic death of macrophages by Mycobacterium tuberculosis represents an important mechanism of virulence that results in pathogen survival both in vitro and in vivo. To identify M. tuberculosis virulence determinants involved in the modulation of apoptosis, we previously screened a transposon bank of mutants in human macrophages, and an M. tuberculosis clone with a nonfunctional Rv3354 gene was identified as incompetent to suppress apoptosis. Here, we show that the Rv3354 gene encodes a protein kinase that is secreted within mononuclear phagocytic cells and is required for M. tuberculosis virulence. The Rv3354 effector targets the metalloprotease (JAMM) domain within subunit 5 of the COP9 signalosome (CSN5), resulting in suppression of apoptosis and in the destabilization of CSN function and regulatory cullin-RING ubiquitin E3 enzymatic activity. Our observation suggests that alteration of the metalloprotease activity of CSN by Rv3354 possibly prevents the ubiquitin-dependent proteolysis of M. tuberculosis-secreted proteins. IMPORTANCE  Macrophage protein degradation is regulated by a protein complex called a signalosome. One of the signalosomes associated with activation of ubiquitin and protein labeling for degradation was found to interact with a secreted protein from M. tuberculosis, which binds to the complex and inactivates it. The interference with the ability to inactivate bacterial proteins secreted in the phagocyte cytosol may have crucial importance for bacterial survival within the phagocyte. PMID:25139900

  20. [Dynamics of changes in lipid peroxidation and activity of superoxide dismutase in erythrocytes of patients with tuberculosis].

    PubMed

    Karagezian, K G; Karapetian, E T; Safarian, M D

    1989-01-01

    Evaluation of the lipid peroxidation rate and the superoxide dismutase activity in patients with tuberculosis showed that lipid peroxidation was distinctly increased in focal and infiltrative forms of the disease, while the enzymatic activity was altered dissimilarly. Activation of superoxide dismutase observed in focal tuberculosis appears to have a compensatory importance. PMID:2815666

  1. Structure-activity relationships of pyrrole hydrazones as new anti-tuberculosis agents.

    PubMed

    Lessigiarska, Iglika; Pajeva, Ilza; Prodanova, Penka; Georgieva, Maya; Bijev, Atanas

    2012-05-01

    Preliminary investigations of our research team have shown that some pyrrole hydrazones posses strong inhibitory activity against the tuberculosis bacilli, and thus represent a new perspective for development of anti-tuberculosis agents. In this work the anti-tuberculosis activity of an in-house series of pyrrole hydrazones was investigated by quantitative structure-activity relationships (QSAR) analysis and by pharmacophore modelling. Different constitutional, topological, physicochemical, and quantum-mechanical descriptors of the chemical structure were calculated. The QSAR models included the number of chlorine, fluorine and nitrogen atoms, molecular flexibility and shape indexes, and magnitudes of charged molecular surfaces areas and hydrophobic volumes, suggesting importance of these structural characteristics for the activity. Next, a pharmacophore analysis was applied. A possible pharmacophore responsible for the compound interactions with their biological target in the 3D space consisted of five features, including hydrophobic centres, a potential H-bond acceptor and a potential metal ligator. PMID:22530903

  2. A dual read-out assay to evaluate the potency of compounds active against Mycobacterium tuberculosis.

    PubMed

    Ollinger, Juliane; Bailey, Mai Ann; Moraski, Garrett C; Casey, Allen; Florio, Stephanie; Alling, Torey; Miller, Marvin J; Parish, Tanya

    2013-01-01

    Tuberculosis is a serious global health problem caused by the bacterium Mycobacterium tuberculosis. There is an urgent need for discovery and development of new treatments, but this can only be accomplished through rapid and reproducible M. tuberculosis assays designed to identify potent inhibitors. We developed an automated 96-well assay utilizing a recombinant strain of M. tuberculosis expressing a far-red fluorescent reporter to determine the activity of novel compounds; this allowed us to measure growth by monitoring both optical density and fluorescence. We determined that optical density and fluorescence were correlated with cell number during logarithmic phase growth. Fluorescence was stably maintained without antibiotic selection over 5 days, during which time cells remained actively growing. We optimized parameters for the assay, with the final format being 5 days' growth in 96-well plates in the presence of 2% w/v DMSO. We confirmed reproducibility using rifampicin and other antibiotics. The dual detection method allows for a reproducible calculation of the minimum inhibitory concentration (MIC), at the same time detecting artefacts such as fluorescence quenching or compound precipitation. We used our assay to confirm anti-tubercular activity and establish the structure activity relationship (SAR) around the imidazo[1,2-a]pyridine-3-carboxamides, a promising series of M. tuberculosis inhibitors. PMID:23593234

  3. 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

  4. A Dual Read-Out Assay to Evaluate the Potency of Compounds Active against Mycobacterium tuberculosis

    PubMed Central

    Ollinger, Juliane; Bailey, Mai Ann; Moraski, Garrett C.; Casey, Allen; Florio, Stephanie; Alling, Torey; Miller, Marvin J.; Parish, Tanya

    2013-01-01

    Tuberculosis is a serious global health problem caused by the bacterium Mycobacterium tuberculosis. There is an urgent need for discovery and development of new treatments, but this can only be accomplished through rapid and reproducible M. tuberculosis assays designed to identify potent inhibitors. We developed an automated 96-well assay utilizing a recombinant strain of M. tuberculosis expressing a far-red fluorescent reporter to determine the activity of novel compounds; this allowed us to measure growth by monitoring both optical density and fluorescence. We determined that optical density and fluorescence were correlated with cell number during logarithmic phase growth. Fluorescence was stably maintained without antibiotic selection over 5 days, during which time cells remained actively growing. We optimized parameters for the assay, with the final format being 5 days’ growth in 96-well plates in the presence of 2% w/v DMSO. We confirmed reproducibility using rifampicin and other antibiotics. The dual detection method allows for a reproducible calculation of the minimum inhibitory concentration (MIC), at the same time detecting artefacts such as fluorescence quenching or compound precipitation. We used our assay to confirm anti-tubercular activity and establish the structure activity relationship (SAR) around the imidazo[1,2-a]pyridine-3-carboxamides, a promising series of M. tuberculosis inhibitors. PMID:23593234

  5. Prevalence of Tuberculosis, HIV and Respiratory Symptoms in Two Zambian Communities: Implications for Tuberculosis Control in the Era of HIV

    PubMed Central

    Ayles, Helen; Schaap, Albertus; Nota, Amos; Sismanidis, Charalambos; De Haas, Petra; Muyoyeta, Monde; Beyers, Nulda

    2009-01-01

    Background The Stop TB Partnership target for tuberculosis is to have reduced the prevalence of tuberculosis by 50% comparing 2015 to 1990. This target is challenging as few prevalence surveys have been conducted, especially in high burden tuberculosis and HIV countries. Current tuberculosis control strategies in high HIV prevalent settings are therefore based on limited epidemiological evidence and more evidence is needed from community-based surveys to inform improved policy formulation. Methods and Findings 8044 adults were sampled from 2 sub-districts (wards) in Lusaka province, Zambia. Questionnaires were used to screen for symptoms, respiratory samples were obtained for culture and oral secretions collected for HIV testing. 79 individuals were found to have Mycobacterium tuberculosis in their sputum, giving an adjusted overall prevalence of tuberculosis of 870/100,000 (95% CI 570–1160/100,000). The adjusted overall prevalence of HIV was 28.61% (95% CI 26.04–31.19). HIV- infection was significantly associated with prevalent tuberculosis (Adj OR 2.3, 95% CI 1.42–3.74) and the population attributable fraction of HIV for prevalent tuberculosis was 36%. Symptoms such as prolonged cough (adj OR 12.72, 95% CI 7.05–22.94) and fever (Adj OR 2.04, 95%CI 1.23–3.39), were associated with prevalent tuberculosis, but 8 (10%) individuals with prevalent tuberculosis denied having any symptoms at all and only 34 (43%) would have been classified as a TB suspect by current guidelines. Conclusions Undiagnosed tuberculosis is a challenge for tuberculosis control and new approaches are needed if we are to reach international targets. Epidemiological studies can inform screening algorithms for both detection and prevention of active tuberculosis. PMID:19440346

  6. Early Bactericidal Activity of High-Dose Rifampin in Patients with Pulmonary Tuberculosis Evidenced by Positive Sputum Smears?

    PubMed Central

    Diacon, A. H.; Patientia, R. F.; Venter, A.; van Helden, P. D.; Smith, P. J.; McIlleron, H.; Maritz, J. S.; Donald, P. R.

    2007-01-01

    We studied the early bactericidal activity of twice the standard dose of rifampin in subjects with pulmonary tuberculosis evidenced by positive smears. The observed mean 2-day activity was almost double that reported at the standard dose. Further studies are warranted to establish whether higher rifampin doses might assist in shortening tuberculosis treatment. PMID:17517849

  7. 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

  8. Plasma Heme Oxygenase-1 Levels Distinguish Latent or Successfully Treated Human Tuberculosis from Active Disease

    PubMed Central

    Andrade, Bruno B.; Pavan Kumar, Nathella; Mayer-Barber, Katrin D.; Barber, Daniel L.; Sridhar, Rathinam; Rekha, Vaithilingam V. Banu; Jawahar, Mohideen S.; Nutman, Thomas B.

    2013-01-01

    Background Tuberculosis (TB) is associated with oxidative stress and the induction of host anti-oxidants to counteract this response. Heme oxygenase-1 (HO-1) is a critical promoter of cytoprotection in diverse disease models including mycobacterial infection. Nevertheless, the pattern of expression of HO-1 in human tuberculosis has not been studied. Here, we examine expression of HO-1 in M. tuberculosis-exposed and -infected individuals and test its ability to distinguish active from latent and successfully treated TB cases. In addition, we assess correlations between plasma levels of HO-1 and cytokines closely associated with the immunopathogenesis of TB. Methods Cross-sectional and longitudinal analyses of levels of HO-1, acute phase proteins and pro-inflammatory cytokines were performed in plasma samples from individuals with active pulmonary, extra-pulmonary or latent TB infection and healthy controls as part of a prospective cohort study in South India. Results Systemic levels of HO-1 were dramatically increased in individuals with active pulmonary and extra-pulmonary tuberculosis and particularly those with bilateral lung lesions and elevated bacillary loads in sputum. HO-1 levels effectively discriminated active from latent tuberculosis with higher predictive values than either C-reactive protein or serum amyloid protein. Moreover, there was a marked reduction in HO-1 levels in active TB cases following anti-tuberculous therapy but not in those who failed treatment. Pulmonary TB patients displaying the highest concentrations of HO-1 in plasma exhibited significantly elevated plasma levels of interleukin (IL)-10, interferon (IFN)-? and IL-17 and diminished levels of tumor necrosis factor (TNF)-?. Conclusion These findings establish HO-1 levels as a potentially useful parameter for distinguishing active from latent or treated pulmonary tuberculosis, that is superior in this respect to the measurement of other acute inflammatory proteins. PMID:23671613

  9. Stress and host immunity amplify Mycobacterium tuberculosis phenotypic heterogeneity and induce nongrowing metabolically active forms.

    PubMed

    Manina, Giulia; Dhar, Neeraj; McKinney, John D

    2015-01-14

    Nonreplicating and metabolically quiescent bacteria are implicated in latent tuberculosis infections and relapses following "sterilizing" chemotherapy. However, evidence linking bacterial dormancy and persistence in vivo is largely inconclusive. Here we measure the single-cell dynamics of Mycobacterium tuberculosis replication and ribosomal activity using quantitative time-lapse microscopy and a reporter of ribosomal RNA gene expression. Single-cell dynamics exhibit heterogeneity under standard growth conditions, which is amplified by stressful conditions such as nutrient limitation, stationary phase, intracellular replication, and growth in mouse lungs. Additionally, the lungs of chronically infected mice harbor a subpopulation of nongrowing but metabolically active bacteria, which are absent in mice lacking interferon-?, a cytokine essential for antituberculosis immunity. These cryptic bacterial forms are prominent in mice treated with the antituberculosis drug isoniazid, suggesting a role in postchemotherapeutic relapses. Thus, amplification of bacterial phenotypic heterogeneity in response to host immunity and drug pressure may contribute to tuberculosis persistence. PMID:25543231

  10. Tuberculosis (TB): Treatment

    MedlinePLUS

    ... Treating Tuberculosis Active TB Disease Drug-Resistant Tuberculosis Latent TB Infection TB Preventive Treatment History of TB ... to cooperate fully in the therapy program. Both latent TB infection and active TB disease are treated ...

  11. 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

  12. 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

  13. 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

  14. Delayed culture conversion due to cigarette smoking in active pulmonary tuberculosis patients.

    PubMed

    Nijenbandring de Boer, Renee; Oliveira e Souza Filho, João Baptista de; Cobelens, Frank; Ramalho, Daniela de Paula; Campino Miranda, Pryscilla Fernandes; Logo, Karina de; Oliveira, Hedi; Mesquita, Eliene; Oliveira, Martha Maria; Kritski, Afrânio

    2014-01-01

    Although many studies have assessed factors affecting culture conversion during tuberculosis treatment, few have looked into the effect of tobacco smoking. This study included 89 active pulmonary tuberculosis patients with positive sputum culture upon presentation and collected information regarding smoking history and culture conversion after 60 days of therapy. Current smokers had a higher risk (OR 5.6; 95%CI 1.7-18.7) of non-conversion after two months of therapy when compared to never and ex-smokers. Cavities on chest X-ray and alcohol abuse were shown to confound this association. After adjustment for cavities on the chest X-ray and alcohol abuse current smoking compared to current non-smoking remained significantly associated with culture non-conversion at 60 days of treatment (adjusted OR 6.9; 95%CI 1.8-26.7, p = 0.002) with a significant (p = 0.004) trend in adjusted OR with the number of cigarettes smoked daily to 11.6 (1.8-73.4) among those smoking more than 20 cigarettes per day. In conclusion tobacco smoking was found to delay culture conversion during treatment for pulmonary tuberculosis in a dose-dependent manner. More research is needed to elucidate the effects of smoking on tuberculosis treatment response, and of smoking cessation during tuberculosis treatment. PMID:24321739

  15. Activation of Phospholipase D Is Tightly Coupled to the Phagocytosis of Mycobacterium tuberculosis or Opsonized Zymosan by Human Macrophages

    Microsoft Academic Search

    David J. Kusner; Clifton E Hall; Larry S. Schlesinger

    1996-01-01

    Summary Phagocytosis of Mycobacterium tuberculosis by human mononuclear phagocytes is mediated pri- marily by complement receptors (CRs) but the transmembrane signaling mechanisms that reg- ulate phagocytosis of the bacterium are unknown. We have analyzed the activation of phos- pholipase D (PLD) during phagocytosis of the virulent Erdman and attenuated H37Ra strains of M. tuberculosis by human monocyte-derived macrophages (MDMs), radiolabeled

  16. Steroid receptor RNA activator (SRA1): unusual bifaceted gene products with suspected relevance to breast cancer

    PubMed Central

    Leygue, Etienne

    2007-01-01

    The steroid receptor RNA activator (SRA) is a unique modulator of steroid receptor transcriptional activity, as it is able to mediate its coregulatory effects as a RNA molecule. Recent findings, however, have painted a more complex picture of the SRA gene (SRA1) products. Indeed, even though SRA was initially thought to be noncoding, several RNA isoforms have now been found to encode an endogenous protein (SRAP), which is well conserved among Chordata. Although the function of SRAP remains largely unknown, it has been proposed that, much like its corresponding RNA, the protein itself might regulate estrogen and androgen receptor signaling pathways. As such, data suggest that both SRA and SRAP might participate in the mechanisms underlying breast, as well as prostate tumorigenesis. This review summarizes the published literature dealing with these two faces of the SRA gene products and underscores the relevance of this bifaceted system to breast cancer development. PMID:17710122

  17. Synthesis, Optimization and Structure-Activity Relationships of 3,5-Disubstituted Isoxazolines as New Anti-tuberculosis Agents

    PubMed Central

    Rakesh, Dianqing Sun; Lee, Robin B.; Tangallapally, Rajendra; Lee, Richard E.

    2009-01-01

    In the course of the development of a potent series of nitrofuranylamide anti-tuberculosis agents, we investigated if the exceptional activity resulted in part from the isoxazoline core and if it possessed any intrinsic anti-tuberculosis activity. This led to the discovery of an isoxazoline ester with appreciable anti-tuberculosis activity. In this study we explored the anti-tuberculosis structure activity relationship of the isoxazoline ester compound through systematic modification of the 3,5-di-substituted isoxazoline core. Two approaches were used: (i) modification of the potentially metabolically labile ester functionality at the 3-position with acids, amines, amides, reverse amides, alcohols, hydrazides, and 1,3,4-oxadiazoles; (ii) substitution of the distal benzyl piperazine ring in the 5-position of the isoxazoline ring with piperazyl-ureas, piperazyl-carbamates, biaryl systems, piperidines and morpholine. Attempts to replace the ester group at C-3 position of isoxazoline with a variety of bioisosteric head groups led to significant loss of the tuberculosis inhibition indicating that an ester is required for anti-tuberculosis activity. Optimization of the isoxazoline C5-position produced compounds with improved anti-tuberculosis activity, most notably the piperazyl-urea and piperazyl-carbamate analogs. PMID:18524421

  18. M. tuberculosis Induces Potent Activation of IDO-1, but This Is Not Essential for the Immunological Control of Infection

    PubMed Central

    Blumenthal, Antje; Nagalingam, Gayathri; Huch, Jennifer H.; Walker, Lara; Guillemin, Gilles J.; Smythe, George A.; Ehrt, Sabine; Britton, Warwick J.; Saunders, Bernadette M.

    2012-01-01

    Indoleamine 2,3-dioxygenesae-1 (IDO-1) catalyses the initial, rate-limiting step in tryptophan metabolism, thereby regulating tryptophan availability and the formation of downstream metabolites, including picolinic and quinolinic acid. We found that Mycobacterium tuberculosis infection induced marked upregulation of IDO-1 expression in both human and murine macrophages in vitro and in the lungs of mice following aerosol challenge with M. tuberculosis. The absence of IDO-1 in dendritic cells enhanced the activation of mycobacteria-specific T cells in vitro. Interestingly, IDO-1-deficiency during M. tuberculosis infection in mice was not associated with altered mycobacteria-specific T cell responses in vivo. The bacterial burden of infected organs, pulmonary inflammatory responses, and survival were also comparable in M. tuberculosis-infected IDO-1 deficient and wild type animals. Tryptophan is metabolised into either picolinic acid or quinolinic acid, but only picolinic acid inhibited the growth of M. tuberculosis in vitro. By contrast macrophages infected with pathogenic mycobacteria, produced quinolinic, rather than picolinic acid, which did not reduce M. tuberculosis growth in vitro. Therefore, although M. tuberculosis induces robust expression of IDO-1 and activation of tryptophan metabolism, IDO-1-deficiency fails to impact on the immune control and the outcome of the infection in the mouse model of tuberculosis. PMID:22649518

  19. 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

  20. Activity of KRM-1648, a new benzoxazinorifamycin, against Mycobacterium tuberculosis in a murine model.

    PubMed Central

    Klemens, S P; Grossi, M A; Cynamon, M H

    1994-01-01

    The activity of KRM-1648 was evaluated in a murine model of tuberculosis. Approximately 10(7) viable Mycobacterium tuberculosis ATCC 35801 organisms were given intravenously to 4-week-old female outbred mice. Treatment was started 1 week postinfection and given by gavage for 4 weeks. Viable-cell counts were determined from homogenates of spleen and lung tissues. The activity of KRM-1648 was compared with those of rifampin and rifabutin at 20 mg/kg of body weight. KRM-1648 was more active than either rifampin or rifabutin against organisms in spleens and lungs. KRM-1648 alone and in combination with either isoniazid, ethambutol, pyrazinamide, or levofloxacin was evaluated. Other treatment groups received isoniazid, ethambutol, pyrazinamide, or levofloxacin as single agents. KRM-1648 was the most active single agent evaluated. KRM-1648-pyrazinamide and KRM-1648-isoniazid were the most active combinations. These combinations were more active than KRM-1648 alone. The promising activity of KRM-1648 in M. tuberculosis-infected mice suggests that it is a good candidate for clinical development as a new antituberculosis agent. PMID:7840552

  1. 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.

  2. Activity against multidrug-resistant Mycobacterium tuberculosis in Mexican plants used to treat respiratory diseases.

    PubMed

    Jimenez-Arellanes, Adelina; Meckes, Mariana; Ramirez, Raquel; Torres, Javier; Luna-Herrera, Julieta

    2003-09-01

    The increase of multidrug-resistant Mycobacterium tuberculosis (MDR-TB) demands the search for alternative antimycobacterial drugs. The aim of this study was to evaluate plants used in Mexican traditional medicine to treat respiratory diseases for activity against MDR-TB. A group of 22 plants was screened for activity against Mycobacterium tuberculosis H37Rv and Mycobacterium avium at concentrations from 50 to 200 microg/mL. The antimycobacterial effect was determined by a microcolorimetric assay with Alamar blue dye. None of the aqueous extracts had antimycobacterial activity. Hexane extracts from Artemisia ludoviciana, Chamaedora tepejilote, Lantana hispida, Juniperus communis and Malva parviflora, and methanol extracts from Artemisia ludoviciana and Juniperus communis inhibited the growth of Mycobacterium tuberculosis. Mycobacterium avium was inhibited by Juniperus communis hexane extract and by Malva parviflora methanol extract. The active extracts were tested against monoresistant variants of Mycobacterium tuberculosis H37Rv (isoniazid, rifampin, streptomycin and ethambutol resistant) and the hexane extract of Lantana hispida showed the best activity. Lantana hispida hexane extract was also active against a group of MDR-TB clinical isolates. In contrast, it did not inhibit the growth of non-tuberculous mycobacteria. The hexane extract of Lantana hispida was fractionated by column chromatography and one of its fractions (FVI) inhibited the growth of all the MDR-TB clinical isolates at concentrations up to 25 microg/mL. This study supports the fact that selecting plants by ethnobotanical criteria enhances the probability of finding species with activity against mycobacteria, and our results point to Lantana hispida as an important source of potential compounds against MDR-TB. PMID:13680821

  3. Over-expression of thymosin ?4 in granulomatous lung tissue with active pulmonary tuberculosis.

    PubMed

    Kang, Yun-Jeong; Jo, Jin-Ok; Ock, Mee Sun; Yoo, Young-Bin; Chun, Bong-Kwon; Oak, Chul-Ho; Cha, Hee-Jae

    2014-05-01

    Recent studies have shown that thymosin ?4 (T?4) stimulates angiogenesis by inducing vascular endothelial growth factor (VEGF) expression and stabilizing hypoxia inducible factor-1? (HIF-1?) protein. Pulmonary tuberculosis (TB), a type of granulomatous disease, is accompanied by intense angiogenesis and VEGF levels have been reported to be elevated in serum or tissue inflamed by pulmonary tuberculosis. We investigated the expression of T?4 in granulomatous lung tissues at various stages of active pulmonary tuberculosis, and we also examined the expression patterns of VEGF and HIF-1? to compare their T?4 expression patterns in patients' tissues and in the tissue microarray of TB patients. T?4 was highly expressed in both granulomas and surrounding lymphocytes in nascent granulomatous lung tissue, but was expressed only surrounding tissues of necrotic or caseous necrotic regions. The expression pattern of HIF-1? was similar to that of T?4. VEGF was expressed in both granulomas and blood vessels surrounding granulomas. The expression pattern of VEGF co-localized with CD31 (platelet endothelial cell adhesion molecule, PECAM-1), a blood endothelial cell marker, and partially co-localized with T?4. However, the expression of T?4 did not co-localize with alveolar macrophages. Stained alveolar macrophages were present surrounding regions of granuloma highly expressing T?4. We also analyzed mRNA expression in the sputum of 10 normal and 19 pulmonary TB patients. Expression of T?4 was significantly higher in patients with pulmonary tuberculosis than in normal controls. These data suggest that T?4 is highly expressed in granulomatous lung tissue with active pulmonary TB and is associated with HIF-1?- and VEGF-mediated inflammation and angiogenesis. Furthermore, the expression of T?4 in the sputum of pulmonary tuberculosis patients can be used as a potential marker for diagnosis. PMID:24556076

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

    PubMed Central

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

    2013-01-01

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

  5. Please answer all of the following questions: 1. Have you ever had close contact with persons known or suspected to have active TB? o Yes o No

    E-print Network

    Rhode Island, University of

    settings (e.g., correctional o Yes o No facilities, long-term care facilities, and homeless shelters)? 3 of the subsequent semester. Please have your health care provider complete the en- closed Yellow TB Risk Assessment or suspected to have active TB? o Yes o No 2. Have you been a resident and/or employee of high-risk congregate

  6. The activity of low-clearance liposomal amikacin in experimental murine tuberculosis.

    PubMed

    Dhillon, J; Fielding, R; Adler-Moore, J; Goodall, R L; Mitchison, D

    2001-12-01

    Most of the amikacin in low-clearance liposomal amikacin is excreted very slowly, offering the possibility of maintaining effective treatment of pulmonary tuberculosis with widely separated supervised doses. As a preliminary to explorations in humans, its efficacy was assessed in acute experimental murine tuberculosis by weekly counts of viable bacilli in spleen and lungs over a 4 week period. Liposomal amikacin in dosages of 160, 80 and 40 mg/kg given iv three times a week was 2.4-5.0 times more active than free amikacin and 6.6-6.7 times more active than streptomycin with the non-liposomal drugs given im five times a week. When the free amikacin and the streptomycin were also given iv three times a week, liposomal amikacin was 2.7-2.9 times more active than free amikacin and 3.7-5.6 more active than streptomycin. In a model of chronic tuberculosis, initial BCG vaccination was followed by challenge with virulent Mycobacterium tuberculosis and a 2 week stabilization period. Thereafter, treatment with liposomal amikacin 160 and 80 mg/kg three times a week for the first 4 weeks and then once a week for a further 4 weeks, had greater initial bactericidal activity than free amikacin 160 mg/kg five times a week, but had less eventual sterilizing activity than five times a week oral isoniazid 25 mg/kg or rifampicin 15 mg/kg. Although low-clearance liposomes increased the safety, potency and dosing interval of amikacin in these models, all aminoglycosides, including liposomal amikacin, were only bactericidal in the presence of bacillary metabolism and growth. PMID:11733471

  7. Tuberculosis Exposure Control 1.0 BACKGROUND

    E-print Network

    de Lijser, Peter

    1 Tuberculosis Exposure Control 1.0 BACKGROUND Since 1985, the rate of new cases of tuberculosis, more than 26,000 new cases of active tuberculosis were reported in the US. In New York City alone, 3,700 cases of active tuberculosis were reported in 1991. Tuberculosis is a contagious disease that causes

  8. In Vitro and In Vivo Activities of Moxifloxacin and Clinafloxacin against Mycobacterium tuberculosis

    Microsoft Academic Search

    BAOHONG JI; NACER LOUNIS; CAROLINE MASLO; CHANTAL TRUFFOT-PERNOT; PASCALE BONNAFOUS; JACQUES GROSSET

    On 10% oleic acid-albumin-dextrose-catalase-enriched 7H11 agar medium, the MIC at which 90% of the isolates are inhibited for 20 strains of Mycobacterium tuberculosis was 0.5 mg of sparfloxacin (SPFX) or moxifloxacin (MXFX) per ml and 1.0 mg of clinafloxacin (CNFX) per ml, indicating that the in vitro activities of SPFX and MXFX were virtually identical and were slightly greater than

  9. 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

  10. In vitro and in vivo activities of the nitroimidazole CGI 17341 against Mycobacterium tuberculosis.

    PubMed Central

    Ashtekar, D R; Costa-Perira, R; Nagrajan, K; Vishvanathan, N; Bhatt, A D; Rittel, W

    1993-01-01

    CGI 17341 (2-ethyl-5-nitro-2,3-dihydro[2-1b]imidazo-oxazole) is a novel orally active representative of the 5-nitroimidazole series of antimicrobial agents. At concentrations ranging from 0.1 to 0.3 micrograms/ml, CGI 17341 inhibited the drug-susceptible and multi-drug-resistant strains of Mycobacterium tuberculosis. CGI 17341 had no cross-resistance with isoniazid, rifampin, streptomycin, or ethambutol. While the in vitro activity of CGI 17341 against M. tuberculosis was comparable to those of isoniazid and rifampin, it was superior to those of streptomycin, ciprofloxacin or norfloxacin, and oxazolidinone DuP 721. The MIC of CGI 17341 was not affected when the pH of the medium was decreased from 6.8 to 5.6, while four- to sixfold increases in the MICs of ciprofloxacin and isoniazid were observed. In mice infected with M. tuberculosis, the 50% effective dose for CGI 17341 was 7.7 mg/kg of body weight (95% confidence limits, 3.5 and 10.27) when administered on days 11 and 12 postinfection. CGI 17341 gave a dose-dependent (r = 0.995) and significant increase in the survival time. Our data indicate that the 5-nitroimidazole CGI 17341 is a promising and novel antituberculosis compound with potent in vitro and in vivo activities. Further investigations on this compound are warranted. PMID:8452346

  11. 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

  12. 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

  13. Measurement of Phenotype and Absolute Number of Circulating Heparin-Binding Hemagglutinin, ESAT-6 and CFP-10, and Purified Protein Derivative Antigen-Specific CD4 T Cells Can Discriminate Active from Latent Tuberculosis Infection.

    PubMed

    Hutchinson, Paul; Barkham, Timothy M S; Tang, Wenying; Kemeny, David M; Chee, Cynthia Bin-Eng; Wang, Yee T

    2015-02-01

    The tuberculin skin test (TST) and interferon gamma (IFN-?) release assays (IGRAs) are used as adjunctive tests for the evaluation of suspected cases of active tuberculosis (TB). However, a positive test does not differentiate latent from active TB. We investigated whether flow cytometric measurement of novel combinations of intracellular cytokines and surface makers on CD4 T cells could differentiate between active and latent TB after stimulation with Mycobacterium tuberculosis-specific proteins. Blood samples from 60 patients referred to the Singapore Tuberculosis Control Unit for evaluation for active TB or as TB contacts were stimulated with purified protein derivative (PPD), ESAT-6 and CFP-10, or heparin-binding hemagglutinin (HBHA). The CD4 T cell cytokine response (IFN-?, interleukin-2 [IL-2], interleukin-17A [IL-17A], interleukin-22 [IL-22], granulocyte-macrophage colony-stimulating factor [GM-CSF], and tumor necrosis factor alpha [TNF-?]) and surface marker expression (CD27, CXCR3, and CD154) were then measured. We found that the proportion of PPD-specific CD4 T cells, defined as CD154(+) TNF-?(+) cells that were negative for CD27 and positive for GM-CSF, gave the strongest discrimination between subjects with latent and those with active TB (area under the receiver operator characteristic [ROC] curve of 0.9277; P < 0.0001). Also, the proportions and absolute numbers of HBHA-specific CD4 T cells were significantly higher in those with latent TB infection, particularly CD154(+) TNF-?(+) IFN-?(+) IL-2(+) and CD154(+) TNF-?(+) CXCR3(+). Finally, we found that the ratio of ESAT-6- and CFP-10-responding to HBHA-responding CD4 T cells was significantly different between the two study populations. In conclusion, we found novel markers of M. tuberculosis-specific CD4 cells which differentiate between active and latent TB. PMID:25520147

  14. In Vitro Activity of AZD5847 against Geographically Diverse Clinical Isolates of Mycobacterium tuberculosis

    PubMed Central

    Wijkander, Maria; Perskvist, Nasrin; Balasubramanian, V.; Sambandamurthy, Vasan K.; Hoffner, Sven

    2014-01-01

    The MIC of the novel antituberculosis (anti-TB) drug AZD5847 was determined against 146 clinical isolates from diverse geographical regions, including eastern Europe, North America, Africa, and Asia, using the automated Bactec Mycobacterial Growth Indicator Tube (MGIT) 960 system. These isolates originated from specimen sources such as sputum, bronchial alveolar lavage fluid, pleural fluid, abscess material, lung biopsies, and feces. The overall MIC90 was 1.0 mg/liter (range, 0.125 to 4 mg/liter). The MICs of AZD5847 for isolates of Mycobacterium tuberculosis were similar among drug-sensitive strains, multidrug-resistant (MDR) strains, and extensively drug resistant (XDR) strains. The good in vitro activity of AZD5847 against M. tuberculosis and the lack of cross-resistance make this agent a promising anti-TB drug candidate. PMID:24777103

  15. Crystal Structure and Activity Studies of the Mycobacterium tuberculosis ?-Lactamase Reveal Its Critical Role in Resistance to ?-Lactam Antibiotics

    PubMed Central

    Wang, Feng; Cassidy, Craig; Sacchettini, James C.

    2006-01-01

    ?-Lactam antibiotics are extremely effective in disrupting the synthesis of the bacterial cell wall in both gram-positive and gram-negative bacteria. However, they are ineffective against Mycobacterium tuberculosis, due to the production of a ?-lactamase enzyme encoded on the chromosome of M. tuberculosis that degrades these antibiotics. Indeed, recent studies have demonstrated that deletion of the blaC gene, the only gene encoding a ?-lactamase in M. tuberculosis, or inhibition of the encoded enzyme resulted in significantly increased sensitivity to ?-lactam antibiotics. In this paper we present a biochemical and structural characterization of M. tuberculosis BlaC. Recombinant BlaC shows a broad range of specificity with almost equal penicillinase and cepholothinase activity. While clavulanate is a mechanism-based inhibitor to class A ?-lactamase with high potency (typically Ki < 0.1 ?M), it is a relatively poor inhibitor of the M. tuberculosis BlaC (Ki = 2.4 ?M). The crystal structure of the enzyme, determined at a resolution of 1.7 Å, shows that the overall fold of the M. tuberculosis enzyme is similar to other class A ?-lactamases. There are, however, several distinct features of the active site, such as the amino acid substitutions N132G, R164A, R244A, and R276E, that explain the broad specificity of the enzyme, relatively low penicillinase activity, and resistance to clavulanate. PMID:16870770

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

    PubMed Central

    2014-01-01

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

  17. 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

  18. Whole body MR imaging in ankylosing spondylitis: a descriptive pilot study in patients with suspected early and active confirmed ankylosing spondylitis

    PubMed Central

    Weber, Ulrich; Pfirrmann, Christian WA; Kissling, Rudolf O; Hodler, Juerg; Zanetti, Marco

    2007-01-01

    Background Ankylosing spondylitis is a chronic inflammatory rheumatic disorder which usually begins in early adulthood. The diagnosis is often delayed by many years. MR imaging has become the preferred imaging method for detection of early inflammation of the axial skeleton in ankylosing spondylitis. The goal of this study was to assess the frequency and distribution of abnormalities on whole body MR imaging in patients with suspected early ankylosing spondylitis and with active confirmed ankylosing spondylitis. Methods Ten patients with suspected early ankylosing spondylitis and ten patients with confirmed ankylosing spondylitis were enrolled. On an 18-channel MR system, coronal and sagittal T1 weighted and STIR sequences were acquired covering the entire spine, sacrum, anterior chest wall, shoulder girdle, and pelvis. The total examination time was 30 minutes. Results In both groups inflammatory lesions of the lower thoracic spine were frequent (number of patients with suspected early/confirmed ankylosing spondylitis: 7/9). In confirmed ankylosing spondylitis the upper thoracic spine (3/6) and the lumbar spine (4/8) were more commonly involved. The inferior iliac quadrant of the sacroiliac joints was frequently altered in both groups (8/8). The superior iliac (2/5), inferior sacral (6/10) and superior sacral (3/6) quadrants were more frequently affected in confirmed ankylosing spondylitis. Abnormalities of the manubriosternal joint (2/4), the sternoclavicular joints (1/2) and hip joint effusion (4/3) were also seen. Conclusion In both suspected early ankylosing spondylitis and confirmed ankylosing spondylitis, whole body MR examinations frequently demonstrate inflammatory lesions outside the sacroiliac joints. These lesions are similarly distributed but occur less frequently in suspected early compared to confirmed ankylosing spondylitis. Due to the small sample size in this pilot study these results need to be confirmed in larger studies with this emerging technique. PMID:17326845

  19. Whole-Blood Flow-Cytometric Analysis of Antigen-Specific CD4 T-Cell Cytokine Profiles Distinguishes Active Tuberculosis from Non-Active States

    Microsoft Academic Search

    Urban Sester; Mathias Fousse; Jan Dirks; Ulrich Mack; Antje Prasse; Mahavir Singh; Ajit Lalvani; Martina Sester; T. Mark Doherty

    2011-01-01

    T-cell based IFN-? release assays do not permit distinction of active tuberculosis (TB) from successfully treated disease or latent M. tuberculosis infection. We postulated that IFN-? and IL-2 cytokine profiles of antigen-specific T cells measured by flow-cytometry ex vivo might correlate with TB disease activity in vivo. Tuberculin (PPD), ESAT-6 and CFP-10 were used as stimuli to determine antigen-specific cytokine

  20. Pulmonary tuberculosis

    MedlinePLUS

    Pulmonary tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (M. tuberculosis) . You can get TB by breathing ... chap 332. Fitzgerald DW, Sterling TR, Haas DW. Mycobacterium tuberculosis . In: Mandell GL, Bennett JE, Dolan R, eds. ...

  1. Early Bactericidal Activity and Pharmacokinetics of PA-824 in Smear-Positive Tuberculosis Patients? †

    PubMed Central

    Diacon, Andreas H.; Dawson, Rodney; Hanekom, Madeleine; Narunsky, Kim; Maritz, Stefan J.; Venter, Amour; Donald, Peter R.; van Niekerk, Christo; Whitney, Karl; Rouse, Doris J.; Laurenzi, Martino W.; Ginsberg, Ann M.; Spigelman, Melvin K.

    2010-01-01

    PA-824 is a novel nitroimidazo-oxazine being evaluated for its potential to improve tuberculosis (TB) therapy. This randomized study evaluated safety, tolerability, pharmacokinetics, and extended early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive, adult pulmonary tuberculosis patients. Fifteen patients per cohort received 1 of 4 doses of oral PA-824: 200, 600, 1,000, or 1,200 mg per day for 14 days. Eight subjects received once daily standard antituberculosis treatment as positive control. The primary efficacy endpoint was the mean rate of change in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log10 CFU/day/ml (± standard deviation [SD]). The drug demonstrated increases that were dose linear but less than dose proportional in serum concentrations in doses from 200 to 1,000 mg daily. Dosing of 1,200 mg gave no additional exposure compared to 1,000 mg daily. The mean daily CFU fall under standard treatment was 0.148 (±0.055), consistent with that found in previous studies. The mean daily fall under PA-824 was 0.098 (±0.072) and was equivalent for all four dosages. PA-824 appeared safe and well tolerated; the incidence of adverse events potentially related to PA-824 appeared dose related. We conclude that PA-824 demonstrated bactericidal activity over the dose range of 200 to 1,200 mg daily over 14 days. Because maximum efficacy was unexpectedly achieved at the lowest dosage tested, the activity of lower dosages should now be explored. PMID:20498324

  2. Mycobacterium tuberculosis protein ESAT-6 is a potent activator of the NLRP3/ASC inflammasome.

    PubMed

    Mishra, Bibhuti B; Moura-Alves, Pedro; Sonawane, Avinash; Hacohen, Nir; Griffiths, Gareth; Moita, Luis F; Anes, Elsa

    2010-08-01

    Interleukin-1beta (IL-1beta) represents one of the most important mediators of inflammation and host responses to infection. Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, induces IL-1beta secretion at the site of infection, but the underlying mechanism(s) are poorly understood. In this work we show that Mtb infection of macrophages stimulates caspase-1 activity and promotes the secretion of IL-1beta. This stimulation requires live intracellular bacteria expressing a functional ESX-1 secretion system. ESAT-6, an ESX-1 substrate implicated in membrane damage, is both necessary and sufficient for caspase-1 activation and IL-1beta secretion. ESAT-6 promotes the access of other immunostimulatory agents such as AG85 into the macrophage cytosol, indicating that this protein may contribute to caspase-1 activation largely by perturbing host cell membranes. Using a high-throughput shRNA-based screen we found that numerous NOD-like receptors (NLRs) and CARD domain-containing proteins (CARDs) were important for IL-1beta secretion upon Mtb infection. Most importantly, NLRP3, ASC and caspase-1 form an infection-inducible inflammasome complex that is essential for IL-1beta secretion. In summary, we show that recognition of Mtb infection by the NLRP3 inflammasome requires the activity of the bacterial virulence factor ESAT-6, and the subsequent IL-1beta response is regulated by a number of NLR/CARD proteins. PMID:20148899

  3. Synthesis and Anti-Tuberculosis Activity of the Marine Natural Product Caulerpin and Its Analogues

    PubMed Central

    Canché Chay, Cristina I.; Gómez Cansino, Rocío; Espitia Pinzón, Clara I.; Torres-Ochoa, Rubén O.; Martínez, Roberto

    2014-01-01

    Caulerpin (1a), a bis-indole alkaloid from the marine algal Caulerpa sp., was synthesized in three reaction steps with an overall yield of 11%. The caulerpin analogues (1b–1g) were prepared using the same synthetic pathway with overall yields between 3% and 8%. The key reaction involved a radical oxidative aromatic substitution involving xanthate (3) and 3-formylindole compounds (4a–4g). All bis-indole compounds synthesized were evaluated against the Mycobacterium tuberculosis strain H37Rv, and 1a was found to display excellent activity (IC50 0.24 µM). PMID:24681629

  4. 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

  5. Carcinoma of the Lung and Coexistent Active Pulmonary Tuberculosis: Diverse Morphologic and Radiographic Presentations

    PubMed Central

    Phillips, Lloyd G.; Cunningham, John; Hillman, Nosrat M.; Lewis, Jeanne

    1984-01-01

    Five patients with coexistent carcinoma of the lung and active tuberculosis within the same pulmonary lesion were studied. These cases represent five distinctly varying radiographic presentations and point out the extreme diversity of the morphological pictures of this particular disease combination. Physicians who regularly deal with patients who might present with either entity alone are cautioned to be alert to the possibility that these two diseases may be present simultaneously within single, specific pulmonary lesions. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5 PMID:6708120

  6. The MprB Extracytoplasmic Domain Negatively Regulates Activation of the Mycobacterium tuberculosis MprAB Two-Component System

    PubMed Central

    Bretl, Daniel J.; Bigley, Tarin M.; Terhune, Scott S.

    2014-01-01

    Mycobacterium tuberculosis is an acid-fast pathogen of humans and the etiological agent of tuberculosis (TB). It is estimated that one-third of the world's population is latently (persistently) infected with M. tuberculosis. M. tuberculosis persistence is regulated, in part, by the MprAB two-component signal transduction system, which is activated by and mediates resistance to cell envelope stress. Here we identify MprAB as part of an evolutionarily conserved cell envelope stress response network and demonstrate that MprAB-mediated signal transduction is negatively regulated by the MprB extracytoplasmic domain (ECD). In particular, we report that deregulated production of the MprB sensor kinase, or of derivatives of this protein, negatively impacts M. tuberculosis growth. The observed growth attenuation is dependent on MprAB-mediated signal transduction and is exacerbated in strains of M. tuberculosis producing an MprB variant lacking its ECD. Interestingly, full-length MprB, and the ECD of MprB specifically, immunoprecipitates the Hsp70 chaperone DnaK in vivo, while overexpression of dnaK inhibits MprAB-mediated signal transduction in M. tuberculosis grown in the absence or presence of cell envelope stress. We propose that under nonstress conditions, or under conditions in which proteins present in the extracytoplasmic space are properly folded, signaling through the MprAB system is inhibited by the MprB ECD. Following exposure to cell envelope stress, proteins present in the extracytoplasmic space become unfolded or misfolded, leading to removal of the ECD-mediated negative regulation of MprB and subsequent activation of MprAB. PMID:24187094

  7. 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

  8. Diagnostic utility of anti-cyclic citrullinated peptide antibodies for rheumatoid arthritis in patients with active lung tuberculosis

    Microsoft Academic Search

    Shunsuke Mori; Hiromichi Naito; Sumire Ohtani; Tohru Yamanaka; Mineharu Sugimoto

    2009-01-01

    This study was intended to evaluate the utility of anti-cyclic citrullinated peptide antibodies (second generation, anti-CCP2)\\u000a as a diagnostic marker for rheumatoid arthritis (RA) in patients with active tuberculosis. Among 89 patients with active tuberculosis,\\u000a anti-CCP2 was detected in six (6.7%), and three of these (3.4%) were strongly positive for anti-CCP2. The positive rate of\\u000a anti-CCP2 in patients with newly

  9. The Two PPX-GppA Homologues from Mycobacterium tuberculosis Have Distinct Biochemical Activities

    PubMed Central

    Choi, Mei Y.; Wang, Ying; Wong, Leo L. Y.; Lu, Bing-tai; Chen, Wen-yang; Huang, Jian-Dong; Tanner, Julian A.; Watt, Rory M.

    2012-01-01

    Inorganic polyphosphate (poly-P), guanosine pentaphosphate (pppGpp) and guanosine tetraphosphate (ppGpp) are ubiquitous in bacteria. These molecules play a variety of important physiological roles associated with stress resistance, persistence, and virulence. In the bacterial pathogen Mycobacterium tuberculosis, the identities of the proteins responsible for the metabolism of polyphosphate and (p)ppGpp remain to be fully established. M. tuberculosis encodes two PPX-GppA homologues, Rv0496 (MTB-PPX1) and Rv1026, which share significant sequence similarity with bacterial exopolyphosphatase (PPX) and guanosine pentaphosphate 5?-phosphohydrolase (GPP) proteins. Here we delineate the respective biochemical activities of the Rv0496 and Rv1026 proteins and benchmark these against the activities of the PPX and GPP proteins from Escherichia coli. We demonstrate that Rv0496 functions as an exopolyphosphatase, showing a distinct preference for relatively short-chain poly-P substrates. In contrast, Rv1026 has no detectable exopolyphosphatase activities. Analogous to the E. coli PPX and GPP enzymes, the exopolyphosphatase activities of Rv0496 are inhibited by pppGpp and, to a lesser extent, by ppGpp alarmones, which are produced during the bacterial stringent response. However, neither Rv0496 nor Rv1026 have the ability to hydrolyze pppGpp to ppGpp; a reaction catalyzed by E. coli PPX and GPP. Both the Rv0496 and Rv1026 proteins have modest ATPase and to a lesser extent ADPase activities. pppGpp alarmones inhibit the ATPase activities of Rv1026 and, to a lesser extent, the ATPase activities of Rv0496. We conclude that PPX-GppA family proteins may not possess all the catalytic activities implied by their name and may play distinct biochemical roles involved in polyphosphate and (p)ppGpp metabolic pathways. PMID:22880033

  10. Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis

    E-print Network

    tuberculosis H37Rv and the b-Ketoacyl-ACP Synthase mtFabH Qosay Al-Balas1 , Nahoum G. Anthony1 , Bilal Al of Birmingham, Edgebaston, Birmingham, United Kingdom Abstract Background: Tuberculosis (TB) is a disease which. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance

  11. 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.

  12. HIV Infection Does Not Affect Active Case Finding of Tuberculosis in South African Gold Miners

    PubMed Central

    Lewis, James J.; Charalambous, Salome; Day, John H.; Fielding, Katherine L.; Grant, Alison D.; Hayes, Richard J.; Corbett, Elizabeth L.; Churchyard, Gavin J.

    2009-01-01

    Rationale: Gold miners in South Africa undergo annual radiological screening for tuberculosis in an occupational health center of a gold mining company, but the optimal screening algorithm is unclear. Objectives: To evaluate methods for active case detection of tuberculosis. Methods: A sequential sample of miners attending annual medical examination was screened for tuberculosis using a symptom questionnaire, chest radiograph, and two sputum specimens for microscopy and culture. Measurements and Main Results: There were 1,955 miners included in this study; all were male with a median age of 41 years (range, 20–61 yr). Presence of at least one of a trio of symptoms (new or worsening cough, night sweats, or weight loss) had similar sensitivity (29.4%) to either chest radiograph (25.5%) or sputum smear (25.5%). These sensitivities did not differ by HIV status. Presence of one or more elements of the symptom trio and/or new radiological abnormality substantially increased sensitivity to 49.0%. Specificity of the symptom trio was higher in HIV-uninfected (91.8%) than in HIV-infected persons (88.2%; P = 0.018). Specificity of chest radiography and smear were similar (98.7% and 99.0%, respectively) and did not differ by HIV status (both P values > 0.8). Conclusions: In a population of gold miners who undergo regular radiological screening, the addition of chest radiography to symptom screening substantially improved the sensitivity and positive predictive value. HIV infection did not alter the sensitivity of the screening tool. PMID:19745207

  13. Evaluation of the anti-mycobacterium tuberculosis activity and in vivo acute toxicity of Annona sylvatic

    PubMed Central

    2014-01-01

    Background The recent emergence of extensively multidrug-resistant Mycobacterium tuberculosis strains has further complicated the control of tuberculosis. There is an urgent need for the development of new molecular candidates antitubercular drugs. Medicinal plants have been an excellent source of leads for the development of drugs. The aim of this study was to evaluate the in vitro activity of 28 alcoholic extracts and essential oils of native and exotic Brazilian plants against Mycobacterium tuberculosis and to further study these extracts through chemical fractionation, the isolation of their constituents, and an evaluation of the in vivo acute toxicity of the active extracts. To the best of our knowledge this is the first chemical characterization, antituberculosis activity and acute toxicity evaluation of Annona sylvatica. Methods The anti-mycobacterial activity of these extracts and their constituent compounds was evaluated using the resazurin reduction microtiter assay (REMA). To investigate the acute toxicity of these extracts in vivo, female Swiss mice were treated with the extracts at doses of 500, 1000 and 2000 mg?·?kg-1 of body weight. The extracts were characterized by LC-MS, and the constituents were isolated and identified by chromatographic analysis of spectroscopic data. Results Of the 28 extracts, the methanol extract obtained from the leaves of Annona sylvatica showed anti-mycobacterial activity with an minimal inhibitory concentration (MIC) of 184.33 ?g/mL, and the ethyl acetate fraction (EAF) resulting from liquid-liquid partitioning of the A. sylvatica extract showed an MIC of 115.2 ?g/mL. The characterization of this extract by LC-MS identified flavonoids and acetogenins as its main constituents. The phytochemical study of the A. sylvatica EAF resulted in the isolation of quercetin, luteolin, and almunequin. Conclusions Among the compounds isolated from the EAF, luteolin and almunequin were the most promising, with MICs of 236.8 ?g/mL (827.28 ?M) and 209.9 ?g/mL (328.48 ?M), respectively. The acute administration of the EAF fraction in doses of 500, 1000, and 2000 mg?·?kg-1 of body weight did not cause signs of toxicity in the treated animals. PMID:24974069

  14. Hypoxia triggers the expression of human ? defensin 2 and antimicrobial activity against Mycobacterium tuberculosis in human macrophages.

    PubMed

    Nickel, Daniel; Busch, Martin; Mayer, Daniel; Hagemann, Benjamin; Knoll, Valeska; Stenger, Steffen

    2012-04-15

    Low oxygen tension is a metabolic hallmark of chronic infection. To investigate the influence of hypoxia on macrophage biology, we analyzed the interaction between the intracellular pathogen Mycobacterium tuberculosis and primary human macrophages. Although the metabolic activity of extracellular M. tuberculosis was reduced at oxygen levels between 0.5 and 10%, the bacilli remained viable throughout the 4 d of culture. Phagocytosis of virulent M. tuberculosis and the pathogen-induced release of inflammatory cytokines by macrophages were not affected by oxygen levels as low as 1%. However, we detected the upregulation of an antimicrobial effector pathway mediated by the vitamin D receptor and human ? defensin 2. This finding was functionally relevant, because intracellular mycobacterial growth was inhibited by 58 ± 8% at 1% O(2). We conclude that a hypoxic microenvironment, which is characteristic of infected tissue, supports the efficacy of antimicrobial immunity, in part by the upregulation of the antimicrobial peptide human ? defensin 2. PMID:22427634

  15. Novel Conjugate of Moxifloxacin and Carboxymethylated Glucan with Enhanced Activity against Mycobacterium tuberculosis

    PubMed Central

    Schwartz, Y. S.; Dushkin, M. I.; Vavilin, V. A.; Melnikova, E. V.; Khoschenko, O. M.; Kozlov, V. A.; Agafonov, A. P.; Alekseev, A. Y.; Rassadkin, Y.; Shestapalov, A. M.; Azaev, M. S.; Saraev, D. V.; Filimonov, P. N.; Kurunov, Y.; Svistelnik, A. V.; Krasnov, V. A.; Pathak, A.; Derrick, S. C.; Reynolds, R. C.; Morris, S.; Blinov, V. M.

    2006-01-01

    Mycobacterium tuberculosis is an intracellular pathogen that persists within macrophages of the human host. One approach to improving the treatment of tuberculosis (TB) is the targeted delivery of antibiotics to macrophages using ligands to macrophage receptors. The moxifloxacin-conjugated dansylated carboxymethylglucan (M-DCMG) conjugate was prepared by chemically linking dansylcadaverine (D) and moxifloxacin (M) to carboxymethylglucan (CMG), a known ligand of macrophage scavenger receptors. The targeted delivery to macrophages and the antituberculosis activity of the conjugate M-DCMG were studied in vitro and in vivo. Using fluorescence microscopy, fluorimetry, and the J774 macrophage cell line, M-DCMG was shown to accumulate in macrophages through scavenger receptors in a dose-dependent (1 to 50 ?g/ml) manner. After intravenous administration of M-DCMG into C57BL/6 mice, the fluorescent conjugate was concentrated in the macrophages of the lungs and spleen. Analyses of the pharmacokinetics of the conjugate demonstrated that M-DCMG was more rapidly accumulated and more persistent in tissues than free moxifloxacin. Importantly, therapeutic studies of mycobacterial growth in C57BL/6 mice showed that the M-DCMG conjugate was significantly more potent than free moxifloxacin. PMID:16723555

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

    PubMed

    Magombedze, Gesham; Mulder, Nicola

    2012-01-01

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

  17. 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

  18. C4-Alkylthiols with activity against Moraxella catarrhalis and Mycobacterium tuberculosis

    PubMed Central

    Kostova, Maya B.; Myers, Carey J.; Beck, Tim N.; Plotkin, Balbina J.; Green, Jacalyn M.; Boshoff, Helena I.M.; Barry, Clifton E.; Deschamps, Jeffrey R.; Konaklieva, Monika I.

    2013-01-01

    Antimicrobial resistance represents a global threat to healthcare. The ability to adequately treat infectious diseases is increasingly under siege due to the emergence of drug-resistant microorganisms. New approaches to drug development are especially needed to target organisms that exhibit broad antibiotic resistance due to expression of ?-lactamases which is the most common mechanism by which bacteria become resistant to ?-lactam antibiotics. We designed and synthesized 20 novel monocyclic ?-lactams with alkyl- and aryl-thio moieties at C4, and subsequently tested these for antibacterial activity. These compounds demonstrated intrinsic activity against serine ?-lactamase producing Mycobacterium tuberculosis wild type strain (Mtb) and multiple (n = 6) ?-lactamase producing Moraxella catarrhalis clinical isolates. PMID:22014754

  19. Mycobacterium tuberculosis Multidrug Resistant Strain M Induces an Altered Activation of Cytotoxic CD8+ T Cells

    PubMed Central

    Geffner, Laura; Kviatcovsky, Denise; Sabio y García, Carmen; Ritacco, Viviana; López, Beatriz; Sasiain, María del Carmen; de la Barrera, Silvia

    2014-01-01

    In human tuberculosis (TB), CD8+ T cells contribute to host defense by the release of Th1 cytokines and the direct killing of Mycobacterium tuberculosis (Mtb)-infected macrophages via granule exocytosis pathway or the engagement of receptors on target cells. Previously we demonstrated that strain M, the most prevalent multidrug-resistant (MDR) Mtb strain in Argentine, is a weak inducer of IFN-? and elicits a remarkably low CD8-dependent cytotoxic T cell activity (CTL). In contrast, the closely related strain 410, which caused a unique case of MDR-TB, elicits a CTL response similar to H37Rv. In this work we extend our previous study investigating some parameters that can account for this discrepancy. We evaluated the expressions of the lytic molecules perforin, granzyme B and granulysin and the chemokine CCL5 in CD8+ T cells as well as activation markers CD69 and CD25 and IL-2 expression in CD4+ and CD8+ T cells stimulated with strains H37Rv, M and 410. Our results demonstrate that M-stimulated CD8+ T cells from purified protein derivative positive healthy donors show low intracellular expression of perforin, granzyme B, granulysin and CCL5 together with an impaired ability to form conjugates with autologous M-pulsed macrophages. Besides, M induces low CD69 and IL-2 expression in CD4+ and CD8+ T cells, being CD69 and IL-2 expression closely associated. Furthermore, IL-2 addition enhanced perforin and granulysin expression as well as the degranulation marker CD107 in M-stimulated CD8+ T cells, making no differences with cells stimulated with strains H37Rv or 410. Thus, our results highlight the role of IL-2 in M-induced CTL activity that drives the proper activation of CD8+ T cells as well as CD4+ T cells collaboration. PMID:24836916

  20. Plasma Drug Activity in Patients on Treatment for Multidrug-Resistant Tuberculosis

    PubMed Central

    Mpagama, Stellah G.; Ndusilo, Norah; Stroup, Suzanne; Kumburu, Happiness; Peloquin, Charles A.; Gratz, Jean; Houpt, Eric R.; Kibiki, Gibson S.

    2014-01-01

    Little is known about plasma drug concentrations relative to quantitative susceptibility in patients with multidrug-resistant tuberculosis (MDR-TB). We previously described a TB drug activity (TDA) assay that determines the ratio of the time to detection of plasma-cocultured Mycobacterium tuberculosis versus control growth in a Bactec MGIT system. Here, we assess the activity of individual drugs in a typical MDR-TB regimen using the TDA assay. We also examined the relationship of the TDA to the drug concentration at 2 h (C2) and the MICs among adults on a MDR-TB regimen in Tanzania. These parameters were also compared to the treatment outcome of sputum culture conversion. Individually, moxifloxacin yielded superior TDA results versus ofloxacin, and only moxifloxacin and amikacin yielded TDAs equivalent to a ?2-log killing. In the 25 patients enrolled on a regimen of kanamycin, levofloxacin, ethionamide, pyrazinamide, and cycloserine, the C2 values were found to be below the expected range for levofloxacin in 13 (52%) and kanamycin in 10 (40%). Three subjects with the lowest TDA result (<1.5, a finding indicative of poor killing) had significantly lower kanamycin C2/MIC ratios than subjects with a TDA of ?1.5 (9.8 ± 8.7 versus 27.0 ± 19.1; P = 0.04). The mean TDAs were 2.52 ± 0.76 in subjects converting to negative in ?2 months and 1.88 ± 0.57 in subjects converting to negative in >2 months (P = 0.08). In Tanzania, MDR-TB drug concentrations were frequently low, and a wide concentration/MIC range was observed that affected plasma drug activity ex vivo. An opportunity exists for pharmacokinetic optimization in current MDR-TB regimens, which may improve treatment response. PMID:24247125

  1. Tuberculosis among Children in Alaska.

    ERIC Educational Resources Information Center

    Gessner, Bradford D.

    1997-01-01

    The incidence of tuberculosis among Alaskan children under 15 was more than twice the national rate, with Alaska Native children showing a much higher incidence. Children with household exposure to adults with active tuberculosis had a high risk of infection. About 22 percent of pediatric tuberculosis cases were identified through school…

  2. [Dynamics of the activity of antioxidant enzymes in the blood of patients with pulmonary tuberculosis].

    PubMed

    Safarian, M D; Karapetian, E T

    1990-01-01

    The given article deals with the results of analysing antioxidative enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GP) and glutathione reductase (GR) in the blood of pulmonary tuberculosis patients. It is demonstrated that with focal tuberculosis, lipid peroxidation rises, compensatory increase in SOD, GP and GR levels takes place. In infiltrative and disseminated tuberculosis, multidirectional changes of SOD, GP and GR levels are observed depending on a certain stage of the disease accompanied by an increased lipid peroxidation. PMID:2255703

  3. 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

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

    PubMed Central

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

    2015-01-01

    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

  5. Noninvasive Test for Tuberculosis Detection among Primates

    PubMed Central

    Mugisha, Lawrence; Shoyama, Fernanda Miyagaki; O’Malley, Melanie J.; Flynn, JoAnne L.; Asiimwe, Benon; Travis, Dominic A.; Singer, Randall S.; Sreevatsan, Srinand

    2015-01-01

    Traditional testing methods have limited epidemiologic studies of tuberculosis among free-living primates. PCR amplification of insertion element IS6110 of Mycobacterium tuberculosis from fecal samples was evaluated as a noninvasive screening test for tuberculosis in primates. Active tuberculosis was detected among inoculated macaques and naturally exposed chimpanzees, demonstrating the utility of this test. PMID:25695329

  6. 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

  7. Tuberculosis mimicking cervical carcinoma--case report.

    PubMed

    Micha, J P; Brown, J V; Birk, C; Van Horn, D; Rettenmaier, M A; Goldstein, B H

    2007-01-01

    Tuberculosis is a chronic bacterial infection that primarily results in pulmonary disease. Although there are several reported cases of extra-pulmonary tuberculosis, very few reports have described this disease in the female genital tract. We present a case involving a 67-year-old woman who presented with vaginal discharge, abdominal discomfort, and a pelvic mass in 2006. Clinically, cervical carcinoma was suspected, but pathologic diagnosis eventually revealed tuberculosis of the cervix. Tuberculosis is associated with a significant inflammatory reaction, which may mimic a gynecologic malignancy on exam or with diagnostic imaging. Despite the rare incidence, tuberculosis of the cervix should be considered in the differential diagnosis when cervical carcinoma is initially suspected. PMID:17713102

  8. Partial and ineffective activation of V gamma 9V delta 2 T cells by Mycobacterium tuberculosis-infected dendritic cells.

    PubMed

    Meraviglia, Serena; Caccamo, Nadia; Salerno, Alfredo; Sireci, Guido; Dieli, Francesco

    2010-08-01

    Gammadelta T cells and dendritic cells (DCs) participate in early phases of immune response against Mycobacterium tuberculosis. We investigated whether a close functional relationship exists between these two cell populations using an in vitro coculture in a human system. Vgamma9Vdelta2 T cells induce full maturation of M. tuberculosis-infected immature DCs, as demonstrated by upregulation of the costimulatory CD80, CD86, CD40, and HLA-DR molecules on infected DCs after 24 h of coculture. Reciprocally, infected DCs induced substantial activation of Vgamma9Vdelta2 T cells upon coculture, which was cell-to-cell contact and TCR dependent, as demonstrated in transwell experiments. However, infected DCs selectively induced proliferative, but not cytokine or cytolytic, responses of Vgamma9Vdelta2 T cells, and this was associated with the expansion of phenotypically immature, central memory-type Vgamma9Vdelta2 T cells. Importantly, expansion of central memory Vgamma9Vdelta2 T cells and reduction of the pool of Vgamma9Vdelta2 T cells with immediate effector functions (effector memory and terminally differentiated cells) were also detected in vivo in the peripheral blood of patients with active tuberculosis, which reversed after antimycobacterial therapy. M. tuberculosis-infected DCs produced many different cytokines, but not IL-15, and addition of IL-15 to cocultures of infected DCs and Vgamma9Vdelta2 T cells caused efficient differentiation of these latter with generation of effector memory and terminally differentiated cells, which were capable of reducing the viability of intracellular M. tuberculosis. Overall, this study provides a further piece of information on the complex relationship between important players of innate immunity during mycobacterial infection. PMID:20592281

  9. An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity

    PubMed Central

    Danilchanka, Olga; Sun, Jim; Pavlenok, Mikhail; Maueröder, Christian; Speer, Alexander; Siroy, Axel; Marrero, Joeli; Trujillo, Carolina; Mayhew, David L.; Doornbos, Kathryn S.; Muñoz, Luis E.; Herrmann, Martin; Ehrt, Sabine; Berens, Christian; Niederweis, Michael

    2014-01-01

    The ability to control the timing and mode of host cell death plays a pivotal role in microbial infections. Many bacteria use toxins to kill host cells and evade immune responses. Such toxins are unknown in Mycobacterium tuberculosis. Virulent M. tuberculosis strains induce necrotic cell death in macrophages by an obscure molecular mechanism. Here we show that the M. tuberculosis protein Rv3903c (channel protein with necrosis-inducing toxin, CpnT) consists of an N-terminal channel domain that is used for uptake of nutrients across the outer membrane and a secreted toxic C-terminal domain. Infection experiments revealed that CpnT is required for survival and cytotoxicity of M. tuberculosis in macrophages. Furthermore, we demonstrate that the C-terminal domain of CpnT causes necrotic cell death in eukaryotic cells. Thus, CpnT has a dual function in uptake of nutrients and induction of host cell death by M. tuberculosis. PMID:24753609

  10. The effect of anti-tuberculosis treatment on levels of anti-phospholipid and anti-neutrophil cytoplasmatic antibodies in patients with active tuberculosis.

    PubMed

    Elkayam, Ori; Bendayan, Daniele; Segal, Refael; Shapira, Yinon; Gilburd, Boris; Reuter, Sandra; Agmon-Levin, Nancy; Shoenfeld, Yehuda

    2013-04-01

    The aim of this study is to determine the prevalence and effect of anti-tuberculosis treatment on anti-phospholipid antibodies and anti-neutrophil cytoplasmatic antibodies (ANCA) in patients with active mycobacterial infections. Thirty-three consecutive patients (age 56 years, 26 males) with recently diagnosed active tuberculosis (TB) were enrolled. Data included clinical disease features, symptom duration, multidrug resistance and presence of HIV. Serum samples taken before and after TB treatment were frozen at -20 °C and tested for anti-cardiolipin IgG (aCL), anti-?2 glycoprotein IgG (anti-?2GPI), anti-prothrombin, anti-proteinase 3 (PR3), myeloperoxidase (MPO), bactericidal/permeability (BPI) and lactoferrin. Thirty percent of patients had higher than cut-off value for anti-?2GPI, and 9 % had increased aCL. The levels of antibodies against ?2GPI and aCL normalized post-treatment. A substantial proportion of patients had high baseline anti-PR3, MPO, BPI and lactoferrin levels. Most anti-lactoferrin and anti-MPO levels decreased post-treatment, while anti-PR3 increased in most of the baseline-positive patients. Some patients had de novo anti-PR3 and MPO formation after 6-month treatment. Patients with active TB have significantly increased anti-?2GPI and ANCA titers. While anti-?2GPI titers normalize post-treatment, ANCA behave in a complex way. Anti-TB treatment may induce normalization of anti-lactoferrin and anti-MPO, and de novo anti-PR3 and MPO formation. PMID:23011089

  11. 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

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

    PubMed Central

    Wang, Feng; Sambandan, Dhinakaran; Halder, Rajkumar; Wang, Jianing; Batt, Sarah M.; Weinrick, Brian; Ahmad, Insha; Yang, Pengyu; Zhang, Yong; Kim, John; Hassani, Morad; Huszar, Stanislav; Trefzer, Claudia; Ma, Zhenkun; Kaneko, Takushi; Mdluli, Khisi E.; Franzblau, Scott; Chatterjee, Arnab K.; Johnsson, Kai; Mikusova, Katarina; Besra, Gurdyal S.; Fütterer, Klaus; Robbins, Scott H.; Barnes, S. Whitney; Walker, John R.; Jacobs, William R.; Schultz, Peter G.

    2013-01-01

    A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-?-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

  13. 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

  14. 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

  15. Design and synthesis of novel antimicrobials with activity against Gram-positive bacteria and mycobacterial species, including M. tuberculosis

    PubMed Central

    Tiruveedhula, V.V.N. Phani Babu; Witzigmann, Christopher M.; Verma, Ranjit; Kabir, M. Shahjahan; Rott, Marc; Schwan, William R.; Medina-Bielski, Sara; Lane, Michelle; Close, William; Polanowski, Rebecca L.; Sherman, David; Monte, Aaron; Deschamps, Jeffrey R.; Cook, James M.

    2013-01-01

    The alarming increase in bacterial resistance over the last decade along with a dramatic decrease in new treatments for infections has led to problems in the healthcare industry. Tuberculosis (TB) is caused mainly by Mycobacterium tuberculosis which is responsible for 1.4 million deaths per year. A world-wide threat with HIV co-infected with multi and extensively drug-resistant strains of TB has emerged. In this regard, herein, novel acrylic acid ethyl ester derivatives were synthesized in simple, efficient routes and evaluated as potential agents against several Mycobacterium species. These were synthesized via a stereospecific process for structure activity relationship (SAR) studies. Minimum inhibitory concentration (MIC) assays indicated that esters 12, 13, and 20 exhibited greater in vitro activity against Mycobacterium smegmatis than rifampin, one of the current, first-line anti-mycobacterial chemotherapeutic agents. Based on these studies the acrylic ester 20 has been developed as a potential lead compound which was found to have an MIC value of 0.4 ?g/mL against Mycobacterium tuberculosis. The SAR and biological activity of this series is presented; a Michael – acceptor mechanism appears to be important for potent activity of this series of analogs. PMID:24200931

  16. Design and synthesis of novel antimicrobials with activity against Gram-positive bacteria and mycobacterial species, including M. tuberculosis.

    PubMed

    Tiruveedhula, V V N Phani Babu; Witzigmann, Christopher M; Verma, Ranjit; Kabir, M Shahjahan; Rott, Marc; Schwan, William R; Medina-Bielski, Sara; Lane, Michelle; Close, William; Polanowski, Rebecca L; Sherman, David; Monte, Aaron; Deschamps, Jeffrey R; Cook, James M

    2013-12-15

    The alarming increase in bacterial resistance over the last decade along with a dramatic decrease in new treatments for infections has led to problems in the healthcare industry. Tuberculosis (TB) is caused mainly by Mycobacterium tuberculosis which is responsible for 1.4 million deaths per year. A world-wide threat with HIV co-infected with multi and extensively drug-resistant strains of TB has emerged. In this regard, herein, novel acrylic acid ethyl ester derivatives were synthesized in simple, efficient routes and evaluated as potential agents against several Mycobacterium species. These were synthesized via a stereospecific process for structure activity relationship (SAR) studies. Minimum inhibitory concentration (MIC) assays indicated that esters 12, 13, and 20 exhibited greater in vitro activity against Mycobacterium smegmatis than rifampin, one of the current, first-line anti-mycobacterial chemotherapeutic agents. Based on these studies the acrylic ester 20 has been developed as a potential lead compound which was found to have an MIC value of 0.4 ?g/mL against Mycobacterium tuberculosis. The SAR and biological activity of this series is presented; a Michael-acceptor mechanism appears to be important for potent activity of this series of analogs. PMID:24200931

  17. Granulocytic Myeloid Derived Suppressor Cells Expansion during Active Pulmonary Tuberculosis Is Associated with High Nitric Oxide Plasma Level

    PubMed Central

    El Daker, Sary; Sacchi, Alessandra; Tempestilli, Massimo; Carducci, Claudia; Goletti, Delia; Vanini, Valentina; Colizzi, Vittorio; Lauria, Francesco Nicola; Martini, Federico; Martino, Angelo

    2015-01-01

    Tuberculosis (TB) is still the principal cause of death caused by a single infectious agent, and the balance between the bacillus and host defense mechanisms reflects the different manifestations of the pathology. The aim of this work was to study the role of myeloid-derived suppressor cells (MDSCs) during active pulmonary tuberculosis at the site of infection. We observed an expansion of MDSCs in the lung and blood of patients with active TB, which are correlated with an enhanced amount of nitric oxide in the plasma. We also found that these cells have the remarkable ability to suppress T-cell response, suggesting an important role in the modulation of the immune response against TB. Interestingly, a trend in the diminution of MDSCs was found after an efficacious anti-TB therapy, suggesting that these cells may be used as a potential biomarker for monitoring anti-TB therapy efficacy. PMID:25879532

  18. Structure of Ddn, the Deazaflavin-Dependent Nitroreductase from Mycobacterium tuberculosis Involved in Bioreductive Activation of PA-824

    PubMed Central

    Cellitti, Susan E.; Shaffer, Jennifer; Jones, David H.; Mukherjee, Tathagata; Gurumurthy, Meera; Bursulaya, Badry; Boshoff, Helena I.; Choi, Inhee; Nayyar, Amit; Lee, Yong Sok; Cherian, Joseph; Niyomrattanakit, Pornwaratt; Dick, Thomas; Manjunatha, Ujjini H.; Barry, Clifton E.; Spraggon, Glen; Geierstanger, Bernhard H.

    2012-01-01

    Summary Tuberculosis continues to be a global health threat, making bicyclic nitroimidazoles an important new class of therapeutics. A deazaflavin-dependent nitroreductase (Ddn) from Mycobacterium tuberculosis catalyzes the reduction of nitroimidazoles such as PA-824, resulting in intracellular release of lethal reactive nitrogen species. The N-terminal 30 residues of Ddn are functionally important but are flexible or access multiple conformations, preventing structural characterization of the full-length, enzymatically active enzyme. Several structures were determined of a truncated, inactive Ddn protein core with and without bound F420 deazaflavin coenzyme as well as of a catalytically competent homolog from Nocardia farcinica. Mutagenesis studies based on these structures identified residues important for binding of F420 and PA-824. The proposed orientation of the tail of PA-824 toward the N terminus of Ddn is consistent with current structure-activity relationship data. PMID:22244759

  19. 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.…

  20. Early Bactericidal Activity and Pharmacokinetics of the Diarylquinoline TMC207 in Treatment of Pulmonary Tuberculosis?

    PubMed Central

    Rustomjee, R.; Diacon, A. H.; Allen, J.; Venter, A.; Reddy, C.; Patientia, R. F.; Mthiyane, T. C. P.; De Marez, T.; van Heeswijk, R.; Kerstens, R.; Koul, A.; De Beule, K.; Donald, P. R.; McNeeley, D. F.

    2008-01-01

    Tibotec Medicinal Compound 207 (TMC207) is a novel diarylquinoline with a unique mode of action that targets mycobacterial ATP synthase. TMC207 exhibits high in vitro activity against mycobacterial strains either susceptible or resistant to all first-line and many second-line drugs, including fluoroquinolones, and has shown exceptional in vivo activity against several mycobacterial species in different animal models. In this early bactericidal activity study, 75 treatment-naïve patients with smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Sixteen-hour overnight sputum collected at baseline and on each treatment day was plated in serial dilutions on selective agar plates. The bactericidal activity was expressed as the log10 decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of TMC207 administration up to 24 h postdose. The decreases in log10 CFU counts (± standard deviation) from baseline to day 7 were 0.04 ± 0.46 for 25 mg TMC207 (n = 14), 0.26 ± 0.64 for 100 mg TMC207 (n = 14), 0.77 ± 0.58 for 400 mg TMC207 (n = 14), 1.88 ± 0.74 for INH (n = 11), and 1.70 ± 0.71 for RIF (n = 14). Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in magnitude to those of INH and RIF over the same period. The pharmacokinetics of TMC207 were linear across the dose range. In summary, TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred. PMID:18505852

  1. Moonlighting function of glutamate racemase from Mycobacterium tuberculosis: racemization and DNA gyrase inhibition are two independent activities of the enzyme

    Microsoft Academic Search

    Sugopa Sengupta; Soumitra Ghosh; Valakunja Nagaraja

    2008-01-01

    Glutamate racemase (MurI) provides D-glutamate, a key building block in the peptidoglycan of the bacterial cell wall. Besides having a crucial role in cell wall biosynthesis, MurI proteins from some bacteria have been shown to act as an inhibitor of DNA gyrase. Mycobacterium tuberculosis and Mycobacterium smegmatis MurI exhibit these dual characteristics. Here, we show that the two activities of

  2. Cordilleran suspect terranes

    USGS Publications Warehouse

    Coney, P.J.; Jones, D.L.; Monger, J.W.H.

    1980-01-01

    Over 70% of the North American Cordillera is made up of 'suspect terranes'. Many of these geological provinces are certainly allochthonous to the North American continent and seem to have been swept from far reaches of the Pacific Ocean before collision and accretion into the Cordilleran margin mostly in Mesozoic to early Cenozoic time. ?? 1980 Nature Publishing Group.

  3. Serodiagnosis of tuberculosis: due to shift track.

    PubMed

    Ivanyi, Juraj

    2012-01-01

    Development of novel diagnostics for tuberculosis has so far been governed by the clinical requirement of improving the detection of patients with paucibacillary forms of the disease. For this aim, serological assays have been evaluated using several antigens, but were found insufficiently sensitive, because antibody production associates with the bacterial load of the disease. Consequently, detection of antibodies against a relatively small number of selected well-defined antigens has a much higher sensitivity for sputum smear-positive pulmonary disease in adult HIV-negative patients. They are the most active in generating and spreading aerosols containing live tubercle bacilli, but their detection is often delayed, thus perpetuating the transmission of the infection and disease in the population. High volume throughput serological screening of clinical suspects with mild clinical symptoms may help to achieve diagnosis earlier, than currently used procedures. Such expanded testing could be done more efficiently in laboratories, than at 'points-of-care' and at a lower cost than other tests. The feasibility of this approach towards reducing the delayed diagnosis of the most infectious cases of pulmonary tuberculosis needs to be ascertained in prospective diagnostic trials, in populations at a high risk. Reducing the transmission of tuberculosis is of key importance for achieving its continued decline and therefore it is proposed, that the aims of serological screening should shift from clinical to public health priorities. PMID:21930430

  4. Comparison of symptoms and treatment outcomes between actively and passively detected tuberculosis cases: the additional value of active case finding.

    PubMed

    den Boon, S; Verver, S; Lombard, C J; Bateman, E D; Irusen, E M; Enarson, D A; Borgdorff, M W; Beyers, N

    2008-10-01

    Passive detection of tuberculosis (TB) cases may lead to delay in treatment which may contribute to increased severity of disease and mortality. Active case finding may be an alternative. In a community survey in Cape Town, South Africa, we actively detected 27 bacteriologically positive TB cases and compared those with 473 passively detected TB cases. Seven of 27 (26%) actively detected TB cases did not start treatment within 2 months and were considered initial defaulters. Those who did start treatment had similar treatment success rates as passively detected TB cases (both 80%) (OR 1.01, CI 0.33-3.09). Passively detected cases reported the presence of the symptoms cough (OR 3.72, 95% CI 1.47-9.39), haemoptysis (OR 3.20, 95% CI 1.03-9.93), night sweats (OR 3.35, 95% CI 1.40-7.99), fever (OR 4.28, 95% CI 1.21-15.14), and weight loss (OR 11.14, 95% CI 4.17-29.74) more often than those detected actively. We conclude that although TB cases detected by a community survey are less symptomatic and are prone to a high initial default rate, active case finding can potentially identify a substantial portion of the existing caseload at an earlier stage of disease, thereby reducing the risk of transmission. PMID:18177518

  5. Comparison of symptoms and treatment outcomes between actively and passively detected tuberculosis cases: the additional value of active case finding

    PubMed Central

    DEN BOON, S.; VERVER, S.; LOMBARD, C. J.; BATEMAN, E. D.; IRUSEN, E. M.; ENARSON, D. A.; BORGDORFF, M. W.; BEYERS, N.

    2008-01-01

    SUMMARY Passive detection of tuberculosis (TB) cases may lead to delay in treatment which may contribute to increased severity of disease and mortality. Active case finding may be an alternative. In a community survey in Cape Town, South Africa, we actively detected 27 bacteriologically positive TB cases and compared those with 473 passively detected TB cases. Seven of 27 (26%) actively detected TB cases did not start treatment within 2 months and were considered initial defaulters. Those who did start treatment had similar treatment success rates as passively detected TB cases (both 80%) (OR 1·01, 95% CI 0·33–3·09). Passively detected cases reported the presence of the symptoms cough (OR 3·72, 95% CI 1·47–9·39), haemoptysis (OR 3·20, 95% CI 1·03–9·93), night sweats (OR 3·35, 95% CI 1·40–7·99), fever (OR 4·28, 95% CI 1·21–15·14), and weight loss (OR 11·14, 95% CI 4·17–29·74) more often than those detected actively. We conclude that although TB cases detected by a community survey are less symptomatic and are prone to a high initial default rate, active case finding can potentially identify a substantial portion of the existing caseload at an earlier stage of disease, thereby reducing the risk of transmission. PMID:18177518

  6. Quantitative purity-activity relationships of natural products: the case of anti-tuberculosis active triterpenes from Oplopanax horridus.

    PubMed

    Qiu, Feng; Cai, Geping; Jaki, Birgit U; Lankin, David C; Franzblau, Scott G; Pauli, Guido F

    2013-03-22

    The present study provides an extension of the previously developed concept of purity-activity relationships (PARs) and enables the quantitative evaluation of the effects of multiple minor components on the bioactivity of residually complex natural products. The anti-tuberculosis active triterpenes from the Alaskan ethnobotanical Oplopanax horridus were selected as a case for the development of the quantitative PAR (QPAR) concept. The residual complexity of the purified triterpenes was initially evaluated by 1D- and 2D-NMR and identified as a combination of structurally related and unrelated impurities. Using a biochemometric approach, the qHNMR purity and anti-TB activity of successive chromatographic fractions of O. horridus triterpenes were correlated by linear regression analysis to generate a mathematical QPAR model. The results demonstrate that impurities, such as widely occurring monoglycerides, can have a profound impact on the observed antimycobacterial activity of triterpene-enriched fractions. The QPAR concept is shown to be capable of providing a quantitative assessment in situations where residually complex constitution contributes toward the biological activity of natural products. PMID:23356207

  7. Contrast-enhanced ultrasound in the diagnosis of patients suspected of having active Crohn's disease: meta-analysis.

    PubMed

    Ma, Xuelei; Li, Yanyan; Jia, Hongyuan; Zhang, Jing; Wang, Guoping; Liu, Xiaoxiao; Song, Yanlin

    2015-03-01

    This meta-analysis was aimed at assessing the performance of oral/microbubble contrast-enhanced ultrasound (CEUS) in the detection of active Crohn's disease (CD). A literature search of PubMed, Medline, the China National Knowledge Infrastructure and the Cochrane Library was conducted. Published articles that evaluated the diagnostic potency of CEUS in CD were included in the study. A total of eight articles, which included 428 patients, were finally analyzed. Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and area under the curve were calculated to examine the diagnostic accuracy of CEUS. The pooled sensitivity and specificity of CEUS for active CD were 93% (95% confidence interval: 89%-95%) and 87% (81%-91%), respectively. The summary diagnostic odds ratio was 80.35 (30.93-208.73), and the area under the curve was 0.9633. In conclusion, this meta-analysis pooled results from previous studies to evaluate the accuracy of CEUS in the detection of CD. We found that CEUS has high accuracy in the detection of active CD using endoscopy/biopsy or clinical index as the reference standard. In the future, CEUS may also be widely used in other diseases, reducing the necessity for invasive diagnostic procedure. PMID:25619783

  8. A coupled assay measuring Mycobacterium tuberculosis antigen 85C enzymatic activity.

    PubMed

    Boucau, Julie; Sanki, Aditya K; Voss, Bradley J; Sucheck, Steven J; Ronning, Donald R

    2009-02-01

    The prevalence of drug-resistant strains of Mycobacterium tuberculosis (M. tb) emphasizes the need for new antitubercular drugs. An essential component of the drug discovery process is the development of tools to rapidly screen potential drug libraries against important biological targets. Similarly to well-documented M. tb targets, the antigen 85 (Ag85) enzymes are involved in the maintenance of the mycobacterial cell wall. The products synthesized by these mycolyltransferases are the cell wall components most responsible for the reduced permeability of drugs into the bacterial cell, thereby linking Ag85 activity directly with drug resistance. This article presents the development of a high-throughput colorimetric assay suitable for direct monitoring of the enzymatic activity. The assay uses a synthetic substrate containing three chemical moieties: an octanoyl fatty acid, beta-D-glucose, and p-nitrophenyl. In the context of the assay, Ag85 catalyzes the removal of the fatty acid and releases p-nitrophenyl-beta-D-glucoside. The glucoside is hydrolyzed by beta-glucosidase to release the p-nitrophenolate chromophore. With this assay, the K(M) and k(cat) values of Ag85C were determined to be 0.047 +/- 0.008 mM and 0.062 s(-1), respectively. In addition, the assay exhibits a Z' value of 0.81 +/- 0.06, indicating its suitability for high-throughput screening applications and drug development. PMID:18992216

  9. Effects of conserved residues and naturally occurring mutations on Mycobacterium tuberculosis RecG helicase activity

    PubMed Central

    Zegeye, Ephrem Debebe; Balasingham, Seetha V.; Laerdahl, Jon K.; Homberset, Håvard; Kristiansen, Per E.

    2014-01-01

    RecG is a helicase that is conserved in nearly all bacterial species. The prototypical Escherichia coli RecG promotes regression of stalled replication forks, participates in DNA recombination and DNA repair, and prevents aberrant replication. Mycobacterium tuberculosis RecG (RecGMtb) is a DNA-dependent ATPase that unwinds a variety of DNA substrates, although its preferred substrate is a Holliday junction. Here, we performed site-directed mutagenesis of selected residues in the wedge domain and motifs Q, I, Ib and VI of RecGMtb. Three of the 10 substitution mutations engineered were detected previously as naturally occurring SNPs in the gene encoding RecGMtb. Alanine substitution mutations at residues Q292, F286, K321 and R627 abolished the RecGMtb unwinding activity, whilst RecGMtb F99A, P285S and T408A mutants exhibited ~25–50?% lower unwinding activity than WT. We also found that RecGMtb bound ATP in the absence of a DNA cofactor. PMID:24169816

  10. A novel molecule with notable activity against multi-drug resistant tuberculosis.

    PubMed

    Nair, Vasu; Okello, Maurice O; Mangu, Naveen K; Seo, Byung I; Gund, Machhindra G

    2015-03-15

    Multi-drug resistant tuberculosis (MDR-TB) is emerging as a serious global health problem, which has been elevated through co-infection involving HIV and MDR-Mtb. The discovery of new compounds with anti-MDR TB efficacy and favorable metabolism profiles is an important scientific challenge. Using computational biology and ligand docking data, we have conceived a multifunctional molecule, 2, as a potential anti-MDR TB agent. This compound was produced through a multi-step synthesis. It exhibited significant in vitro activity against MDR-TB (MIC 1.56?g/mL) and its half-life (t1/2) in human liver microsomes was 14.4h. The metabolic profiles of compound 2 with respect to human cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) isozymes were favorable. Compound 2 also had relatively low in vitro cytotoxicity in uninfected macrophages. It displayed synergistic behavior against MDR-TB in combination with PA-824. Interestingly, compound 2 also displayed in vitro anti-HIV activity. PMID:25677656

  11. Ofloxacin resistance in Mycobacterium tuberculosis is associated with efflux pump activity independent of resistance pattern and genotype.

    PubMed

    Sun, Zhaogang; Xu, Yuhui; Sun, Yong; Liu, Yi; Zhang, Xuxia; Huang, Hairong; Li, Chuanyou

    2014-12-01

    Drug-resistance to ofloxacin (OFX) in Mycobacterium tuberculosis is due to missense mutations in gyrA and other factors, such as alterations in the activity of drug efflux pumps. In this study, we identified 8 extensively drug resistant tuberculosis (XDR-TB), 40 multidrug resistant TB (MDR-TB), 38 polydrug resistant TB (PDR-TB), and 16 single OFX-resistant TB from 102 clinical isolates. We tested the effect of three efflux inhibitors, reserpine, verapamil, and carbonyl cyanide m-chlorophenyl hydrazone (CCCP), on changes in the OFX minimum inhibitory concentration (MIC) using Resazurin microtitre assay. These three inhibitors changed the MICs from 2- to 32-fold, with CCCP having the strongest effect. A total of 55%, 74%, and 83% of the tested isolates had changes in MIC of more than two-fold by reserpine, verapamil, and CCCP, respectively. The inhibitors led to similar fold-changes of OFX MICs in the XDR, MDR, PDR, and single OFX-resistant isolates. For each inhibitor, a higher resistance to OFX was associated with the greater efflux pump activity. There were no significant differences in the effect of efflux pump inhibitors upon Beijing and non-Beijing M. tuberculosis genotypes. Taken together, these results indicate that the efflux pump activity was greater in the isolates higher resistant to OFX and had similar effects on isolates with different drug resistant pattern, and had similar effects on Beijing and non-Beijing genotypes. PMID:24940805

  12. Bacterial expression and antibiotic activities of recombinant variants of human ?-defensins on pathogenic bacteria and M. tuberculosis.

    PubMed

    Corrales-Garcia, Ligia; Ortiz, Ernesto; Castañeda-Delgado, Julio; Rivas-Santiago, Bruno; Corzo, Gerardo

    2013-05-01

    Five variants of human ?-defensins (HBDs) were expressed in Escherichia coli using two vector systems (pET28a(+) and pQE30) with inducible expression by IPTG. The last vector has not been previously reported as an expression system for HBDs. The recombinant peptides were different in their lengths and overall charge. The HBDs were expressed as soluble or insoluble proteins depending on the expression system used, and the final protein yields ranged from 0.5 to 1.6 mg of peptide/g of wet weight cells, with purities higher than 90%. The recombinant HBDs demonstrated a direct correlation between antimicrobial activity and the number of basic charged residues; that is, their antimicrobial activity was as follows: HBD3-M-HBD2 > HBD3 = HBD3-M = HB2-KLK > HBD2 when assayed against E. coli, Staphylococcus aureus and Pseudomonas aeruginosa. Interestingly, HBD2 had the best antimicrobial activity against the Mycobacterium tuberculosis strain H37Rv (1.5 ?M) and the heterologous tandem peptide, HBD3-M-HBD2, had the best minimal inhibitory concentration (MIC) value (2.7 ?M) against a multidrug resistance strain (MDR) of M. tuberculosis, demonstrating the feasibility of the use of HBDs against pathogenic M. tuberculosis reported to be resistant to commercial antibiotics. PMID:23459290

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

    PubMed Central

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

    2012-01-01

    Background The World Health Organization is currently developing guidelines on screening for tuberculosis disease to inform national screening strategies. This process is complicated by significant gaps in knowledge regarding mass screening. This study aimed to assess feasibility, uptake, yield, treatment outcomes, and costs of adding an active tuberculosis case-finding program to an existing mobile HIV testing service. Methods and Findings The study was conducted at a mobile HIV testing service operating in deprived communities in Cape Town, South Africa. All HIV-negative individuals with symptoms suggestive of tuberculosis, and all HIV-positive individuals regardless of symptoms were eligible for participation and referred for sputum induction. Samples were examined by microscopy and culture. Active tuberculosis case finding was conducted on 181 days at 58 different sites. Of the 6,309 adults who accessed the mobile clinic, 1,385 were eligible and 1,130 (81.6%) were enrolled. The prevalence of smear-positive tuberculosis was 2.2% (95% CI 1.1–4.0), 3.3% (95% CI 1.4–6.4), and 0.4% (95% CI 1.4 015–6.4) in HIV-negative individuals, individuals newly diagnosed with HIV, and known HIV, respectively. The corresponding prevalence of culture-positive tuberculosis was 5.3% (95% CI 3.5–7.7), 7.4% (95% CI 4.5–11.5), 4.3% (95% CI 2.3–7.4), respectively. Of the 56 new tuberculosis cases detected, 42 started tuberculosis treatment and 34 (81.0%) completed treatment. The cost of the intervention was US$1,117 per tuberculosis case detected and US$2,458 per tuberculosis case cured. The generalisability of the study is limited to similar settings with comparable levels of deprivation and TB and HIV prevalence. Conclusions Mobile active tuberculosis case finding in deprived populations with a high burden of HIV and tuberculosis is feasible, has a high uptake, yield, and treatment success. Further work is now required to examine cost-effectiveness and affordability and whether and how the same results may be achieved at scale. PMID:22879816

  14. A Broad Profile of Co-Dominant Epitopes Shapes the Peripheral Mycobacterium tuberculosis Specific CD8+ T-Cell Immune Response in South African Patients with Active Tuberculosis

    PubMed Central

    Axelsson-Robertson, Rebecca; Loxton, André G.; Walzl, Gerhard; Ehlers, Marthie M.; Kock, Marleen M.; Zumla, Alimuddin; Maeurer, Markus

    2013-01-01

    We studied major histocompatibility complex (MHC) class I peptide-presentation and nature of the antigen-specific CD8+ T-cell response from South African tuberculosis (TB) patients with active TB. 361 MHC class I binding epitopes were identified from three immunogenic TB proteins (ESAT-6 [Rv3875], Ag85B [Rv1886c], and TB10.4 [Rv0288], including amino acid variations for Rv0288, i.e., A10T, G13D, S27N, and A71S for MHC allotypes common in a South African population (e.g., human leukocyte antigen [HLA]-A*30, B*58, and C*07). Inter-allelic differences were identified regarding the broadness of the peptide-binding capacity. Mapping of frequencies of Mycobacterium tuberculosis (M. tb) antigen-specific CD8+ T-cells using 48 different multimers, including the newly constructed recombinant MHC class I alleles HLA-B*58:01 and C*0701, revealed a low frequency of CD8+ T-cell responses directed against a broad panel of co-dominant M. tb epitopes in the peripheral circulation of most patients. The antigen-specific responses were dominated by CD8+ T-cells with a precursor-like phenotype (CD45RA+CCR7+). The data show that the CD8+ T-cell response from patients with pulmonary TB (prior to treatment) is directed against subdominant epitopes derived from secreted and non-secreted M. tb antigens and that variant, natural occurring M. tb Rv0288 ligands, have a profound impact on T-cell recognition. PMID:23555576

  15. Impact of ?-Lactamase Inhibition on the Activity of Ceftaroline against Mycobacterium tuberculosis and Mycobacterium abscessus.

    PubMed

    Dubée, Vincent; Soroka, Daria; Cortes, Mélanie; Lefebvre, Anne-Laure; Gutmann, Laurent; Hugonnet, Jean-Emmanuel; Arthur, Michel; Mainardi, Jean-Luc

    2015-05-01

    The production of ?-lactamases BlaMab and BlaC contributes to ?-lactam resistance in Mycobacterium abscessus and Mycobacterium tuberculosis, respectively. Ceftaroline was efficiently hydrolyzed by these enzymes. Inhibition of M. tuberculosis BlaC by clavulanate decreased the ceftaroline MIC from ?256 to 16 to 64 ?g/ml, but these values are clinically irrelevant. In contrast, the ceftaroline-avibactam combination should be evaluated against M. abscessus since it inhibited growth at lower and potentially achievable drug concentrations. PMID:25733512

  16. Field assessment of a model tuberculosis outbreak response plan for low-incidence areas

    PubMed Central

    Freimanis Hance, Laura; Steingart, Karen R; Hahn, Christine G; Pascopella, Lisa; Nolan, Charles M

    2007-01-01

    Background For a regional project in four low-incidence states, we designed a customizable tuberculosis outbreak response plan. Prior to dissemination of the plan, a tuberculosis outbreak occurred, presenting an opportunity to perform a field assessment of the plan. The purpose of the assessment was to ensure that the plan included essential elements to help public health professionals recognize and respond to outbreaks. Methods We designed a semi-structured questionnaire and interviewed all key stakeholders involved in the response. We used common themes to assess validity of and identify gaps in the plan. A subset of participants provided structured feedback on the plan. Results We interviewed 11 public health and six community stakeholders. The assessment demonstrated that (1) almost all of the main response activities were reflected in the plan; (2) the plan added value by providing a definition of a tuberculosis outbreak and guidelines for communication and evaluation. These were areas that lacked written protocols during the actual outbreak response; and (3) basic education about tuberculosis and the interpretation and use of genotyping data were important needs. Stakeholders also suggested adding to the plan questions for evaluation and a section for specific steps to take when an outbreak is suspected. Conclusion An interactive field assessment of a programmatic tool revealed the value of a systematic outbreak response plan with a standard definition of a tuberculosis outbreak, guidelines for communication and evaluation, and response steps. The assessment highlighted the importance of education and training for tuberculosis in low-incidence areas. PMID:17963502

  17. In vitro Anti-mycobacterial activity of selected medicinal plants against Mycobacterium tuberculosis and Mycobacterium bovis Strains

    PubMed Central

    2013-01-01

    Background Tuberculosis (TB) is a global burden with one –third of the world’s population infected with the pathogen Mycobacterium tuberculosis complex and annually 1.4 million deaths occur due to the disease. This high incidence of infection and the increased rate of multi-drug resistant and extensively-drug resistant strains of the organism further complicated the problem of TB control and have called for an urgent need to develop new anti-TB drugs from plants. In this study, the in vitro activity of root of Calpurnia aurea, seeds of Ocimum basilicum, leaves of Artemisia abyssinica, Croton macrostachyus, and Eucalyptus camaldulensis were evaluated against M. tuberculosis and M. bovis strains. Methods Five Ethiopian medicinal plants, root of Calpurnia aurea, seeds of Ocimum basilicum, leaves of Artemisia abyssinica, Croton macrostachyus, and Eucalyptus camaldulensis used locally for the management of TB. They were investigated for in vitro antimycobacterial activity against M. tuberculosis and M. bovis strains. 80% methanolic extracts of the plant materials were obtained by maceration. The antimycobacterial activity was determined using 96 wells of microplate with the help of visual Resazurin Microtiter Assay. Results The crude 80% methanolic extracts of the root of C. aurea, seeds of O. basilicum, and leaves of A. abyssinica, C. macrostachyus, and E. camaldulensis had anti-mycobacterial activity with minimum inhibitory concentration (MIC) ranging from 6.25–100 ?g/mL. The MIC of 80% methanol extracts in the order mentioned above ranged 25-100 ?g/ml and 12.5-75 ?g/mL, 25–100 ?g/mL and 25–50 ?g/mL, 6.25-50 ?g/mL and 12.5-50 ?g/mL, 12.5-100 ?g/mL and 18.25-50 ?g/mL and 6.25-50 ?g/mL and 12.5-50 ?g/mL, respectively for M. tuberculosis and M. bovis strains. Conclusions The results support the local use of these plants in the treatment of TB and it is suggested that these plants may have therapeutic value in the treatment of TB. However, further investigations are needed on isolating chemical constituents responsible for eliciting the observed activity in these plants. PMID:24168665

  18. 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

  19. Unique Transcriptome Signature of Mycobacterium tuberculosis in Pulmonary Tuberculosis

    PubMed Central

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

    2006-01-01

    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

  20. 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...

  1. [The early warning and prognostic value of serum soluble TREM-1 for active pulmonary tuberculosis].

    PubMed

    Zeng, Jincheng; Kong, Bin; Xiang, Wenyu; Gao, Yuchi; Lu, Yuanbin; Wang, Wandang; Zhang, Junai; Lin, Dongzi; Liu, Ganbin; Xu, Junfa

    2015-02-01

    Objective To investigate the role of serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in patients with active pulmonary tuberculosis (ATB) and explore its clinical significance. Methods The study included 78 cases of ATB patients and 40 cases of healthy volunteers from Dongguan Hospital for Chronic Diseases. Peripheral blood neutrophils and monocytes were counted by automated hematology analyzer. Serum sTREM-1 levels were detected by ELISA, and then the relevance with neutrophils and monocytes were analyzed by Pearson correlation test, respectively. Results The absolute numbers of neutrophils and monocytes, and the levels of serum sTREM-1 were higher in ATB patients than those in normal controls. In smear positive patients, the absolute numbers of neutrophils and monocytes, and the levels of serum sTREM-1 were higher than those in smear negative patients. The absolute numbers of neutrophils and monocytes, and the levels of serum sTREM-1 decreased in ATB patients after anti-TB drug treatments. Serum sTREM-1 level ?528.14 pg/mL was very useful to diagnosis the smear positive ATB, and the accuracy was 100%. Pearson correlation test revealed that the absolute numbers of neutrophils and monocytes were both positively correlated to the levels of serum sTREM-1. Conclusion High serum levels of sTREM-1 may be of high value for early warning and prediction of poor prognosis in ATB patients. PMID:25652867

  2. Mycobacterium tuberculosis FtsX extracellular domain activates the peptidoglycan hydrolase, RipC

    PubMed Central

    Mavrici, Daniela; Marakalala, Mohlopheni J.; Holton, James M.; Prigozhin, Daniil M.; Gee, Christine L.; Zhang, Yanjia J.; Rubin, Eric J.; Alber, Tom

    2014-01-01

    Bacterial growth and cell division are coordinated with hydrolysis of the peptidoglycan (PG) layer of the cell wall, but the mechanisms of regulation of extracellular PG hydrolases are not well understood. Here we report the biochemical, structural, and genetic analysis of the Mycobacterium tuberculosis homolog of the transmembrane PG-hydrolase regulator, FtsX. The purified FtsX extracellular domain binds the PG peptidase Rv2190c/RipC N-terminal segment, causing a conformational change that activates the enzyme. Deletion of ftsEX and ripC caused similar phenotypes in Mycobacterium smegmatis, as expected for genes in a single pathway. The crystal structure of the FtsX extracellular domain reveals an unprecedented fold containing two lobes connected by a flexible hinge. Mutations in the hydrophobic cleft between the lobes reduce RipC binding in vitro and inhibit FtsX function in M. smegmatis. These studies suggest how FtsX recognizes RipC and support a model in which a conformational change in FtsX links the cell division apparatus with PG hydrolysis. PMID:24843173

  3. High Mortality in Adults Hospitalized for Active Tuberculosis in a Low HIV Prevalence Setting

    PubMed Central

    Lui, Grace; Wong, Rity Y. K.; Li, Florence; Lee, May K. P.; Lai, Raymond W. M.; Li, Timothy C. M.; Kam, Joseph K. M.; Lee, Nelson

    2014-01-01

    Background This study aims to evaluate the outcomes of adults hospitalized for tuberculosis in a higher-income region with low HIV prevalence. Methods A retrospective cohort study was conducted on all adults hospitalized for pulmonary and/or extrapulmonary tuberculosis in an acute-care hospital in Hong Kong during a two-year period. Microscopy and solid-medium culture were routinely performed. The diagnosis of tuberculosis was made by: (1) positive culture of M. tuberculosis, (2) positive M. tuberculosis PCR result, (3) histology findings of tuberculosis infection, and/or (4) typical clinico-radiological manifestations of tuberculosis which resolved after anti-TB treatment, in the absence of alternative diagnoses. Time to treatment (‘early’, started during initial admission; ‘late’, subsequent periods), reasons for delay, and short- and long-term survival were analyzed. Results Altogether 349 patients were studied [median(IQR) age 62(48–77) years; non-HIV immunocompromised conditions 36.7%; HIV/AIDS 2.0%]. 57.9%, 16.3%, and 25.8% had pulmonary, extrapulmonary, and pulmonary-extrapulmonary tuberculosis respectively. 58.2% was smear-negative; 0.6% multidrug-resistant. 43.4% developed hypoxemia. Crude 90-day and 1-year all-cause mortality was 13.8% and 24.1% respectively. 57.6% and 35.8% received ‘early’ and ‘late’ treatment respectively, latter mostly culture-guided [median(IQR) intervals, 5(3–9) vs. 43(25–61) days]. Diagnosis was unknown before death in 6.6%. Smear-negativity, malignancy, chronic lung diseases, and prior exposure to fluoroquinolones (adjusted-OR 10.6, 95%CI 1.3–85.2) delayed diagnosis of tuberculosis. Failure to receive ‘early’ treatment independently predicted higher mortality (Cox-model, adjusted-HR 1.8, 95%CI 1.1–3.0). Conclusions Mortality of hospitalized tuberculosis patients is high. Newer approaches incorporating methods for rapid diagnosis and initiation of anti-tuberculous treatment are urgently required to improve outcomes. PMID:24642794

  4. 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

  5. Tuberculosis Fluoroscopy

    Cancer.gov

    Follow-up though Dec 31, 2002 has been completed for a study of site-specific cancer mortality among tuberculosis patients treated with artificial lung collapse therapy in Massachusetts tuberculosis sanatoria (1930-1950).

  6. Tuberculosis (TB)

    MedlinePLUS

    ... JavaScript on. Read more information on enabling JavaScript. Tuberculosis (TB) Skip Content Marketing Share this: Main Content ... thought to be infected with TB bacteria, Mycobacterium tuberculosis ( Mtb ). TB is a chronic bacterial infection. It ...

  7. Tuberculosis Prevention

    MedlinePLUS

    ... JavaScript on. Read more information on enabling JavaScript. Tuberculosis (TB) Skip Content Marketing Share this: Main Content ... patients. Many people who are infected with Mycobacterium tuberculosis ( Mtb ) do not get sick or spread the ...

  8. Spectrum of urogenital tuberculosis.

    PubMed

    Kulchavenya, Ekaterina; Zhukova, Irina; Kholtobin, Denis

    2013-10-01

    Urogenital tuberculosis (UGTB) plays an important role because its complications may be fatal, it significantly reduces quality of life, and it is often associated with AIDS. Diagnosis of UGTB is often delayed. We analyzed 131 case histories of UGTB patients from the years 2009-2011. Gender, age, and the clinical form and main features of the disease were taken into account. The most common form was kidney tuberculosis (74.8%). Isolated kidney tuberculosis (KTB) more often occurs in women: 56.8%. Patients of middle and old age more often showed the stage of cavernous KTB; younger patients had smaller forms. Among all cases, an asymptomatic course was seen in 12.2% and, among cases of KTB, in 15.9%. Every third patient complained of flank pain and dysuria (35.2% and 39.8%, respectively); 17% presented with toxicity symptoms, 9.1% with renal colic, and 7.9% with gross hematuria. Mycobacterium tuberculosis (MTB) in urine was found in 31.8% of cases in all levels of isolated KTB. UGTB has no specific symptom; even sterile pyuria occurs only in 25%. The acute onset of tuberculous orchiepididymitis was seen in 35.7% of patients, hemospermia in 7.1%, and dysuria in 35.7%. The most common complaints for prostate tuberculosis were perineal pain (31.6%), dysuria (also 31.6%), and hemospermia (26.3%). MTB in prostate secretion/ejaculate was revealed in 10.5% of this group. All urogenital tract infections should be suspected as UGTB in patients who are living in a region with a high incidence rate, who have had contact with tuberculosis infection, and who have a recurrence of the disease that is resistant to standard therapy. PMID:23526041

  9. Two cutinase-like proteins secreted by Mycobacterium tuberculosis show very different lipolytic activities reflecting their physiological function.

    PubMed

    Schué, Mathieu; Maurin, Damien; Dhouib, Rabeb; Bakala N'Goma, Jean-Claude; Delorme, Vincent; Lambeau, Gérard; Carrière, Frédéric; Canaan, Stéphane

    2010-06-01

    Cutinases are extracellular enzymes that are able to degrade cutin, a polyester protecting plant leaves and many kinds of lipids. Although cutinases are mainly found in phytopathogenic fungi or bacteria, 7 genes related to the cutinase family have been predicted in the genome of Mycobacterium tuberculosis. These genes may encode proteins that are involved in the complex lipid metabolism of the bacterium. Here, we report on the biochemical characterization of two secreted proteins of M. tuberculosis, Rv1984c and Rv3452, belonging to the cutinase family. Although their amino acid sequence shows 50% identity with that of the well-characterized cutinase from Fusarium solani pisi, and a high level of homology has been found to exist between these two enzymes, they show distinct substrate specificities. Rv1984c preferentially hydrolyzes medium-chain carboxylic esters and monoacylglycerols, whereas Rv3452 behaves like a phospholipase A(2), and it is able to induce macrophage lysis. The tetrahydrolipstatin inhibitor, a specific lipase inhibitor, abolishes the activity of both enzymes. Site-directed mutagenesis was performed to identify the catalytic triad of Rv1984c. Structural models for Rv1984c and Rv3452 were built, based on the crystal structure of F. solani cutinase, with a view to investigating the contribution of specific residues to the substrate specificity. Our findings open new prospects for investigating the physiological roles of cutinase-like proteins in the lipid metabolism and virulence of M. tuberculosis. PMID:20103719

  10. Bovine Tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tuberculosis (TB) in animals and humans may result from exposure to bacilli within the Mycobacterium tuberculosis complex (i.e., M. tuberculosis, M. bovis, M. africanum, M. pinnipedii, M. microti, M. caprae, or M. canetti). Mycobacterium bovis is the species most often isolated from tuberculous catt...

  11. Mineral nutrient uptake from prey and glandular phosphatase activity as a dual test of carnivory in semi-desert plants with glandular leaves suspected of carnivory

    PubMed Central

    P?achno, Bartosz Jan; Adamec, Lubomír; Huet, Hervé

    2009-01-01

    Background and Aims Ibicella lutea and Proboscidea parviflora are two American semi-desert species of glandular sticky plants that are suspected of carnivory as they can catch small insects. The same characteristics might also hold for two semi-desert plants with glandular sticky leaves from Israel, namely Cleome droserifolia and Hyoscyamus desertorum. The presence of proteases on foliar hairs, either secreted by the plant or commensals, detected using a simple test, has long been considered proof of carnivory. However, this test does not prove whether nutrients are really absorbed from insects by the plant. To determine the extent to which these four species are potentially carnivorous, hair secretion of phosphatases and uptake of N, P, K and Mg from fruit flies as model prey were studied in these species and in Roridula gorgonias and Drosophyllum lusitanicum for comparison. All species examined possess morphological and anatomical adaptations (hairs or emergences secreting sticky substances) to catch and kill small insects. Methods The presence of phosphatases on foliar hairs was tested using the enzyme-labelled fluorescence method. Dead fruit flies were applied to glandular sticky leaves of experimental plants and, after 10–15 d, mineral nutrient content in their spent carcasses was compared with initial values in intact flies after mineralization. Key Results Phosphatase activity was totally absent on Hyoscyamus foliar hairs, a certain level of activity was usually found in Ibicella, Proboscidea and Cleome, and a strong response was found in Drosophyllum. Roridula exhibited only epidermal activity. However, only Roridula and Drosophyllum took up nutrients (N, P, K and Mg) from applied fruit flies. Conclusions Digestion of prey and absorption of their nutrients are the major features of carnivory in plants. Accordingly, Roridula and Drosophyllum appeared to be fully carnivorous; by contrast, all other species examined are non-carnivorous as they did not meet the above criteria. PMID:19556266

  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.

  13. Tuberculosis in the elderly

    Microsoft Academic Search

    S. Rajagopalan; T. T. Yoshikawa

    2000-01-01

    Summary   Tuberculosis (TB) today remains one of the world’s most lethal infectious diseases. An estimated one-third of the world’s\\u000a population is infected with the tubercle bacillus-Mycobacterium tuberculosis (Mtb), and 7 to 8 million people develop TB disease each year (27). For purpose of clarity, TB infection (latent TB) is defined\\u000a as harboring Mtb without evidence of active infection, and TB

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

    PubMed Central

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

    2014-01-01

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

  15. MODS for Tuberculosis Screening Prior to Isoniazid Preventive Therapy in HIV-Infected Persons

    PubMed Central

    Reddy, Krishna P.; Brady, Mark F.; Gilman, Robert H.; Coronel, Jorge; Ñavincopa, Marcos; Ticona, Eduardo; Chavez, Gonzalo; Sánchez, Eduardo; Rojas, Christian; Solari, Lely; Valencia, Jorge; Pinedo, Yvett; Benites, Carlos; Friedland, Jon S.; Moore, David A.J.

    2010-01-01

    Background Active tuberculosis (TB) must be excluded before initiating isoniazid preventive therapy (IPT) in HIV-infected persons, but currently used screening strategies suffer from poor sensitivity and specificity and high patient attrition rates. Liquid TB culture is now recommended for the detection of Mycobacterium tuberculosis in TB suspects. This study compared the efficacy, effectiveness and speed of the microscopic-observation drug-susceptibility (MODS) assay with currently used strategies for tuberculosis screening prior to IPT in HIV-infected persons. Methods 471 HIV-infected IPT candidates at three hospitals in Lima, Peru, were enrolled into a prospective comparison of tuberculosis screening strategies, including laboratory, clinical and radiographic assessments. Results Of 435 patients who provided two sputum samples, M. tuberculosis was detected in 27 (6.2%) by MODS, 22 (5.1%) by Lowenstein-Jensen culture and 7 (1.6%) by smear. Of patients with any positive microbiological test, a MODS culture was positive in 96% by 14 days and 100% by 21 days. MODS simultaneously detected multidrug-resistant tuberculosis in two patients. Screening strategies involving combinations of clinical assessment, chest radiograph and sputum smear were less effective than two liquid TB cultures in accurately diagnosing and excluding tuberculosis (p<0.01). Screening strategies that included non-culture tests had poor sensitivity and specificity. Conclusions MODS identified, and reliably excluded, cases of pulmonary tuberculosis more accurately than other screening strategies, while providing results significantly faster than Lowenstein-Jensen culture. The streamlining of TB rule-out through the use of liquid culture-based strategies could help facilitate the massive upscaling of IPT required to reduce HIV and TB morbidity and mortality. PMID:20192727

  16. Plasma granulysin levels and cellular interferon-gamma production correlate with curative host responses in tuberculosis, while plasma interferon-gamma levels correlate with tuberculosis disease activity in adults

    Microsoft Academic Search

    E. Sahiratmadja; B. Alisjahbana; S. Buccheri; D. Di Liberto; T. de Boer; I. Adnan; R. van Crevel; M. R. Klein; K. E. van Meijgaarden; R. H. Nelwan; E. van de Vosse; F. Dieli; T. H. M. Ottenhoff

    2007-01-01

    Granulysin is a recently identified cytolytic protein which is expressed by human cytotoxic T-lymphocytes and natural killer (NK)-cells, and has broad antimicrobial and tumoricidal activity. Circulating granulysin levels are associated with T- and NK-cell activity, and may thus reflect protection-associated cellular immune responses. In a case-control study in Indonesia, a highly tuberculosis (TB)-endemic country, we therefore determined plasma granulysin levels

  17. resistant strains of Mycobacterium tuberculosis

    Microsoft Academic Search

    Ying Zhang; Steven Denkin; Dmitriy Volokhov; Vladimir Chizhikov

    Drug-resistant Mycobacterium tuberculosis poses a significant threat to the treatment of tuberculosis (TB). The current susceptibility testing for the first-line TB drug pyrazinamide (PZA) is not only time-consuming but also difficult, due to the requirement for acid pH for drug activity. Predominantly, resistance to PZA in M. tuberculosis is caused by mutations in the pncA gene, and the detection of

  18. Active use of coyotes (Canis latrans) to detect Bovine Tuberculosis in northeastern Michigan, USA.

    PubMed

    Berentsen, A R; Dunbar, M R; Johnson, S R; Robbe-Austerman, S; Martinez, L; Jones, R L

    2011-07-01

    Bovine tuberculosis (bTB) is endemic in white-tailed deer (Odocoileus virginianus) in northeastern Michigan, USA, and research suggests transmission to cattle. Prevalence of the disease in deer is estimated at 1.8%, but as prevalence decreases the difficulty of detection increases. Research suggests coyotes (Canis latrans) have a higher prevalence of bTB in Michigan than deer and sampling coyotes may be a more efficient surveillance tool to detect presence or spread of the disease. Coyotes possess suitable ecological characteristics to serve as a sentinel species, assuming transmission between coyotes is not significant. The question of whether free-ranging coyotes shed Mycobacterium bovis, the causative agent of bTB, has not been previously addressed. We actively used coyotes as a sentinel to detect bTB in infected and uninfected counties in Michigan's Northeastern Lower Peninsula. We determined whether bTB infection was present through bacteriologic culture of lymph nodes and tissues containing lesions and cultured oral/nasal swabs and feces to establish shedding. Seventeen of 171 coyotes were M. bovis culture positive, one of which was from a previously uninfected county. All oral, nasal secretions and feces were culture negative suggesting minimal, if any, shedding of M. bovis. Thus, infection of coyotes is likely to occur through ingestion of infected deer carcasses and not from interaction with conspecifics. These findings support previous research suggesting that coyotes are useful sentinels for bTB. The use of coyotes as a sentinel, may allow wildlife managers to detect the spread of bTB into naïve counties. With earlier detection managers may be able to take proactive surveillance measures to detect the disease in deer and reduce the potential risk to domestic livestock and captive deer herds. PMID:21420801

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

    PubMed Central

    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 control programme activities within a strengthened health system. Discussion HIV and tuberculosis share many similarities in terms of their disease burden and the recommended stratagems for their control. HIV and tuberculosis programmes implement similar sorts of control activities, e.g. case finding and treatment, which depend for success on generic health system issues, including vital registration, drug procurement and supply, laboratory network, human resources, and financing. However, the current health system approach to HIV and tuberculosis control often involves separate specialised services. Despite some recent progress, collaboration between the programmes remains inadequate, progress in obtaining synergies has been slow, and results remain far below those needed to achieve universal access to key interventions. A fundamental re-think of the current strategic approach involves promoting integrated delivery of HIV and tuberculosis programme activities as part of strengthened general health services: epidemiological surveillance, programme monitoring and evaluation, community awareness of health-seeking behavior, risk behaviour modification, infection control, treatment scale-up (first-line treatment regimens), drug-resistance surveillance, containing and countering drug-resistance (second-line treatment regimens), research and development, global advocacy and global partnership. Health agencies should review policies and progress in HIV and tuberculosis epidemic control, learn mutual lessons for policy development and scaling up interventions, and identify ways of joint planning and joint funding of integrated delivery as part of strengthened health systems. Summary As both a danger and an opportunity, the global financial crisis may entail disaster or recovery for global health sector efforts for HIV and tuberculosis epidemic control. Review of policies and progress in control paves the way for identification of synergies between the two programmes, within strengthened health services. The silver lining in the global economic crisis could be better control of the HIV and tuberculosis epidemics, better overall health system performance and outcomes, and better value for money. PMID:20602774

  20. 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

  1. Interferon gamma +874T/A polymorphism is associated with susceptibility to active pulmonary tuberculosis development in Tunisian patients.

    PubMed

    Ben Selma, Walid; Harizi, Hedi; Bougmiza, Iheb; Hannachi, Naila; Ben Kahla, Imen; Zaieni, Radhia; Boukadida, Jalel

    2011-06-01

    Interferon gamma (IFN-?) is a key cytokine involved mainly in the defense against intracellular pathogens such as Mycobacterium tuberculosis. Given its key role in the control of tuberculosis (TB), in the present article we have investigated a possible association between IFN-? gene single-nucleotide polymorphism linked to high and low producer phenotypes (IFN-? [+874T(high)???A(low)]) (rs2430561) and risk development of active TB in Tunisian patients. Genomic DNA samples were obtained from 223 patients with active TB (168 pulmonary and 55 extrapulmonary cases) and 150 healthy blood donors. Genotypes were analyzed using polymerase chain reaction-restriction fragment length polymorphism method. The +874 AA genotype (low IFN-? producer) was significantly associated with increased risk of developing of active pulmonary TB (odds ratio [OR]?=?2.18; 95% confidence intervals [CI], 1.33-3.57; P corrected for the number of genotypes [Pc]?=?0.003). By contrast, the AT genotype was found to be significantly associated with resistance to pulmonary TB (OR?=?0.46; 95% CI, 0.28-0.74; Pc?=?0.0018) and extrapulmonary TB development (OR?=?0.46; 95% CI, 0.23-0.91; Pc?=?0.045). Collectively, our data showed that the IFN-? +874T/A polymorphism is a determinant in the resistance or susceptibility to the development of active TB in the studied population. PMID:21332391

  2. 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

  3. 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...

  4. 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-g) assay has been applied for more than a decade. Briefly, IFN-g responses in whole blood cultures stimulated with puri...

  5. In Vitro Activity of Rifampicin and Verapamil Combination in Multidrug-Resistant Mycobacterium tuberculosis

    PubMed Central

    Demitto, Fernanda de Oliveira; do Amaral, Renata Claro Ribeiro; Maltempe, Flaviane Granero; Siqueira, Vera Lúcia Dias; Scodro, Regiane Bertin de Lima; Lopes, Mariana Aparecida; Caleffi-Ferracioli, Katiany R.; Canezin, Pedro Henrique; Cardoso, Rosilene Fressatti

    2015-01-01

    The aim of the present study was to evaluate the effect of the combination of rifampicin (RIF) and verapamil (VP) against the Mycobacterium tuberculosis H37Rv reference strain and six multidrug-resistant (MDR) M. tuberculosis clinical isolates by determining Time-Kill Curves and the ability to efflux drug by fluorometry. The RIF+VP combination showed synergism in one MDR clinical isolate. For the other five MDR clinical isolates, the drug combination showed no interaction. The MDR clinical isolate had lower ethidium bromide (EtBr) accumulation when exposed to the RIF+VP combination, compared with RIF and VP exposure alone. The other MDR clinical isolates showed no significant difference in EtBr accumulation. These results suggest greater efflux action in one of the MDR clinical isolates compared with the M. tuberculosis H37Rv reference strain. The other five MDR isolates may have additional mechanisms of drug resistance to RIF. The use of the RIF+VP combination made one MDR bacillus more susceptible to RIF probably by inhibiting efflux pumps, and this combination therapy, in some cases, may contribute to a reduction of resistance to RIF in M. tuberculosis. PMID:25689777

  6. 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

  7. Increased resistin may suppress reactive oxygen species production and inflammasome activation in type 2 diabetic patients with pulmonary tuberculosis infection.

    PubMed

    Chao, Wen-Cheng; Yen, Chia-Liang; Wu, Ying-Hsun; Chen, Shin-Yi; Hsieh, Cheng-Yuan; Chang, Tsung-Chain; Ou, Horng-Yih; Shieh, Chi-Chang

    2015-03-01

    Although it has been known for decades that patients with type 2 diabetes mellitus (DM) are more susceptible to severe tuberculosis (TB) infection, the underlying immunological mechanisms remain unclear. Resistin, a protein produced by immune cells in humans, causes insulin resistance and has been implicated in inhibiting reactive oxygen species (ROS) production in leukocytes. Recent studies suggested that IL-1? production in patients with Mycobacteria tuberculosis infection correlates with inflammasome activation which may be regulated by ROS production in the immune cells. By investigating the level of resistin in different patient groups, we found that serum resistin levels were significantly higher in severe TB and DM-only groups when compared with mild TB cases and healthy controls. Moreover, elevation of serum resistin correlated with impairment of ROS production of neutrophils in patients with both DM and TB. In human macrophages, exogenous resistin inhibits the production of ROS which are important in the mycobacterium-induced inflammasome activation. Moreover, macrophages with defective ROS production had poor IL-1? production and ineffective control of mycobacteria growth. Our results suggest that increased resistin in severe TB and DM patients may suppress the mycobacterium-induced inflammasome activation through inhibiting ROS production by leukocytes. PMID:25528597

  8. Moxifloxacin (BAY12-8039), a New 8-Methoxyquinolone, Is Active in a Mouse Model of Tuberculosis

    PubMed Central

    Miyazaki, Eishi; Miyazaki, Miki; Chen, Jong Min; Chaisson, Richard E.; Bishai, William R.

    1999-01-01

    Moxifloxacin (BAY12-8039) is a new 8-methoxyquinolone shown to be active against Mycobacterium tuberculosis in vitro. We tested moxifloxacin for activity in mice against M. tuberculosis CSU93, a highly virulent, recently isolated clinical strain. The MIC of moxifloxacin for the CSU93 strain was 0.25 ?g/ml. The serum moxifloxacin concentration after oral administration in mice peaked within 0.25 h, reaching 7.8 ?g/ml with doses of 100 mg/kg of body weight; the maximum concentration and the analysis of the area under the concentration-time curve revealed dose dependency. When mice were infected with a sublethal inoculum of mycobacteria and then treated with moxifloxacin at 100 mg/kg per day for 8 weeks, the log10 CFU counts in the organs of treated mice were significantly lower than those for the control group (0.6 ± 0.2 versus 5.6 ± 0.3 in the lungs and 1.5 ± 0.7 versus 4.9 ± 0.5 in the spleens, respectively; P < 0.001 in both organs). The effectiveness of moxifloxacin monotherapy was comparable to that seen in mice receiving isoniazid alone. Combination therapy with moxifloxacin plus isoniazid was superior to that with moxifloxacin or with isoniazid alone in reducing bacillary counts in the organs studied. Using a sensitive broth-passage subculture method, we demonstrated that 8 weeks of treatment with moxifloxacin (100 mg/kg per day) or with moxifloxacin plus isoniazid (100 mg/kg and 25 mg/kg, respectively, per day) sterilized the lungs in seven of eight and in eight of eight mice, respectively. Among surviving bacilli isolated from animals infected with a high-titer inoculum and treated for 7 weeks with low-dose moxifloxacin (20 mg/kg per day), breakthrough resistance to moxifloxacin was not observed. These results indicate that moxifloxacin is highly effective in reducing M. tuberculosis infection in mice and has activity comparable to that of isoniazid. Combination therapy with moxifloxacin and isoniazid was highly effective, suggesting that moxifloxacin may be useful in multiple-drug regimens for human tuberculosis. PMID:9869570

  9. 38 CFR 3.959 - Tuberculosis.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...2011-07-01 2011-07-01 false Tuberculosis. 3.959 Section 3.959 Pensions...Compensation Protection § 3.959 Tuberculosis. Any veteran who, on August...for active or inactive (arrested) tuberculosis may receive compensation under...

  10. 38 CFR 3.959 - Tuberculosis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...2010-07-01 2010-07-01 false Tuberculosis. 3.959 Section 3.959 Pensions...Compensation Protection § 3.959 Tuberculosis. Any veteran who, on August...for active or inactive (arrested) tuberculosis may receive compensation under...

  11. Mechanisms of latency in Mycobacterium tuberculosis

    Microsoft Academic Search

    Nikki M Parrish; James D Dick; William R Bishai

    1998-01-01

    Mycobacterium tuberculosis can persist within the human host for years without causing disease, in a syndrome known as latent tuberculosis (TB). As one-third of the world population has latent TB, placing them at risk for active TB, the mechanisms by which M. tuberculosis establishes a latent metabolic state, eludes immune surveillance and responds to triggers that stimulate reactivation are a

  12. 38 CFR 3.959 - Tuberculosis.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...2014-07-01 2014-07-01 false Tuberculosis. 3.959 Section 3.959 Pensions...Compensation Protection § 3.959 Tuberculosis. Any veteran who, on August...for active or inactive (arrested) tuberculosis may receive compensation under...

  13. 38 CFR 3.959 - Tuberculosis.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...2012-07-01 2012-07-01 false Tuberculosis. 3.959 Section 3.959 Pensions...Compensation Protection § 3.959 Tuberculosis. Any veteran who, on August...for active or inactive (arrested) tuberculosis may receive compensation under...

  14. 38 CFR 3.959 - Tuberculosis.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...2013-07-01 2013-07-01 false Tuberculosis. 3.959 Section 3.959 Pensions...Compensation Protection § 3.959 Tuberculosis. Any veteran who, on August...for active or inactive (arrested) tuberculosis may receive compensation under...

  15. High-content screening technology combined with a human granuloma model as a new approach to evaluate the activities of drugs against Mycobacterium tuberculosis.

    PubMed

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

    2015-01-01

    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

  16. A case of isoniazid-resistant miliary tuberculosis in which tuberculous meningitis paradoxically developed despite systemic improvement.

    PubMed

    Ikegame, Satoshi; Wakamatsu, Kentaro; Fujita, Masaki; Nakanishi, Yoichi; Harada, Mine; Kajiki, Akira

    2011-10-01

    A 63-year-old man with chronic myelomonocytic leukemia was admitted to our hospital with miliary tuberculosis. He received anti-tuberculosis drugs: isoniazid (INH), rifampicin (RFP), ethambutol (EB), and pyrazinamide (PZA). His condition clearly and immediately improved after the therapy, but he experienced a high fever of about 38°C every day from 1 month after the initiation of the therapy. Drug-induced fever and tumor fever were suspected as causes, but the etiology could not be determined. The tuberculosis was identified as an INH-resistant strain, so INH was stopped and levofloxacin (LVFX) was introduced, with streptomycin (SM), in addition to RFP, EB, and PZA. At 2 months after the initiation of the therapy (about one week after the change in the anti-tuberculosis drug regimen), his spinal fluid was examined, given his complaints of headache and vomiting. The spinal fluid analysis revealed invasion of lymphocytic inflammatory cells and high adenosine deaminase activity; the patient was thus diagnosed with tuberculous meningitis. His condition gradually improved after the changing of the anti-tuberculosis drugs. Thus, to summarize, the tuberculous meningitis had worsened paradoxically despite his systemic improvement, although it was successfully treated by the addition of LVFX and SM. We must keep in mind that a potential cause of fever during anti-tuberculosis therapy may be INH-resistant tuberculous meningitis. PMID:21327690

  17. Immunogenicity of a fusion protein containing immunodominant epitopes of Ag85C, MPT51, and HspX from Mycobacterium tuberculosis in mice and active TB infection.

    PubMed

    de Sousa, Eduardo Martins; da Costa, Adeliane Castro; Trentini, Monalisa Martins; de Araújo Filho, João Alves; Kipnis, André; Junqueira-Kipnis, Ana Paula

    2012-01-01

    Tuberculosis (TB) remains a major global health problem. The only vaccine against tuberculosis, attenuated Mycobacterium bovis Bacillus Calmette-Guerin (BCG), has demonstrated relatively low efficacy and does not provide satisfactory protection against the disease in adults. More effective vaccines and better therapies are urgently needed to reduce the global spread of TB. This study evaluated the immunogenicity of a recombinant M. tuberculosis Ag85C-MPT51-HspX fusion protein (CMX) in mice and individuals with active tuberculosis. BALB/c mice were immunized with the CMX protein liposome-encapsulated with CpG DNA or with CpGDNA liposome-encapsulated, liposome or saline as negative controls. The immunization produced high levels of anti-CMX -specific IgG1 and IgG2a antibodies and induced an increase in the relative and absolute numbers of specific TCD4 IFN-?(+) and TNF-?(+) cells in the spleen. Sera from a cohort of individuals with active tuberculosis contained higher levels of IgG and IgM that recognized CMX when compared to healthy individuals. In conclusion, this protein was shown to be immunogenic both in mice and humans. PMID:23133523

  18. Optimization of Pyrrolamides as Mycobacterial GyrB ATPase Inhibitors: Structure-Activity Relationship and In Vivo Efficacy in a Mouse Model of Tuberculosis

    PubMed Central

    P, Shahul Hameed; Mukherjee, Kakoli; Nandi, Vrinda; Waterson, David; Shandil, Radha; Balganesh, Meenakshi; Sambandamurthy, Vasan K.; Raichurkar, Anand Kumar; Deshpande, Abhijeet; Ghosh, Anirban; Awasthy, Disha; Shanbhag, Gajanan; Sheikh, Gulebahar; McMiken, Helen; Puttur, Jayashree; Reddy, Jitendar; Werngren, Jim; Read, Jon; Kumar, Mahesh; R, Manjunatha; Chinnapattu, Murugan; Madhavapeddi, Prashanti; Manjrekar, Praveena; Basu, Reetobrata; Gaonkar, Sheshagiri; Sharma, Sreevalli; Hoffner, Sven; Humnabadkar, Vaishali; Subbulakshmi, Venkita; Panduga, Vijender

    2014-01-01

    Moxifloxacin has shown excellent activity against drug-sensitive as well as drug-resistant tuberculosis (TB), thus confirming DNA gyrase as a clinically validated target for discovering novel anti-TB agents. We have identified novel inhibitors in the pyrrolamide class which kill Mycobacterium tuberculosis through inhibition of ATPase activity catalyzed by the GyrB domain of DNA gyrase. A homology model of the M. tuberculosis H37Rv GyrB domain was used for deciphering the structure-activity relationship and binding interactions of inhibitors with mycobacterial GyrB enzyme. Proposed binding interactions were later confirmed through cocrystal structure studies with the Mycobacterium smegmatis GyrB ATPase domain. The most potent compound in this series inhibited supercoiling activity of DNA gyrase with a 50% inhibitory concentration (IC50) of <5 nM, an MIC of 0.03 ?g/ml against M. tuberculosis H37Rv, and an MIC90 of <0.25 ?g/ml against 99 drug-resistant clinical isolates of M. tuberculosis. The frequency of isolating spontaneous resistant mutants was ?10?6 to 10?8, and the point mutation mapped to the M. tuberculosis GyrB domain (Ser208 Ala), thus confirming its mode of action. The best compound tested for in vivo efficacy in the mouse model showed a 1.1-log reduction in lung CFU in the acute model and a 0.7-log reduction in the chronic model. This class of GyrB inhibitors could be developed as novel anti-TB agents. PMID:24126580

  19. 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

  20. Early dynamics of T helper cell cytokines and T regulatory cells in response to treatment of active Mycobacterium tuberculosis infection

    PubMed Central

    Feruglio, S L; Tonby, K; Kvale, D; Dyrhol-Riise, A M

    2015-01-01

    Biomarkers that can identify tuberculosis (TB) disease and serve as markers for efficient therapy are requested. We have studied T cell cytokine production [interferon (IFN)-?, interleukin (IL)-2, tumour necrosis factor (TNF)-?] and degranulation (CD107a) as well as subsets of CD4+ T regulatory cells (Tregs) after in-vitro Mycobacterium tuberculosis (Mtb) antigen stimulation [early secretory antigenic target (ESAT)-6, culture filtrate protein (CFP)-10, antigen 85 (Ag85)] in 32 patients with active tuberculosis (TB) disease throughout 24 weeks of effective TB treatment. A significant decline in the fraction of Mtb-specific total IFN-? and single IFN-?-producing T cells was already observed after 2 weeks of treatment, whereas the pool of single IL-2+?cells increased over time for both CD4+ and CD8+ T cells. The Treg subsets CD25highCD127low, CD25highCD147++ and CD25highCD127lowCD161+ expanded significantly after Mtb antigen stimulation in vitro at all time-points, whereas the CD25highCD127lowCD39+ Tregs remained unchanged. The fraction of CD25highCD127low Tregs increased after 8 weeks of treatment. Thus, we revealed an opposing shift of Tregs and intracellular cytokine production during treatment. This may indicate that functional signatures of the CD4+ and CD8+ T cells can serve as immunological correlates of early curative host responses. Whether such signatures can be used as biomarkers in monitoring and follow-up of TB treatment needs to be explored further. PMID:25313008

  1. Active use of coyotes ( Canis latrans) to detect Bovine Tuberculosis in northeastern Michigan, USA

    Microsoft Academic Search

    A. R. Berentsen; M. R. Dunbar; S. R. Johnson; S. Robbe-Austerman; L. Martinez; R. L. Jones

    2011-01-01

    Bovine tuberculosis (bTB) is endemic in white-tailed deer (Odocoileus virginianus) in northeastern Michigan, USA, and research suggests transmission to cattle. Prevalence of the disease in deer is estimated at 1.8%, but as prevalence decreases the difficulty of detection increases. Research suggests coyotes (Canis latrans) have a higher prevalence of bTB in Michigan than deer and sampling coyotes may be a

  2. Evaluating the anti Mycobacterium tuberculosis activity of Alpinia galanga (L.) Willd. axenically under reducing oxygen conditions and in intracellular assays

    PubMed Central

    2014-01-01

    Background In tuberculosis (TB), the steadily increasing bacterial resistance to existing drugs and latent TB continue to be major concerns. A combination of conventional drugs and plant derived therapeutics can serve to expand the antimicrobial spectrum, prevent the emergence of drug resistant mutants and minimize toxicity. Alpinia galanga, used in various traditional medicines, possesses broad spectrum antibacterial properties. The study was undertaken to assess the antimycobacterial potential of A. galanga in axenic (under aerobic and anaerobic conditions) and intracellular assays. Methods Phytochemical analysis was done using HPTLC. The acetone, aqueous and ethanolic extracts (1, 10, 25, 50 and 100 ?g/ml) of A. galanga were tested axenically using Microplate Alamar Blue Assay (MABA) against Mycobacterium tuberculosis (M.tb) H37Rv and three drug sensitive and three multi drug resistant clinical isolates. The activity of the extracts was also evaluated intracellularly in A549 cell line against these strains. The extracts active under intracellular conditions were further tested in an axenic setup under reducing oxygen concentrations using only H37Rv. Results 1´ acetoxychavicol acetate, the reference standard used, was present in all the three extracts. The acetone and ethanolic extracts were active in axenic (aerobic and anaerobic) and intracellular assays. The aqueous extract did not demonstrate activity under the defined assay parameters. Conclusion A. galanga exhibits anti M.tb activity with multiple modes of action. Since the activity of the extracts was observed under reducing oxygen concentrations, it may be effective in treating the dormant and non-replicating bacteria of latent TB. Though the hypothesis needs further testing, A. galanga being a regular dietary component may be utilized in combination with the conventional TB therapy for enhanced efficacy. PMID:24592852

  3. FDG PET/CT findings of common bile duct tuberculosis.

    PubMed

    Dong, Aisheng; Wang, Yang; Gong, Jing; Zuo, Changjing

    2014-01-01

    Common bile duct (CBD) tuberculosis is rare. A 39-year-old woman was referred because of a 5-month history of abdominal pain. Abdominal enhanced MRI and CT showed dilatation of the distal CBD with irregularly thickened wall. Enhanced CT revealed enlarged retroperitoneal lymph nodes. FDG PET/CT showed increased FDG uptake of the CBD lesion and several retroperitoneal lymph nodes with slight FDG uptake. CBD cholangiocarcinoma with retroperitoneal lymph node metastasis was suspected. CBD tuberculosis was confirmed by endoluminal biopsy. Tuberculosis should be considered in the differential diagnosis of abnormal biliary FDG accumulation, particularly in tuberculosis endemic areas. PMID:23579971

  4. NF-?B Repressing Factor Inhibits Chemokine Synthesis by Peripheral Blood Mononuclear Cells and Alveolar Macrophages in Active Pulmonary Tuberculosis

    PubMed Central

    Huang, Kuo-Hsiung; Wang, Chun-Hua; Lee, Kang-Yun; Lin, Shu-Min

    2013-01-01

    NF-?B repressing factor (NRF) is a transcriptional silencer implicated in the basal silencing of specific NF-?B targeting genes, including iNOS, IFN-? and IL-8/CXCL8. IP-10/CXCL10 and IL-8/CXCL8 are involved in neutrophil and lymphocyte recruitment against M. tuberculosis (MTb) and disease progression of pulmonary tuberculosis (TB). Alveolar macrophages (AM) and peripheral blood mononuclear cells (PBMC) were used to study the regulatory role of NRF in pulmonary TB. AM and PBMC were purified from 19 TB patients and 15 normal subjects. To study the underlying mechanism, PBMC were exposed to heated TB bacilli. The regulation role of NRF in IP-10/CXCL10 and IL-8/CXCL8 was determined by NRF knock-down or over-expression. NRF binding capabilities in promoter sites were measured by chromatin immunoprecipitation (ChIP) assay. The levels of IP-10/CXCL10, IL-8/CXCL8 and NRF were significantly higher in AM and PBMC in patients with active TB. NRF played an inhibitory role in IP-10/CXCL10 and IL-8/CXCL8 inductions. We delineate the role of NRF in pulmonary TB, which inhibits the expressions of IP-10/CXCL10 and IL-8/CXCL8 in AM and PBMC of patients with high bacterial load. NRF may serve as an endogenous repressor to prevent robust increase in IP-10/CXCL10 and IL-8/CXCL8 when TB bacterial load is high. PMID:24223729

  5. Tuberculosis (TB)

    MedlinePLUS

    ... JavaScript on. Read more information on enabling JavaScript. Tuberculosis (TB) Skip Content Marketing Share this: Main Content ... HIV/AIDS Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis Research Agenda (PDF) TB Research at NIAID Research ...

  6. Diagnosis and therapy for prostate tuberculosis.

    PubMed

    Kulchavenya, Ekaterina; Brizhatyuk, Elena; Khomyakov, Victor

    2014-08-01

    In its 2012 global report on tuberculosis, the World Health Organization estimated that 3-7% (range 2.1-5.2%) of new cases and 20% (range 13-26%) of previously treated cases had multidrug-resistant tuberculosis (defined as tuberculosis caused by Mycobacterium tuberculosis isolates that are resistant to rifampicin and isoniazid). In many countries in Eastern Europe and central Asia, 9-32% of new patients and more than 50% of previously treated patients have multidrug-resistant tuberculosis. Ninety-three patients with suspected prostate tuberculosis were enrolled in this study and all underwent prostate biopsy. This method allowed confirmation of diagnosis in 32 patients (34.4%): 23 by histology, six by culture and five by polymerase chain reaction (PCR) (among them, two also had positive culture). The efficiency of an optimized scheme for the therapy of prostate tuberculosis (the second part of the study) was estimated in 53 patients. The first group (25 patients) was treated with a standard scheme of chemotherapy; the second group (28 prostate tuberculosis patients) received ofloxacin in addition for 2 months during the intensive phase. The phase continuation in both groups was identical, with rifampicin and isoniazid administered for 6 months. Optimization of the standard therapy by additional administration of ofloxacin improved results of the treatment in 33.8% of patients. PMID:25083162

  7. Clinical Effects of Gemifloxacin on the Delay of Tuberculosis Treatment

    PubMed Central

    Kim, Seo Yun; Yim, Jae-Joon; Park, Jong Sun; Park, Sung Soo; Heo, Eun Young; Lee, Chang-Hoon; Chung, Hee Soon

    2013-01-01

    Although gemifloxacin has low in vitro activity against Mycobacterium tuberculosis, the effect of gemifloxacin on the delay of tuberculosis (TB) treatment has not been validated in a clinical setting. The study group included patients with culture-confirmed pulmonary TB who initially received gemifloxacin for suspected community-acquired pneumonia (CAP). Two control groups contained patients treated with other fluoroquinolones or nonfluoroquinolone antibiotics. Sixteen cases were treated with gemifloxacin for suspected CAP before TB diagnosis. Sixteen and 32 patients were treated with other fluoroquinolones and nonfluoroquinolones, respectively. The median period from the initiation of antibiotics to the administration of anti-TB medication was nine days in the gemifloxacin group, which was significantly different from the other fluoroquinolones group (35 days). The median times for the nonfluoroquinolone group and the gemifloxacin group were not significantly different. There were no significant differences between the gemifloxacin and other fluoroquinolone group in terms of symptomatic and radiographic improvements. However, the frequency of radiographic improvement in the other fluoroquinolones group tended to be higher than in the gemifloxacin group. Gemifloxacin might be the preferred fluoroquinolone for treating CAP, to alleviate any concerns about delaying TB treatment. PMID:23486643

  8. Clinical effects of gemifloxacin on the delay of tuberculosis treatment.

    PubMed

    Kim, Seo Yun; Yim, Jae-Joon; Park, Jong Sun; Park, Sung Soo; Heo, Eun Young; Lee, Chang-Hoon; Chung, Hee Soon; Kim, Deog Kyeom

    2013-03-01

    Although gemifloxacin has low in vitro activity against Mycobacterium tuberculosis, the effect of gemifloxacin on the delay of tuberculosis (TB) treatment has not been validated in a clinical setting. The study group included patients with culture-confirmed pulmonary TB who initially received gemifloxacin for suspected community-acquired pneumonia (CAP). Two control groups contained patients treated with other fluoroquinolones or nonfluoroquinolone antibiotics. Sixteen cases were treated with gemifloxacin for suspected CAP before TB diagnosis. Sixteen and 32 patients were treated with other fluoroquinolones and nonfluoroquinolones, respectively. The median period from the initiation of antibiotics to the administration of anti-TB medication was nine days in the gemifloxacin group, which was significantly different from the other fluoroquinolones group (35 days). The median times for the nonfluoroquinolone group and the gemifloxacin group were not significantly different. There were no significant differences between the gemifloxacin and other fluoroquinolone group in terms of symptomatic and radiographic improvements. However, the frequency of radiographic improvement in the other fluoroquinolones group tended to be higher than in the gemifloxacin group. Gemifloxacin might be the preferred fluoroquinolone for treating CAP, to alleviate any concerns about delaying TB treatment. PMID:23486643

  9. 29 CFR 1904.11 - Recording criteria for work-related tuberculosis cases.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...Recording criteria for work-related tuberculosis cases. 1904.11 Section 1904...Recording criteria for work-related tuberculosis cases. (a) Basic requirement...to anyone with a known case of active tuberculosis (TB), and that employee...

  10. 29 CFR 1904.11 - Recording criteria for work-related tuberculosis cases.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...Recording criteria for work-related tuberculosis cases. 1904.11 Section 1904...Recording criteria for work-related tuberculosis cases. (a) Basic requirement...to anyone with a known case of active tuberculosis (TB), and that employee...

  11. 29 CFR 1904.11 - Recording criteria for work-related tuberculosis cases.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...Recording criteria for work-related tuberculosis cases. 1904.11 Section 1904...Recording criteria for work-related tuberculosis cases. (a) Basic requirement...to anyone with a known case of active tuberculosis (TB), and that employee...

  12. 29 CFR 1904.11 - Recording criteria for work-related tuberculosis cases.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...Recording criteria for work-related tuberculosis cases. 1904.11 Section 1904...Recording criteria for work-related tuberculosis cases. (a) Basic requirement...to anyone with a known case of active tuberculosis (TB), and that employee...

  13. 29 CFR 1904.11 - Recording criteria for work-related tuberculosis cases.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...Recording criteria for work-related tuberculosis cases. 1904.11 Section 1904...Recording criteria for work-related tuberculosis cases. (a) Basic requirement...to anyone with a known case of active tuberculosis (TB), and that employee...

  14. [Present and future of tuberculosis care in regions].

    PubMed

    Shigeto, Eriko

    2012-12-01

    As the incidence of active tuberculosis in Japan declines and the healthcare environment changes, restructuring of the medical care system for tuberculosis is required. According to a questionnaire survey in Hiroshima Prefecture, experiences in tuberculosis (TB) care and knowledge, such as standard treatment and DOT, is insufficient in the local medical institutions designated for tuberculosis care. Regional coordination between the tuberculosis hospital and the regional private practitioners will be one of the important issues in proper TB care. In order to strengthen coordination, Higashi-hiroshima Medical Center (HMC) collaborated with Onomichi Medical Association and the health center having jurisdiction over the area (Tobu Health Center) to create liaison clinical paths for doctors, a booklet for patient education and a medication record named "DOTS note". These liaison paths were provided to the regional practitioner from the health center on discharge and referral from HMC. After the start of regional cooperation, treatment outcome of the cohort of sputum smear positive pulmonary tuberculosis in the region were improved: success; 37.0% to 53.3% (cured; 0% to 40.0%, completed; 37.0% to 13.3%), treatment more than 12 months; 17.4% to 6.7%, died 37.0% to 26.7%. It is considered from experience of the regional cooperation in Hiroshima that regional medical cooperation using liaison paths is helpful to provide proper TB care. Treatment of patients with serious complication(s) is another issue in TB care. For example, only a few TB hospitals can treat the patient who needs hemodialysis, on the other hand, most general hospitals do not treat TB patients, because they have no beds and little knowledge. I think the following measures are effective and necessary for the future TB care: 1) one or more of the general hospitals in each region should provide one or more air-controlled bed(s) to treat TB patients, which can be also used for patients with suspected airborne infectious disease, 2) cooperation between tuberculosis experts and general physicians is necessary to provide standard TB care, 3) Rapid communication between TB experts and regional health centers to provide concrete information such as liaison clinical paths, and finally, 4) government commitment is needed to promote the above measures. PMID:23350520

  15. Outcome of tuberculosis treatment in HIV-positive adults diagnosed through active versus passive case-finding

    PubMed Central

    Balcha, Taye T.; Skogmar, Sten; Sturegård, Erik; Björkman, Per; Winqvist, Niclas

    2015-01-01

    Background The World Health Organization strongly recommends regular screening for tuberculosis (TB) in HIV-positive individuals. Objective To compare the outcome of anti-tuberculosis treatment (ATT) in HIV-positive adults diagnosed with TB through active case-finding (ACF) or passive case-finding (PCF). Design Antiretroviral therapy (ART)-naïve adults diagnosed with TB were included from two prospective cohort studies conducted in Ethiopia between September 2010 and March 2013. The PCF cohort was based at out-patient TB clinics, whereas participants in the ACF cohort were actively screened for TB by bacteriological sputum testing (smear microscopy, Xpert MTB/RIF assay, and liquid culture) without pre-selection on the basis of symptoms and signs. Outcomes of ATT were compared between participants in the two cohorts; characteristics at diagnosis and predictors of adverse outcomes were analysed. Results Among 439 TB/HIV co-infected participants, 307 and 132 belonged to PCF and ACF cohorts, respectively. Compared with the ACF participants, hemoptysis, conjunctival pallor, bedridden status, and low mid upper-arm circumference (MUAC) were significantly more common in participants identified through PCF. Sputum smear-positivity rates among pulmonary TB cases were 44.2% and 21.1% in the PCF and ACF cohorts, respectively (p<0.001). Treatment success was ascertained in 247 (80.5%) of the participants in the PCF cohort and 102 (77.2%) of the participants in the ACF cohorts (p=0.223). Low MUAC (p=0.001) independently predicted mortality in the participants in both cohorts. Conclusion Although patients identified through ACF had less advanced TB disease, ATT outcome was similar to the patients identified through PCF. To achieve a better outcome, case management in ACF strategy should be strengthened through enhanced patient-centred counselling and adherence support. PMID:25819037

  16. Characterization of suspected illegal skin whitening cosmetics.

    PubMed

    Desmedt, B; Van Hoeck, E; Rogiers, V; Courselle, P; De Beer, J O; De Paepe, K; Deconinck, E

    2014-03-01

    An important group of suspected illegal cosmetics consists of skin bleaching products, which are usually applied to the skin of the face, hands and décolleté for local depigmentation of hyper pigmented regions or more importantly, for a generalized reduction of the skin tone. These cosmetic products are suspected to contain illegal active substances that may provoke as well local as systemic toxic effects, being the reason for their banning from the EU market. In that respect, illegal and restricted substances in cosmetics, known to have bleaching properties, are in particular hydroquinone, tretinoin and corticosteroids. From a legislative point of view, all cosmetic products containing a prohibited whitening agent are illegal and must be taken off the EU market. A newly developed screening method using ultra high performance liquid chromatography-time off flight-mass spectrometry allows routine analysis of suspected products. 163 suspected skin whitening cosmetics, collected by Belgian inspectors at high risk sites such as airports and so-called ethnic cosmetic shops, were analyzed and 59% were classified as illegal. The whitening agents mostly detected were clobetasol propionate and hydroquinone, which represent a serious health risk when repeatedly and abundantly applied to the skin. PMID:24334193

  17. Biomarkers of Inflammation, Immunosuppression and Stress with Active Disease Are Revealed by Metabolomic Profiling of Tuberculosis Patients

    PubMed Central

    Maertzdorf, Jeroen; Black, Gillian F.; Repsilber, Dirk; Telaar, Anna; Mohney, Robert P.; Arndt-Sullivan, Cordelia; Ganoza, Christian A.; Faé, Kellen C.; Walzl, Gerhard; Kaufmann, Stefan H. E.

    2012-01-01

    Although tuberculosis (TB) causes more deaths than any other pathogen, most infected individuals harbor the pathogen without signs of disease. We explored the metabolome of >400 small molecules in serum of uninfected individuals, latently infected healthy individuals and patients with active TB. We identified changes in amino acid, lipid and nucleotide metabolism pathways, providing evidence for anti-inflammatory metabolomic changes in TB. Metabolic profiles indicate increased activity of indoleamine 2,3 dioxygenase 1 (IDO1), decreased phospholipase activity, increased abundance of adenosine metabolism products, as well as indicators of fibrotic lesions in active disease as compared to latent infection. Consistent with our predictions, we experimentally demonstrate TB-induced IDO1 activity. Furthermore, we demonstrate a link between metabolic profiles and cytokine signaling. Finally, we show that 20 metabolites are sufficient for robust discrimination of TB patients from healthy individuals. Our results provide specific insights into the biology of TB and pave the way for the rational development of metabolic biomarkers for TB. PMID:22844400

  18. Understanding Tuberculosis

    MedlinePLUS

    ... expensive, and last longer. Learn more about symptoms, diagnosis and treatment for tuberculosis ... Top Stories More about Lung Disease Behind the Headlines: COPD February 27, 2015 Personalized Medicine: Don't Guess. ...

  19. [Tuberculosis in the elderly].

    PubMed

    Vétillard, Anne-Laure; Cudennec, Tristan; Teillet, Laurent

    2012-01-01

    For people born in France, age is a major risk factor for developing tuberculosis.This curable pathology still has a high mortality rate which increases with age. Diagnosis difficulties, tolerance and compliance with treatment are issues specific to old age. An active policy of prevention, monitoring and training should enable the incidence of this pathology to continue to fall. PMID:22852503

  20. Crystal Structures of the Response Regulator DosR From Mycobacterium Tuberculosis Suggest a Helix Rearrangement Mechanism for Phosphorylation Activation

    SciTech Connect

    Wisedchaisri, G.; Wu, M.; Sherman, D.R.; Hol, W.G.J.

    2009-05-26

    The response regulator DosR is essential for promoting long-term survival of Mycobacterium tuberculosis under low oxygen conditions in a dormant state and may be responsible for latent tuberculosis in one-third of the world's population. Here, we report crystal structures of full-length unphosphorylated DosR at 2.2 {angstrom} resolution and its C-terminal DNA-binding domain at 1.7 {angstrom} resolution. The full-length DosR structure reveals several features never seen before in other response regulators. The N-terminal domain of the full-length DosR structure has an unexpected ({beta}{alpha}){sub 4} topology instead of the canonical ({beta}{alpha}){sub 5} fold observed in other response regulators. The linker region adopts a unique conformation that contains two helices forming a four-helix bundle with two helices from another subunit, resulting in dimer formation. The C-terminal domain in the full-length DosR structure displays a novel location of helix {alpha}10, which allows Gln199 to interact with the catalytic Asp54 residue of the N-terminal domain. In contrast, the structure of the DosR C-terminal domain alone displays a remarkable unstructured conformation for helix {alpha}10 residues, different from the well-defined helical conformations in all other known structures, indicating considerable flexibility within the C-terminal domain. Our structures suggest a mode of DosR activation by phosphorylation via a helix rearrangement mechanism.

  1. Application of Structure Activity Relationships of the Mycobacterium Tuberculosis Beta-Lactamase (BlaC) and the New Delhi Metallo-Beta-Lactamase (NDM-1) to Combating Beta-Lactamase Mediated Drug Resistance

    E-print Network

    Mire, Joseph Andrew

    2013-07-24

    on the class A ?-lactamase BlaC from Mycobacterium tuberculosis (Mtb) and addresses intermolecular interactions between BlaC and substrates, inhibitors, and biosensors that influence their kinetic parameters with BlaC and activities against Mtb. The substrate...

  2. Serodiagnostic efficacy of Mycobacterium tuberculosis 30/32-kDa mycolyl transferase complex, ESAT-6, and CFP-10 in patients with active tuberculosis.

    PubMed

    Kumar, Gavish; Dagur, Pradeep Kumar; Singh, Prashant Kumar; Shankar, Hari; Yadav, Virendra S; Katoch, Vishwa M; Bajaj, Bharat; Gupta, Rajesh; Sengupta, Utpal; Joshi, Beenu

    2010-02-01

    Elimination of tuberculosis (TB) largely depends upon definitive rapid diagnosis and treatment. Widely used diagnostic tests do not qualify for use in a developing country due to lack of either desired accuracy or their cost. In the present study an enzyme-linked immunosorbent assay was used to evaluate the diagnostic potential of an immuno-dominant 30/32-kDa mycolyl transferase complex (Ag85 complex) and Mycobacterium tuberculosis-specific proteins (ESAT-6 and CFP-10) of the RD1 region. Higher sensitivity (84.1%) with Ag85 complex was observed compared with ESAT-6 (64.9%) and CFP-10 (66%), with almost similar specificity (Ag85: 85.2%, ESAT-6: 88.9%, CFP-10: 85.2%), whereas the individual components of Ag85 complex, i.e. Ag85A, Ag85B, and Ag85C, showed sensitivities of 44.6, 34, and 80.9% and specificities of 55.6, 74.1, and 40.7% respectively. A cocktail of Ag85 complex, ESAT-6, CFP-10, Ag85A, Ag85B, and Ag85C antigens also could not help in increasing either sensitivity (51.1%) or specificity (85.2%). Furthermore, immunoblot analysis using clinical isolates as well as a standard strain (H37Rv) of M. tuberculosis also showed strong reactivity of sera from TB patients to Ag85 complex and, to a lesser extent, also to ESAT-6. To conclude, use of Ag85 complex along with ESAT-6 and CFP-10 seems to be promising in minimizing the heterogeneous sero-responses of adult TB cases. PMID:20049651

  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. Nanoparticle encapsulated lipopeptide conjugate of antitubercular drug isoniazid: in vitro intracellular activity and in vivo efficacy in a Guinea pig model of tuberculosis.

    PubMed

    Horváti, Kata; Bacsa, Bernadett; Kiss, Eva; Gyulai, Gerg?; Fodor, Kinga; Balka, Gyula; Rusvai, Miklós; Szabó, Eleonóra; Hudecz, Ferenc; B?sze, Szilvia

    2014-12-17

    Considering that Mycobacterium tuberculosis (Mtb) can survive in host phagocytes for decades and currently applied drugs are largely ineffective in killing intracellular Mtb, novel targeted delivery approaches to improve tuberculosis chemotherapy are urgently needed. In order to enhance the efficacy of a clinically used antitubercular agent (isoniazid, INH) a novel lipopeptide carrier was designed based on the sequence of tuftsin, which has been reported as a macrophage-targeting molecule. The conjugate showed relevant in vitro activity on Mtb H37Rv culture with low cytotoxicity and hemolytic activity on human cells. The conjugate directly killed intracellular Mtb and shows much greater efficacy than free INH. To improve bioavailability, the conjugate was encapsulated into poly(lactide-co-glycolide) (PLGA) nanoparticles and tested in vivo in a guinea pig infection model. External clinical signs, detectable mycobacterial colonies in the organs, and the histopathological findings substantiate the potent chemotherapeutic effect of orally administered conjugate-loaded nanoparticles. PMID:25394206

  5. A 25-kilodalton fraction from Mycobacterium tuberculosis that inhibits hexose monophosphate shunt activity, lysozyme release, and H2O2 production: reversal by gamma interferon.

    PubMed Central

    Wadee, A A; Clara, A M

    1989-01-01

    This study examined the effects of a 25-kilodalton (kDa) glycolipoprotein derived from Mycobacterium tuberculosis on phagocyte functions associated with antimicrobial activity. The 25-kDa fraction inhibited the ability of both polymorphonuclear cells and cultured monocytes to release lysozyme and produce hydrogen peroxide. In addition, the glycolipoprotein was capable of reducing hexose monophosphate shunt activity and interfered with the ability of polymorphonuclear cells to reduce Nitro Blue Tetrazolium. Inhibition of these antimicrobial systems was optimal at a 50-micrograms/ml concentration of the 25-kDa fraction. Gamma interferon, but not alpha interferon, partially reversed the inhibitory effect of the mycobacterial component in all of the systems assessed. These studies indicate important mechanisms in the understanding of the pathogenesis of tuberculosis and suggest that gamma interferon may have a therapeutic role in mycobacterial diseases. PMID:2492974

  6. 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.

  7. Improvement in Plasma Drug Activity during the Early Treatment Interval among Tanzanian Patients with Multidrug-Resistant Tuberculosis

    PubMed Central

    Ndusilo, Norah D.; Heysell, Scott K.; Mpagama, Stellah G.; Gratz, Jean; Segesela, Farida H.; Pazia, Saumu J.; Wang, Xin-Qun; Houpt, Eric R.; Kibiki, Gibson S.

    2015-01-01

    Background Individual pharmacokinetic variability may be common in patients treated for multidrug-resistant tuberculosis (MDR-TB) but data are sparse from resource-limited settings and across the early treatment interval. Methods Plasma drug activity, as measured by the TB Drug Activity (TDA) assay at 2 and 4 weeks of treatment with a standardized MDR-TB regimen was performed in patients with pulmonary MDR-TB from Tanzania. TDA values were correlated with measures of early treatment outcome including every two week collection of sputum for time-to-positivity (TTP) in liquid culture from the MGIT 960 automated system. Patients were evaluated at 24 weeks and those surviving without delayed sputum culture conversion (>8 weeks), culture reversion after previously negative, or weight loss were defined as having a favorable outcome. Results Twenty-five patients were enrolled with a mean age of 37 ±12 years. All were culture positive from the pretreatment sputum sample with a mean TTP in MGIT of 257 ±134 hours, and the median time to culture conversion on treatment was 6 weeks. Twenty patients (80%) had an increase in TDA, with the overall mean TDA at 2 weeks of 2.1 ±0.7 compared to 2.4 ±0.8 at 4 weeks (p = 0.005). At 2 weeks 13 subjects (52%) had a TDA value > 2-log killing against their own M. tuberculosis isolate compared to 17 subjects (68%) at 4 weeks (McNemar’s exact test p = 0.29). An interim treatment outcome was able to be determined in 23 patients (92%), of whom 7 had a poor outcome (30%). An increase in TDA from week 2 to week 4 was associated with favorable outcome, [unadjusted OR = 20.0, 95% CI: 1.61–247.98, exact p = 0.017 and adjusted OR = 19.33, 95% CI: 1.55–241.5, exact p = 0.023]. Conclusions The majority of patients with MDR-TB in Tanzania had an increase in plasma drug activity from week 2 to week 4 of treatment as measured by the TDA assay. Understanding the etiology and full impact of this dynamic may inform therapeutic intervention. PMID:25816161

  8. Diagnosis of Childhood Tuberculosis and Host RNA Expression in Africa

    PubMed Central

    Banwell, Claire M.; Chagaluka, George; Crampin, Amelia C.; Dockrell, Hazel M.; French, Neil; Hamilton, Melissa S.; Hibberd, Martin L.; Kern, Florian; Langford, Paul R.; Ling, Ling; Mlotha, Rachel; Ottenhoff, Tom H.M.; Pienaar, Sandy; Pillay, Vashini; Scott, J. Anthony G.; Twahir, Hemed; Wilkinson, Robert J.

    2014-01-01

    BACKGROUND Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV). METHODS The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood. RESULTS We identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%. CONCLUSIONS RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others). PMID:24785206

  9. [Extrapulmonary tuberculosis].

    PubMed

    Ramírez-Lapausa, M; Menéndez-Saldaña, A; Noguerado-Asensio, A

    2015-06-01

    Up to 25% of tuberculosis cases present extrapulmonary involvement. This is produced by haematogenous and lymphatic spread of the M. tuberculosis bacillus to other organs. The most common locations are the lymph nodes, pleura and the osteoarticular system. The problem with these types of tuberculosis is the difficulty in establishing a definitive diagnosis, since the clinical symptoms and results of imaging tests may be vague. It is often necessary to resort to invasive diagnostic testing such as ultrasound or CAT-guided FNAB, used to collect biological samples for diagnosis. Despite the growing use of and advances in recent years of molecular methods for early detection of mycobacteria DNA, cultures continue to be the gold standard that enable a firm microbiological diagnosis to be made. Treatment for these types of tuberculosis do not differ from treatment regimens for pulmonary forms of the same disease. The same antibiotic regimens for 6 months are recommended, and any extension of this period is advisable solely in tuberculosis affecting the central nervous system and in Pott's disease. PMID:25803112

  10. 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

  11. Relationship between Pyrazinamide Resistance, Loss of Pyrazinamidase Activity, and Mutations in the pncA Locus in Multidrug-Resistant Clinical Isolates of Mycobacterium tuberculosis

    Microsoft Academic Search

    M. MESTDAGH; P. A. FONTEYNE; L. REALINI; R. ROSSAU; G. JANNES; W. MIJS

    1999-01-01

    Sixty-two Mycobacterium tuberculosis isolates were tested for pyrazinamidase activity, and their pyrazinamide susceptibility was determined by the radiometric method. Sequencing of pncA genes in the 23 resistant strains revealed mutations in 16 pyrazinamidase-negative strains, 11 of which had not been previously described. Six isolates containing wild-type pncA might possess alternative resistance mechanisms. Pyrazinamide (PZA), one of the first-line drugs for

  12. Tuberculosis control activities before and after Hurricane Sandy--northeast and mid-Atlantic states, 2012.

    PubMed

    2013-03-22

    On October 29, 2012, Hurricane Sandy struck the U.S. northeast and mid-Atlantic seaboard; the effects of the storm extended to southeastern and midwestern states and to eastern Canada. At the time, 1,899 residents in the most affected areas were undergoing treatment for tuberculosis (TB) disease or infection. To ascertain the operational abilities of state and local TB programs during and after the storm and to determine whether lessons learned from a previous hurricane were effective in ensuring continuity of TB patient care, CDC interviewed staff members at all of the affected state and city TB control programs, including those in areas with power outages and flooded streets, tunnels, and subway lines. The interviews determined that continuity of care for TB patients in programs affected by Hurricane Sandy was better preserved than it had been during and after Hurricane Katrina in August 2005. This improvement might be attributed to 1) preparedness measures learned from Hurricane Katrina (e.g., preparing line lists of patients, providing patients with as-needed medications, and making back-up copies of patient records in advance of the storm) and 2) less widespread displacement of persons after Hurricane Sandy than occurred after Hurricane Katrina. Maintaining readiness among clinicians and TB control programs to respond to natural disasters remains essential to protecting public health and preserving TB patients' continuity of care. PMID:23515057

  13. Rifabutin encapsulated in liposomes exhibits increased therapeutic activity in a model of disseminated tuberculosis.

    PubMed

    Gaspar, M M; Cruz, A; Penha, A F; Reymão, J; Sousa, A C; Eleutério, C V; Domingues, S A; Fraga, A G; Filho, A Longatto; Cruz, M E M; Pedrosa, J

    2008-01-01

    Tuberculosis (TB) is a leading cause of death amongst infectious diseases. The low permeation of antimycobacterial agents and their difficult access to infected macrophages necessitate long-term use of high drug doses. Liposomes preferentially accumulate in macrophages, increasing the efficacy of antibiotics against intracellular parasites. In the present work, several rifabutin (RFB) liposomal formulations were developed and characterised and their in vivo profile was compared with free RFB following intravenous administration. With the RFB liposomal formulations tested, higher concentrations of the antibiotic were achieved in liver, spleen and lungs 24h post administration compared with free RFB. The concentration of RFB in these organs was dependent on the rigidity of liposomal lipids. The liposomal RFB formulation prepared with dipalmitoyl phosphatidylcholine:dipalmitoyl phosphatidylglycerol (DPPC:DPPG) was the most effective and was selected for biological evaluation in a mouse model of disseminated TB. Compared with mice treated with free RFB, mice treated with the DPPC:DPPG RFB formulation exhibited lower bacterial loads in the spleen (5.53 log(10) vs. 5.18 log(10)) and liver (5.79 log(10) vs. 5.41 log(10)). In the lung, the level of pathology was lower in mice treated with encapsulated RFB. These results suggest that liposomal RFB is a promising approach for the treatment of extrapulmonary TB in human immunodeficiency virus co-infected patients. PMID:18006283

  14. Metabolism of 2-methyladenosine in Mycobacterium tuberculosis.

    PubMed

    Parker, William B; Barrow, Esther W; Allan, Paula W; Shaddix, Sue C; Long, Mary C; Barrow, William W; Bansal, Namita; Maddry, Joseph A

    2004-01-01

    2-Methyladenosine (methyl-Ado) has selective activity against Mycobacterium tuberculosis (M. tuberculosis). In an effort to better understand its mechanism of action, we have characterized its metabolism in M. tuberculosis cells. The primary intracellular metabolite of methyl-Ado was 2-methyl-adenylate (methyl-AMP). Very little of the methyl-AMP was metabolized further. A M. tuberculosis strain that was resistant to methyl-Ado did not express adenosine kinase and did not convert methyl-Ado to methyl-AMP in intact cells. In contrast to these results, the primary intracellular metabolite of adenosine in M. tuberculosis cells was ATP, which was readily incorporated into RNA. The rate of metabolism of methyl-Ado to methyl-AMP was similar to the rate of metabolism of adenosine to ATP. Treatment of M. tuberculosis with methyl-Ado did not affect intracellular ATP levels. Methyl-Ado and Ado were also cleaved to 2-methyladenine and adenine, respectively, which accumulated in the medium outside the cells. These studies suggested that methyl-AMP was the active metabolite responsible for the cytotoxicity of this agent. Furthermore, because methyl-Ado was poorly metabolized in human cells, these studies indicated that the selective activity of methyl-Ado was due to its selective activation by M. tuberculosis. These studies have identified two enzyme reactions (Ado kinase and Ado cleavage) in M. tuberculosis that could be exploited for the rational design of new and selective anti-M. tuberculosis agents. PMID:15207808

  15. In Vitro Antimicrobial Activity of Extracts from Plants Used Traditionally in South Africa to Treat Tuberculosis and Related Symptoms

    PubMed Central

    Madikizela, Balungile; Ndhlala, Ashwell Rungano; Finnie, Jeffrey Franklin; Staden, Johannes Van

    2013-01-01

    Respiratory ailments are major human killers, especially in developing countries. Tuberculosis (TB) is an infectious disease causing a threat to human healthcare. Many South African plants are used in the traditional treatment of TB and related symptoms, but there has not been a sufficient focus on evaluating their antimicrobial properties. The aim of this study was to evaluate the antimicrobial properties of plants used traditionally to treat TB and related symptoms against microorganisms (Klebsiella pneumoniae, Staphylococcus aureus, and Mycobacterium aurum A+) associated with respiratory infections using the microdilution assay. Ten plants were selected based on a survey of available literature of medicinal plants used in South Africa for the treatment of TB and related symptoms. The petroleum ether, dichloromethane, 80% ethanol, and water extracts of the selected plants were evaluated for antibacterial activity. Out of 68 extracts tested from different parts of the 10 plant species, 17 showed good antimicrobial activities against at least one or more of the microbial strains tested, with minimum inhibitory concentration ranging from 0.195 to 12.5?mg/mL. The good antimicrobial properties of Abrus precatorius, Terminalia phanerophlebia, Indigofera arrecta, and Pentanisia prunelloides authenticate their traditional use in the treatment of respiratory diseases. Thus, further pharmacological and phytochemical analysis is required. PMID:23533527

  16. 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

  17. Functional Analysis in Mouse Embryonic Stem Cells Reveals Wild-Type Activity for Three Msh6 Variants Found in Suspected Lynch Syndrome Patients

    PubMed Central

    Wielders, Eva A. L.; Houlleberghs, Hellen; Isik, Gözde; te Riele, Hein

    2013-01-01

    Lynch syndrome confers an increased risk to various types of cancer, in particular early onset colorectal and endometrial cancer. Mutations in mismatch repair (MMR) genes underlie Lynch syndrome, with the majority of mutations found in MLH1 and MSH2. Mutations in MSH6 have also been found but these do not always cause a clear cancer predisposition phenotype and MSH6-defective tumors often do not show the standard characteristics of MMR deficiency, such as microsatellite instability. In particular, the consequences of MSH6 missense mutations are challenging to predict, which further complicates genetic counseling. We have previously developed a method for functional characterization of MSH2 missense mutations of unknown significance. This method is based on endogenous gene modification in mouse embryonic stem cells using oligonucleotide-directed gene targeting, followed by a series of functional assays addressing the MMR functions. Here we have adapted this method for the characterization of MSH6 missense mutations. We recreated three MSH6 variants found in suspected Lynch syndrome families, MSH6-P1087R, MSH6-R1095H and MSH6-L1354Q, and found all three to behave like wild type MSH6. Thus, despite suspicion for pathogenicity from clinical observations, our approach indicates these variants are not disease causing. This has important implications for counseling of mutation carriers. PMID:24040339

  18. Sternal tuberculosis in an immunocompetent adult

    PubMed Central

    Cherif, Eya; Ben Hassine, Lamia; Boukhris, Imen; Khalfallah, Narjess

    2013-01-01

    Skeletal tuberculosis accounts for 1–3% of patients with mycobacterial infection. Any bone can be a site for tuberculosis, but sternum involvement is quite rare. We report the case of a 37-year-old woman admitted because of chest pain and increased swelling over the anterior chest. She was immunocompetent and had no systemic features. She was diagnosed with tuberculosis of the sternum without active pulmonary disease. Conservative management with oral multidrug antituberculous therapy completely cured the patient. PMID:23580679

  19. Psoriatic Disease and Tuberculosis Nowadays

    PubMed Central

    Balato, Nicola; Di Costanzo, Luisa; Ayala, Fabio; Balato, Anna; Sanduzzi, Alessandro; Bocchino, Marialuisa

    2012-01-01

    Psoriasis is a chronic, relapsing and remitting inflammatory skin and joint disease that has a prevalence of 2-3% in the world's population, whereas of 1–2% in Europe. The traditional concept of psoriasis as the “healthy people's” disease has been recently revised because of ever-increasing reports of associations with various pathological conditions (hypertension, Crohn's disease, type II diabetes mellitus, obesity, dyslipidemia, metabolic syndrome, infectious conditions). Particularly, advances in psoriasis therapies have introduced biologic agents. All the tumor necrosis factor-alpha inhibitors are associated with an increased risk of developing active disease in patients with latent tuberculosis infection, because of TNF-? key role against Mycobacterium tuberculosis. For this reason, exclusion of active tuberculosis and treatment of latent tuberculosis infection are clinical imperatives prior to starting this therapy. Moreover active surveillance for a history of untreated or partially treated tuberculosis or latent form has already been shown to be effective in reducing the number of incident tuberculosis cases. PMID:22645622

  20. 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,…

  1. Crystal Structure and Activity Studies of the Mycobacterium tuberculosis  Lactamase Reveal Its Critical Role in Resistance to  Lactam Antibiotics

    Microsoft Academic Search

    Feng Wang; Craig Cassidy; James C. Sacchettini

    2006-01-01

    -Lactam antibiotics are extremely effective in disrupting the synthesis of the bacterial cell wall in both gram-positive and gram-negative bacteria. However, they are ineffective against Mycobacterium tuberculosis, due to the production of a -lactamase enzyme encoded on the chromosome of M. tuberculosis that degrades these antibiotics. Indeed, recent studies have demonstrated that deletion of the blaC gene, the only gene

  2. 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

  3. Influence of diabetes mellitus and risk factors in activating latent tuberculosis infection: a case for targeted screening in malaysia.

    PubMed

    Swarna Nantha, Y

    2012-10-01

    A review of the epidemiology of tuberculosis, its contributing risk factors (excluding HIV) and the role of screening latent tuberculosis infection in Malaysia was done. Despite the global and domestic decrease in prevalence rates of tuberculosis in the past decade, there is an alarming increase in the trend of non communicable diseases in the country. High prevalence rates of major risk factors leading to reactivation of tuberculosis were seen within the population, with diabetes mellitus being in the forefront. The rising numbers in the ageing population of Malaysia poses a further threat of re-emergence of tuberculosis in the years to come. Economically, screening of diabetic patients with comorbidities for latent tuberculosis infection (LTBI) using two major techniques, namely tuberculin sensitivity (TST) and Interferon gamma release assay tests (IGRA) could be a viable option. The role of future research in the detection of LTBI in the Malaysian setting might be necessary to gauge the disease reservoir before implementing prophylactic measures for high risk groups involved. PMID:23770860

  4. Living with Tuberculosis

    MedlinePLUS

    ... for ENews Home > Lung Disease > Tuberculosis Living With Tuberculosis You will need regular checkups to make sure ... breathes the air. View in depth resources for tuberculosis A A A Share Print State of Tobacco ...

  5. Tuberculosis and Diabetes

    MedlinePLUS

    TUBERCULOSIS & DIABETES COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES © WHO Sept 2011 For more information: ... increase by 50% by 2030 THE LINKS BETWEEN TUBERCULOSIS AND DIABETES • People with a weak immune system, ...

  6. Tuberculosis during TNF-? inhibitor therapy, despite screening.

    PubMed

    Hofland, Regina W; Thijsen, Steven F T; Verhagen, Marc A M T; Schenk, Yolande; Bossink, Ailko W J

    2013-11-01

    As part of a prospective study on the safety of TNF-? inhibitor therapy after screening for and treatment of latent tuberculosis infection (LTBI), we report two patients who developed active tuberculosis (TB) infection during TNF-? inhibitor therapy, despite negative screening for LTBI. The clinical history is suggestive of a primary infection acquired during travelling to TB-endemic countries. In this lesson of the month we would like to highlight the risk of travelling to TB-endemic areas in patients treated with TNF-? inhibitor therapy. Screening for latent tuberculosis infection is not enough to prevent tuberculosis in patients treated with TNF-? inhibitor therapy. PMID:23598710

  7. Interferon-? release assay in HIV-infected patients with active tuberculosis: impact of antituberculous drugs on host immune response.

    PubMed

    Sauzullo, Ilaria; Mengoni, Fabio; Ermocida, Angela; Massetti, Anna P; D'Agostino, Claudia; Russo, Gianluca; Salotti, Alessandra; Falciano, Mario; Vullo, Vincenzo; Mastroianni, Claudio M

    2014-04-01

    The objective of the study was to: 1) investigate the performance of QuantiFERON-TB Gold In-Tube (QFT-GIT) in HIV-infected patients with active tuberculosis (TB); 2) evaluate the sequential changes in QFT-GIT assay during the treatment response; 3) investigate the direct in vitro effects of antituberculous drugs on both secretion of IFN-g and apoptosis of T cells. Forty-four HIV-patients with active TB were enrolled and tested with QFT-GIT. Thirteen of them were followed longitudinally by QFT-GIT, performed at baseline and six and nine months after TB-treatment onset. For in vitro experiments, cells from healthy donors and HIV-naive subjects were pretreated with four antituberculous-drugs, and then examined for IFN-g secretion and apoptosis of T-cells. The QFT-GIT was positive in 66%, negative in 11.3% and indeterminate in 22.7%. Longitudinal analysis in 13 HIV-TB subjects showed that at therapy completion a reversion to negative response was found only in 38.4% of patients, but in 30.7% the QFT-GIT remained positive. Overall, during the anti-TB treatment no significant decrease in average IFN-g response was observed in these patients (p<0.001). In vitro experiments showed that the four antituberculous- drugs, within the range of therapeutically achievable concentrations, did not exert any down-regulatory effect on IFN-g production and did not have any effect on apoptosis of T cells from HIV naïve subjects. Despite the high rate of indeterminate results, QFT-GIT assay may represent a good tool in the diagnostic workup for active TB in HIV-patients. Although the antituberculous drugs do not have any direct effect on host immune response to mycobacterial antigen, changes in longitudinal IGRA response have been found during in vivo anti-TB treatment. PMID:24858642

  8. 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

  9. Suppression of Mycobacterium Tuberculosis Induced Reactive Oxygen Species and Tumor Necrosis Factor-Alpha Activity in Human Monocytes of Systemic Lupus Erythematosus Patients by Reduced Glutathione

    PubMed Central

    Azfar, Shah Farhan; Islam, Najmul

    2012-01-01

    Objectives The etiology and pathogenesis of systemic lupus erythematosus remains unknown, evidence exists for the involvement of mycobacterial antigen. This study is aimed to determine the effect of Mycobacterium tuberculosis on clinical course of SLE patients and the role of ROS and TNF-? in the pathogenesis of tuberculosis associated SLE patients. Methods This study was done on 100 patients divided into SLE group (n=30), TB group (n=30), SLE-TB group (n=30) and control group (n=10). All patients underwent clinical, biochemical and immunological evaluation by employing techniques such as SDS-PAGE, direct binding and competition ELISA, PBMC and cell culture. Results Fever, arthritis, skin rash, photosensitivity were more common in both SLE and SLE-TB group. Reduced glutathione showed amelioration of ROS and TNF-? induced action, which in turn, subsequently suppressed the immune-bindings observed in monocytes of TB and SLE patients cultured without glutathione. Conclusion Data shows that SLE patients are more susceptible to developing Mycobacterium tuberculosis, as ROS and TNF-? in SLE patients could activate the replication of mycobacterial Ag85B (30 kDa) after bacilli infection. PMID:22359719

  10. Using Peer Helpers for Tuberculosis Prevention.

    ERIC Educational Resources Information Center

    McCue, Maureen; Afifi, Larry Anna

    1996-01-01

    Describes a peer helper program initiated by the University of Iowa Student Health Services to prevent active tuberculosis development among foreign national students. Before instituting the program, compliance with tuberculosis prevention efforts for those students was less than 5%. Since the peer program was instituted, compliance has risen to…

  11. In vitro activity of antituberculous agents against Mycobacterium tuberculosis isolates from Bogota, DC (Colombia) evaluated by the ETest.

    PubMed

    Sánchez, L; Londoño, D; Arango, A I; Mattar, S

    1999-10-01

    Tuberculosis tests for antimicrobial susceptibility takes weeks. However, delayed therapy, can compromise the patient, as well as lead to an increase in disease incidence. Among infectious diseases, tuberculosis continues to be a leading cause of death in the world. The E-test is a new concept for Minimal Inhibitory Concentrations (MIC) determinations for antimicrobial agents that is based on a predefined antibiotic gradient on a plastic strip calibrated with a continuous logarithmic MIC scale covering 15 two-fold dilutions. MICs of rifampin, isoniazid, and ethambutol were determined by using the E-test (AB BIODISK, Solna, Sweden) for 30 clinical strains of Mycobacterium tuberculosis isolated from four hospitals, and were compared with the Bactec method. To make the inoculum with a turbidity equivalent to a McFarland 3.0 standard, we obtained a sample from an agar surface and the Bactec 460, as described by the manufacturer. Excellent agreement (100% for rifampin, 96.8% for ethambutol, and 90% for isoniazid) was demonstrated between the E-test MIC distributions and the Bactec interpretive criteria for all clinical isolates of M. tuberculosis tested. The E-test appears to be a good alternative method for testing the susceptibility of M. tuberculosis isolates to the three, most-commonly-used therapeutic agents. PMID:10579090

  12. Multifoci Bone Tuberculosis and Lymphadenitis in Mediastinum Mimics Malignancy on FDG-PET/CT: A Case Report

    PubMed Central

    Alan Selçuk, Nalan; Fenercio?lu, Ay?en; Selçuk, Hatem Hakan; Uluçay, Ça?atay; Yencilek, Esin

    2014-01-01

    Positron Emission Tomography with 2-deoxy-[F-18]-fluoro-D-glucose (FDG-PET) has become a reliable diagnostic tool in clinical practice similar to Magnetic Resonance (MR) imaging and Computed Tomography (CT). FDG-PET has especially been used to differentiate malignant from benign lesions, and for staging and follow- up malignant tumors. However, FDG-PET has some pitfalls in cancer screening and FDG tracer accumulates at sites of infection and inflammation. Bone tuberculosis may be confused with malignant tumors of bone and its metastases, and can accumulate focally increased FDG in active period. We present a 60-year-old woman with lytic bone lesions and mediastinal hypermetabolic foci, initially suspected to be malignant by means of FDG-PET and the other imaging modalities; however, bone biopsy confirmed the diagnosis of bone tuberculosis. Conflict of interest:None declared. PMID:24653936

  13. 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

  14. Oesophageal tuberculosis

    PubMed Central

    Bonthala, Latha; Wood, Eleanor

    2011-01-01

    The case discussed is that of a previously healthy 48-year-old female who presented with a week long history of epigastric pain and continuing weight loss. A series of investigations and supporting literature alluded to a diagnosis of oesophageal tuberculosis (TB), and antituberculous medication was commenced accordingly. An accompanying discussion considers the incidence, differential diagnoses, pathogenesis, clinical features, investigations and aspects of management of oesophageal TB. PMID:22669888

  15. Effects of acetyl-L-carnitine oral administration on lymphocyte antibacterial activity and TNF-alpha levels in patients with active pulmonary tuberculosis. A randomized double blind versus placebo study.

    PubMed

    Jirillo, E; Altamura, M; Munno, I; Pellegrino, N M; Sabato, R; Di Fabio, S; De Simone, C

    1991-01-01

    Acetyl-L-carnitine (ALC), a drug for the treatment of ageing-related neuroendocrine dysfunctions, was orally administered--2 gm/day for 30 days--to 10 patients with active pulmonary tuberculosis (TBC). Lymphocyte-mediated antibacterial activity and serum levels of tumor necrosis factor (TNF)-alpha were evaluated before and after treatment, comparing the values with those of 10 TBC patients receiving placebo. Results show that by day 30, antibacterial activity remained unmodified or increased in ALC-treated subjects, while decreased in the placebo group. No influence of ALC on TNF-alpha levels was detectable. These data suggest that the host's immune responses to M. tuberculosis infection can be selectively modulated by drugs acting on the neuroendocrine axis. PMID:1770216

  16. Current tuberculosis screening practices.

    PubMed Central

    Snider, D E; Anderson, H R; Bentley, S E

    1984-01-01

    Health department officials in all 50 states and 14 major cities responded to a survey questionnaire designed to obtain information about current tuberculosis screening practices. Persons being screened fell into the groups designated as high risk by the American Thoracic Society (ATS) and the Centers for Disease Control (CDC). The methods used for screening were generally those advocated by ATS, CDC, and the Food and Drug Administration (FDA), although chest radiographs continue to be overused. Screening in about one-half of the groups is mandated by law or regulation. There appears to be some confusion about the circumstances in which "two-step" tuberculin testing should be used. Data on the productivity and costs of screening activities were very limited. We encourage those responsible for tuberculosis screening programs to evaluate them, discontinue those which are unproductive, and intensify those which are productive. PMID:6507687

  17. Cost-Effectiveness Analysis of Community Active Case Finding and Household Contact Investigation for Tuberculosis Case Detection in Urban Africa

    PubMed Central

    Sekandi, Juliet N.; Dobbin, Kevin; Oloya, James; Okwera, Alphonse; Whalen, Christopher C.; Corso, Phaedra S.

    2015-01-01

    Introduction Case detection by passive case finding (PCF) strategy alone is inadequate for detecting all tuberculosis (TB) cases in high burden settings especially Sub-Saharan Africa. Alternative case detection strategies such as community Active Case Finding (ACF) and Household Contact Investigations (HCI) are effective but empirical evidence of their cost-effectiveness is sparse. The objective of this study was to determine whether adding ACF or HCI compared with standard PCF alone represent cost-effective alternative TB case detection strategies in urban Africa. Methods A static decision modeling framework was used to examine the costs and effectiveness of three TB case detection strategies: PCF alone, PCF+ACF, and PCF+HCI. Probability and cost estimates were obtained from National TB program data, primary studies conducted in Uganda, published literature and expert opinions. The analysis was performed from the societal and provider perspectives over a 1.5 year time-frame. The main effectiveness measure was the number of true TB cases detected and the outcome was incremental cost-effectiveness ratios (ICERs) expressed as cost in 2013 US$ per additional true TB case detected. Results Compared to PCF alone, the PCF+HCI strategy was cost-effective at US$443.62 per additional TB case detected. However, PCF+ACF was not cost-effective at US$1492.95 per additional TB case detected. Sensitivity analyses showed that PCF+ACF would be cost-effective if the prevalence of chronic cough in the population screened by ACF increased 10-fold from 4% to 40% and if the program costs for ACF were reduced by 50%. Conclusions Under our baseline assumptions, the addition of HCI to an existing PCF program presented a more cost-effective strategy than the addition of ACF in the context of an African city. Therefore, implementation of household contact investigations as a part of the recommended TB control strategy should be prioritized. PMID:25658592

  18. 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

  19. A High-Throughput Screen against Pantothenate Synthetase (PanC) Identifies 3-Biphenyl-4-Cyanopyrrole-2-Carboxylic Acids as a New Class of Inhibitor with Activity against Mycobacterium tuberculosis

    PubMed Central

    Kumar, Anuradha; Casey, Allen; Odingo, Joshua; Kesicki, Edward A.; Abrahams, Garth; Vieth, Michal; Masquelin, Thierry; Mizrahi, Valerie; Hipskind, Philip A.; Sherman, David R.; Parish, Tanya

    2013-01-01

    The enzyme pantothenate synthetase, PanC, is an attractive drug target in Mycobacterium tuberculosis. It is essential for the in vitro growth of M. tuberculosis and for survival of the bacteria in the mouse model of infection. PanC is absent from mammals. We developed an enzyme-based assay to identify inhibitors of PanC, optimized it for high-throughput screening, and tested a large and diverse library of compounds for activity. Two compounds belonging to the same chemical class of 3-biphenyl-4- cyanopyrrole-2-carboxylic acids had activity against the purified recombinant protein, and also inhibited growth of live M. tuberculosis in manner consistent with PanC inhibition. Thus we have identified a new class of PanC inhibitors with whole cell activity that can be further developed. PMID:24244263

  20. Rapid Detection of Pyrazinamide-Resistant Mycobacterium tuberculosis by a PCR-Based In Vitro System

    Microsoft Academic Search

    Yasuhiko Suzuki; Aya Suzuki; Aki Tamaru; Chihiro Katsukawa; Hajime Oda

    2002-01-01

    Pyrazinamide (PZA), an analog of nicotinamide, is a prodrug for tuberculosis which requires conversion to the bactericidal compound pyrazinoic acid by bacterial pyrazinamidase activity. Mutations leading to a loss of pyrazinamidase activity cause PZA resistance in Mycobacterium tuberculosis. Thus, the detection of pyrazin- amidase activity makes the discrimination of PZA-resistant tuberculosis possible. However, the detection of the pyrazinamidase activity of

  1. System and method for disrupting suspect objects

    DOEpatents

    Gladwell, T. Scott; Garretson, Justin R; Hobart, Clinton G; Monda, Mark J

    2013-07-09

    A system and method for disrupting at least one component of a suspect object is provided. The system includes a source for passing radiation through the suspect object, a screen for receiving the radiation passing through the suspect object and generating at least one image therefrom, a weapon having a discharge deployable therefrom, and a targeting unit. The targeting unit displays the image(s) of the suspect object and aims the weapon at a disruption point on the displayed image such that the weapon may be positioned to deploy the discharge at the disruption point whereby the suspect object is disabled.

  2. 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.

  3. 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

  4. IL-4R?-Dependent Alternative Activation of Macrophages Is Not Decisive for Mycobacterium tuberculosis Pathology and Bacterial Burden in Mice.

    PubMed

    Guler, Reto; Parihar, Suraj P; 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

  5. 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

  6. Prevalence of smear positive pulmonary tuberculosis among prisoners in North Gondar Zone Prison, northwest Ethiopia

    PubMed Central

    2012-01-01

    Background People concentrated in congregated systems, such as prisons, are important but often neglected reservoirs for TB transmission, and threaten those in the outside community. Therefore, this study was conducted to determine the prevalence of tuberculosis in a prison system of North Gondar Zone. Methods An active case-finding survey in North Gondar Prison was carried out from March to May 2011. All prison inmates who had history of cough for at least a week were included in the study. Three morning sputum samples were collected from suspected inmates and examined through fluorescence microscopy. Fine needle aspiration cytology was done for those having significant lymphadenopathy. Pre and post HIV test counseling was provided after written consent. Binary logistic and multivariable analysis was performed using SPSS version 16. Results A total of 250 prisoners were included in the survey. Among these, 26 (10.4%) prisoners were found to have TB giving a point prevalence of 1482.3 per 100,000 populations of smear positive TB among the TB suspects. All the inmates who participated in the study volunteered for HIV testing and a total of 19(7.6%) inmates were found to be reactive for the HIV antibody test amongst of which 9(47.4%) had TB co-infection. The prevalence of HIV infection in the TB infected inmates was found to be 34.6% (9/26). From the 26 TB cases identified 12 (46.2%) were having under nutrition (BMI?active transmission of TB within the prison. There was a high prevalence of HIV among the TB suspects. Strong cooperation between prison authorities and the national tuberculosis control programmes is urgently required to develop locally appropriate interventions to reduce transmission. The determinants for poor nutrition in the prison need also further investigation. PMID:23241368

  7. UvrD2 Is Essential in Mycobacterium tuberculosis, but Its Helicase Activity Is Not Required ?

    PubMed Central

    Williams, Alan; Güthlein, Carolin; Beresford, Nicola; Böttger, Erik C.; Springer, Burkhard; Davis, Elaine O.

    2011-01-01

    UvrD is an SF1 family helicase involved in DNA repair that is widely conserved in bacteria. Mycobacterium tuberculosishas two annotated UvrD homologues; here we investigate the role of UvrD2. The uvrD2gene at its native locus could be knocked out only in the presence of a second copy of the gene, demonstrating that uvrD2is essential. Analysis of the putative protein domain structure of UvrD2 shows a distinctive domain architecture, with an extended C terminus containing an HRDC domain normally found in SF2 family helicases and a linking domain carrying a tetracysteine motif. Truncated constructs lacking the C-terminal domains of UvrD2 were able to compensate for the loss of the chromosomal copy, showing that these C-terminal domains are not essential. Although UvrD2 is a functional helicase, a mutant form of the protein lacking helicase activity was able to permit deletion of uvrD2at its native locus. However, a mutant protein unable to hydrolyze ATP or translocate along DNA was not able to compensate for lack of the wild-type protein. Therefore, we concluded that the essential role played by UvrD2 is unlikely to involve its DNA unwinding activity and is more likely to involve DNA translocation and, possibly, protein displacement. PMID:21725019

  8. CT-Guided Transthoracic Core Biopsy for Pulmonary Tuberculosis: Diagnostic Value of the Histopathological Findings in the Specimen

    SciTech Connect

    Fukuda, Hozumi, E-mail: fkdhzmrad@mitsuihosp.or.jp; Ibukuro, Kenji; Tsukiyama, Toshitaka; Ishii, Rei [Mitsui Memorial Hospital, Department of Radiology (Japan)

    2004-09-15

    We evaluated the value of CT-guided transthoracic core biopsy for the diagnosis of mycobacterial pulmonary nodules. The 30 subjects in this study had pulmonary nodules that had been either diagnosed histopathologically as tuberculosis or were suspected as tuberculosis based on a specimen obtained by CT-guided transthoracic core biopsy. The histopathological findings, the existence of acid-fast bacilli in the biopsy specimens, and the clinical course of the patients after the biopsy were reviewed retrospectively. Two of the three histological findings for tuberculosis that included epithelioid cells, multinucleated giant cells and caseous necrosis were observed in 21 of the nodules which were therefore diagnosed as histological tuberculosis. Six of these 21 nodules were positive for acid-fast bacilli, confirming the diagnosis of tuberculosis. Thirteen of the 21 nodules did not contain acid-fast bacilli but decreased in size in response to antituberculous treatment and were therefore diagnosed as clinical tuberculosis. Seven nodules with only caseous necrosis were diagnosed as suspected tuberculosis, with a final diagnosis of tuberculosis being made in 4 of the nodules and a diagnosis of old tuberculosis in 2 nodules. Two nodules with only multinucleated giant cells were diagnosed as suspected tuberculosis with 1 of these nodules being diagnosed finally as tuberculosis and the other nodule as a nonspecific granuloma. When any two of the three following histopathological findings - epithelioid cells, multinucleated giant cells or caseous necrosis - are observed in a specimen obtained by CT-guided transthoracic core biopsy, the diagnosis of tuberculosis can be established without the detection of acid-fast bacilli or Mycobacterium tuberculosis.

  9. Novel, potent, orally bioavailable and selective mycobacterial ATP synthase inhibitors that demonstrated activity against both replicating and non-replicating M. tuberculosis.

    PubMed

    Singh, Supriya; Roy, Kuldeep K; Khan, Shaheb R; Kashyap, Vivek Kr; Sharma, Abhisheak; Jaiswal, Swati; Sharma, Sandeep K; Krishnan, Manju Yasoda; Chaturvedi, Vineeta; Lal, Jawahar; Sinha, Sudhir; Gupta, Arnab D; Srivastava, Ranjana; Saxena, Anil K

    2015-02-15

    The mycobacterial F0F1-ATP synthase (ATPase) is a validated target for the development of tuberculosis (TB) therapeutics. Therefore, a series of eighteen novel compounds has been designed, synthesized and evaluated against Mycobacterium smegmatis ATPase. The observed ATPase inhibitory activities (IC50) of these compounds range between 0.36 and 5.45?M. The lead compound 9d [N-(7-chloro-2-methylquinolin-4-yl)-N-(3-((diethylamino)methyl)-4-hydroxyphenyl)-2,3-dichlorobenzenesulfonamide] with null cytotoxicity (CC50>300?g/mL) and excellent anti-mycobacterial activity and selectivity (mycobacterium ATPase IC50=0.51?M, mammalian ATPase IC50>100?M, and selectivity >200) exhibited a complete growth inhibition of replicating Mycobacterium tuberculosis H37Rv at 3.12?g/mL. In addition, it also exhibited bactericidal effect (approximately 2.4log10 reductions in CFU) in the hypoxic culture of non-replicating M. tuberculosis at 100?g/mL (32-fold of its MIC) as compared to positive control isoniazid [approximately 0.2log10 reduction in CFU at 5?g/mL (50-fold of its MIC)]. The pharmacokinetics of 9d after p.o. and IV administration in male Sprague-Dawley rats indicated its quick absorption, distribution and slow elimination. It exhibited a high volume of distribution (Vss, 0.41L/kg), moderate clearance (0.06L/h/kg), long half-life (4.2h) and low absolute bioavailability (1.72%). In the murine model system of chronic TB, 9d showed 2.12log10 reductions in CFU in both lung and spleen at 173?mol/kg dose as compared to the growth of untreated control group of Balb/C male mice infected with replicating M. tuberculosis H37Rv. The in vivo efficacy of 9d is at least double of the control drug ethambutol. These results suggest 9d as a promising candidate molecule for further preclinical evaluation against resistant TB strains. PMID:25614114

  10. Central nervous system tuberculosis.

    PubMed

    Torres, Carlos; Riascos, Roy; Figueroa, Ramon; Gupta, Rakesh K

    2014-06-01

    Tuberculosis (TB) has shown a resurgence in nonendemic populations in recent years and accounts for 8 million deaths annually in the world. Central nervous system involvement is one of the most serious forms of this infection, acting as a prominent cause of morbidity and mortality in developing countries. The rising number of cases in developed countries is mostly attributed to factors such as the pandemic of acquired immunodeficiency syndrome and increased migration in a globalized world. Mycobacterium TB is responsible for almost all cases of tubercular infection in the central nervous system. It can manifest in a variety of forms as tuberculous meningitis, tuberculoma, and tubercular abscess. Spinal infection may result in spondylitis, arachnoiditis, and/or focal intramedullary tuberculomas. Timely diagnosis of central nervous system TB is paramount for the early institution of appropriate therapy, because delayed treatment is associated with severe morbidity and mortality. It is therefore important that physicians and radiologists understand the characteristic patterns, distribution, and imaging manifestations of TB in the central nervous system. Magnetic resonance imaging is considered the imaging modality of choice for the study of patients with suspected TB. Advanced imaging techniques including magnetic resonance perfusion and diffusion tensor imaging may be of value in the objective assessment of therapy and to guide the physician in the modulation of therapy in these patients. PMID:24887691

  11. A novel non-radioactive primase–pyrophosphatase activity assay and its application to the discovery of inhibitors of Mycobacterium tuberculosis primase DnaG

    PubMed Central

    Biswas, Tapan; Resto-Roldán, Esteban; Sawyer, Sean K.; Artsimovitch, Irina; Tsodikov, Oleg V.

    2013-01-01

    Bacterial DNA primase DnaG synthesizes RNA primers required for chromosomal DNA replication. Biochemical assays measuring primase activity have been limited to monitoring formation of radioactively labelled primers because of the intrinsically low catalytic efficiency of DnaG. Furthermore, DnaG is prone to aggregation and proteolytic degradation. These factors have impeded discovery of DnaG inhibitors by high-throughput screening (HTS). In this study, we expressed and purified the previously uncharacterized primase DnaG from Mycobacterium tuberculosis (Mtb DnaG). By coupling the activity of Mtb DnaG to that of another essential enzyme, inorganic pyrophosphatase from M. tuberculosis (Mtb PPiase), we developed the first non-radioactive primase–pyrophosphatase assay. An extensive optimization of the assay enabled its efficient use in HTS (Z? = 0.7 in the 384-well format). HTS of 2560 small molecules to search for inhibitory compounds yielded several hits, including suramin, doxorubicin and ellagic acid. We demonstrate that these three compounds inhibit Mtb DnaG. Both suramin and doxorubicin are potent (low-µM) DNA- and nucleotide triphosphate-competitive priming inhibitors that interact with more than one site on Mtb DnaG. This novel assay should be applicable to other primases and inefficient DNA/RNA polymerases, facilitating their characterization and inhibitor discovery. PMID:23267008

  12. Community-Based Active Tuberculosis Case Finding in Poor Urban Settlements of Phnom Penh, Cambodia: A Feasible and Effective Strategy

    PubMed Central

    Lorent, Natalie; Choun, Kimcheng; Thai, Sopheak; Kim, Tharin; Huy, Sopheaktra; Pe, Reaksmey; van Griensven, Johan; Buyze, Jozefien; Colebunders, Robert; Rigouts, Leen; Lynen, Lutgarde

    2014-01-01

    Background In light of the limitations of the current case finding strategies and the global urgency to improve tuberculosis (TB) case-detection, a renewed interest in active case finding (ACF) has risen. The WHO calls for more evidence on innovative ways of TB screening, especially from low-income countries, to inform global guideline development. We aimed to assess the feasibility of community-based ACF for TB among the urban poor in Cambodia and determine its impact on case detection, treatment uptake and outcome. Methods Between 9/2/2012-31/3/2013 the Sihanouk Hospital Center of HOPE conducted a door-to-door survey for TB in deprived communities of Phnom Penh. TB workers and community health volunteers performed symptom screening, collected sputum and facilitated specimen transport to the laboratories. Fluorescence microscopy was introduced at three referral hospitals. The GeneXpert MTB/RIF assay (Xpert) was performed at tertiary level for individuals at increased risk of HIV-associated, drug-resistant or smear-negative TB. Mobile phone/short message system (SMS) was used for same-day issuing of positive results. TB workers contacted diagnosed patients and referred them for care at their local health centre. Results In 14 months, we screened 315.874 individuals; we identified 12.201 aged ?15 years with symptoms suggestive of TB; 84% provided sputum. We diagnosed 783, including 737 bacteriologically confirmed, TB cases. Xpert testing yielded 41% and 48% additional diagnoses among presumptive HIV-associated and multidrug-resistant TB cases, respectively. The median time from sputum collection to notification (by SMS) of the first positive (microscopy or Xpert) result was 3 days (IQR 2–6). Over 94% commenced TB treatment and 81% successfully completed it. Conclusion Our findings suggest that among the urban poor ACF for TB, using a sensitive symptom screen followed by smear-microscopy and targeted Xpert, contributed to improved case detection of drug-susceptible and drug-resistant TB, shortening the diagnostic delay, and successfully bringing patients into care. PMID:24675985

  13. Epidemiology of Tuberculosis in an Urban Slum of Dhaka City, Bangladesh

    PubMed Central

    Banu, Sayera; Rahman, Md. Toufiq; Uddin, Mohammad Khaja Mafij; Khatun, Razia; Ahmed, Tahmeed; Rahman, Md. Mojibur; Husain, Md. Ashaque; van Leth, Frank

    2013-01-01

    Background The objectives of this study were to assess the tuberculosis (TB) burden and to provide an insight into the type of circulating M. tuberculosis species in urban slums of Bangladesh. We also aimed to test the feasibility of a larger transmission study in this setting. Methods This cross-sectional study was conducted in an urban slum of Dhaka city. The household members were actively screened to assess the presence of TB-related signs and symptoms; cough ?3 weeks and body mass index (BMI) <17 kg/m2. Sputum specimens from suspects were collected for acid fast bacilli (AFB) microscopy, culture and drug susceptibility testing. Genotyping of M. tuberculosis was done using spoligotyping and variable number tandem repeats of mycobacterial interspersed repetitive units typing. Results Among 9,877 adult screened for pulmonary TB (PTB), 25 were positive for AFB on microscopy and/or culture and the prevalence of new PTB cases was estimated to be 253/100,000. Only one child TB case was diagnosed among 5,147 child screened. Out of 26 cases, 21(81%) had cough for several duration and 5(19%) did not present with cough at the time of screening. One multidrug resistant case was found. Fifty two percent of all TB cases had BMI <17 kg/m2 (p?=?<0.001). Among the 20 analyzed isolates, 13 different spoligotype patterns were identified in which 5 clusters contained 12 strains and 8 strains had unique pattern. Conclusions The study revealed high prevalence of TB in urban slums. Screening using low BMI can be beneficial among risk group population. It is important to conduct larger study to validate clinical variables like cough <3 weeks and low BMI to define TB suspect and also to investigate the transmission of TB in slum settings. PMID:24204933

  14. Clinical application of whole-genome sequencing to inform treatment for multidrug-resistant tuberculosis cases.

    PubMed

    Witney, Adam A; Gould, Katherine A; Arnold, Amber; Coleman, David; Delgado, Rachel; Dhillon, Jasvir; Pond, Marcus J; Pope, Cassie F; Planche, Tim D; Stoker, Neil G; Cosgrove, Catherine A; Butcher, Philip D; Harrison, Thomas S; Hinds, Jason

    2015-05-01

    The treatment of drug-resistant tuberculosis cases is challenging, as drug options are limited, and the existing diagnostics are inadequate. Whole-genome sequencing (WGS) has been used in a clinical setting to investigate six cases of suspected extensively drug-resistant Mycobacterium tuberculosis (XDR-TB) encountered at a London teaching hospital between 2008 and 2014. Sixteen isolates from six suspected XDR-TB cases were sequenced; five cases were analyzed in a clinically relevant time frame, with one case sequenced retrospectively. WGS identified mutations in the M. tuberculosis genes associated with antibiotic resistance that are likely to be responsible for the phenotypic resistance. Thus, an evidence base was developed to inform the clinical decisions made around antibiotic treatment over prolonged periods. All strains in this study belonged to the East Asian (Beijing) lineage, and the strain relatedness was consistent with the expectations from the case histories, confirming one contact transmission event. We demonstrate that WGS data can be produced in a clinically relevant time scale some weeks before drug sensitivity testing (DST) data are available, and they actively help clinical decision-making through the assessment of whether an isolate (i) has a particular resistance mutation where there are absent or contradictory DST results, (ii) has no further resistance markers and therefore is unlikely to be XDR, or (iii) is identical to an isolate of known resistance (i.e., a likely transmission event). A small number of discrepancies between the genotypic predictions and phenotypic DST results are discussed in the wider context of the interpretation and reporting of WGS results. PMID:25673793

  15. Optimal intervention strategies for tuberculosis

    NASA Astrophysics Data System (ADS)

    Bowong, Samuel; Aziz Alaoui, A. M.

    2013-06-01

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

  16. Anti-tuberculosis neolignans from Piper regnellii.

    PubMed

    Scodro, R B L; Pires, C T A; Carrara, V S; Lemos, C O T; Cardozo-Filho, L; Souza, V A; Corrêa, A G; Siqueira, V L D; Lonardoni, M V C; Cardoso, R F; Cortez, D A G

    2013-05-15

    The present study determined the anti-Mycobacterium tuberculosis activities of supercritical CO2 extracts, neolignans eupomatenoid-5 (1), conocarpan (4) and eupomatenoid-3 (7) and their derivatives (2, 3, 5, 6, and 8) from Piper regnellii, as well as their cytotoxicities. The supercritical CO2 extract from leaves was purified by chromatographic methods, yielding compounds (1), (4) and (7), which were identified by (1)H NMR and comparison with literature data. Anti-M. tuberculosis activity (H37Rv and clinical isolates) was evaluated using a resazurin microtiter assay plate (REMA) to determine the MIC. The cytotoxicity assay was carried out in macrophages J774G.8 by sulforhodamine B colorimetric assay. The supercritical CO2 extracts from leaves and stems, and compound (4) showed activity against M. tuberculosis (MIC 15.6 ?g/ml). Compound (1) showed the best activity (MIC 1.9 ?g/ml), with good SI. Compounds (7) and (8) showed low activity against M. tuberculosis H37Rv. The derivative compounds did not show increased anti-M. tuberculosis activity. This is the first report, to our knowledge, to describe neolignans from P. regnellii with activity against M. tuberculosis, and compound (1) is a potential candidate for future antituberculosis drugs. PMID:23474218

  17. Phosphodiesterase-4 Inhibition Combined with Isoniazid Treatment of Rabbits with Pulmonary Tuberculosis Reduces Macrophage Activation and Lung Pathology

    PubMed Central

    Subbian, Selvakumar; Tsenova, Liana; O'Brien, Paul; Yang, Guibin; Koo, Mi-Sun; Peixoto, Blas; Fallows, Dorothy; Zeldis, Jerome B.; Muller, George; Kaplan, Gilla

    2011-01-01

    Tuberculosis (TB) is responsible for significant morbidity and mortality worldwide. Even after successful microbiological cure of TB, many patients are left with residual pulmonary damage that can lead to chronic respiratory impairment and greater risk of additional TB episodes due to reinfection with Mycobacterium tuberculosis. Elevated levels of the proinflammatory cytokine tumor necrosis factor-? and several other markers of inflammation, together with expression of matrix metalloproteinases, have been associated with increased risk of pulmonary fibrosis, tissue damage, and poor treatment outcomes in TB patients. In this study, we used a rabbit model of pulmonary TB to evaluate the impact of adjunctive immune modulation, using a phosphodiesterase-4 inhibitor that dampens the innate immune response, on the outcome of treatment with the antibiotic isoniazid. Our data show that cotreatment of M. tuberculosis infected rabbits with the phosphodiesterase-4 inhibitor CC-3052 plus isoniazid significantly reduced the extent of immune pathogenesis, compared with antibiotic alone, as determined by histologic analysis of infected tissues and the expression of genes involved in inflammation, fibrosis, and wound healing in the lungs. Combined treatment with an antibiotic and CC-3052 not only lessened disease but also improved bacterial clearance from the lungs. These findings support the potential for adjunctive immune modulation to improve the treatment of pulmonary TB and reduce the risk of chronic respiratory impairment. PMID:21703411

  18. Tuberculosis in Pregnant and Postpartum Women: Epidemiology, Management, and Research Gaps

    PubMed Central

    Mathad, Jyoti S.; Gupta, Amita

    2012-01-01

    Tuberculosis is most common during a woman's reproductive years and is a major cause of maternal–child mortality. National guidelines for screening and management vary widely owing to insufficient data. In this article, we review the available data on (1) the global burden of tuberculosis in women of reproductive age; (2) how pregnancy and the postpartum period affect the course of tuberculosis; (3) how to screen and diagnose pregnant and postpartum women for active and latent tuberculosis; (4) the management of active and latent tuberculosis in pregnancy and the postpartum period, including the safety of tuberculosis medications; and (5) infant outcomes. We also include data on HIV/tuberculosis coinfection and drug-resistant tuberculosis. Finally, we highlight research gaps in tuberculosis in pregnant and postpartum women. PMID:22942202

  19. Characterization of pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis isolates from Korea and analysis of the correlation between the mutations and pyrazinamidase activity.

    PubMed

    Yoon, Jee-Hyun; Nam, Ji-Sun; Kim, Kyung-Jin; Ro, Young-Tae

    2014-11-01

    To investigate the effect of natural pyrazinamidase (PncA) mutations on protein function, we analyzed expression and PncA activity of eight pncA point mutants identified in nineteen pyrazinamide-resistant Mycobacterium tuberculosis clinical isolates. Among them, two mutants (Y99D and T135P) showed high expression level and solubility comparable to those of the wild-type PncA protein, two (K48E and G97D) displayed low expression level and solubility, and four (C14R, H51P, W68S, and A146V) were insoluble. Interestingly, when possible structural effects of these mutations were predicted by the CUPSAT program based on the proposed three-dimensional structure of M. tuberculosis PncA, only two highly soluble mutant proteins (Y99D and T135P) were predicted to be stabilizing and have favorable torsion angles. However, the others exhibiting either low solubility or precipitation were foreseen to be destabilizing and/or have unfavorable torsion angles, suggesting that the alterations could interfere with proper protein folding, thereby decreasing or depleting protein solubility. A PncA activity assay demonstrated that two mutants (G97D and T135P) showed virtually no activity, but two other mutants (K48E and Y99D) exhibited wild-type activity, indicating that the PncA residues (Cys14, His51, Trp68, Gly97, Thr135, and Ala146) may be important for PncA activity and/or proper protein folding. PMID:25034468

  20. New Anti-tuberculosis Agents Amongst Known Drugs

    PubMed Central

    Lougheed, Kathryn E.A.; Taylor, Debra L.; Osborne, Simon A.; Bryans, Justin S.; Buxton, Roger S.

    2010-01-01

    Summary Mycobacterium tuberculosis has an on-going impact on global public health and new therapeutics to treat tuberculosis are urgently required. The emergence of drug resistant tuberculosis poses a serious threat to the control of this pathogen, and the development of drugs that are active against the resistant strains is vital. A medium-throughput assay using the Alamar Blue reagent was set-up to identify novel inhibitors of M. tuberculosis from a library of known drugs, for which there has already been extensive research investigating their suitability and safety as human therapeutics. Of the 1514 compounds screened, 53 were demonstrated to possess inhibitory properties against M. tuberculosis at a concentration of 5 ?M or below. Of these, 17 were novel inhibitors while 36 were known tuberculosis drugs or had been previously described as possessing anti-tuberculosis activity. Five compounds were selected as those which represent the most promising starting points for new anti-tuberculosis agents. It was demonstrated that all five were active against intracellular M. tuberculosis in a macrophage model of infection. The anti-tuberculosis agents identified in this screen represent promising new scaffolds on which future drug development efforts can be focused. PMID:19699151

  1. Evaluation of Suspected Deep Venous Thrombosis in Oncologic Patients

    Microsoft Academic Search

    Deborah L. Keefe; Nancy Roistacher; Mary Kathryn Pierri

    1994-01-01

    Impedance plethysmography (IPG) and duplex scanning with color flow Doppler were performed in 100 consecutive high-risk patients with clinically suspected deep venous thrombosis. Risk factors included recent surgery (activity in 70%. Lower limb findings of either edema, calf tenderness, or both occurred in 92%. There was

  2. 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

  3. Anti-mycobacterial activity of garlic (Allium sativum) against multi-drug resistant and non-multi-drug resistant mycobacterium tuberculosis.

    PubMed

    Hannan, Abdul; Ikram Ullah, Muhammad; Usman, Muhammad; Hussain, Shahid; Absar, Muhammad; Javed, Khursheed

    2011-01-01

    Emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB throughout the developing world is very disturbing in the present scenario of TB management. There is a fundamental need to explore alternative anti-TB agents. Hence natural plants should be investigated to understand their antimicrobial properties and safety. Garlic (Allium sativum) is one of natural plant which possesses variety of biological properties like anti-tumor, anti-hyperlipedemic and anti-microbial etc. The present study was evaluated for anti-bacterial activity of garlic against non-MDR and MDR isolates of M. tuberculosis. A total of 20 clinical isolates of MTB including 15 MDR and 5 non-MDR were investigated. Ethanolic extract of garlic was prepared by maceration method. Minimum inhibitory concentration (MIC) was performed by using 7H9 middle brook broth dilution technique. MIC of garlic extract was ranged from 1 to 3 mg/ml; showing inhibitory effects of garlic against both non-MDR and MDR M. tuberculosis isolates. Alternate medicine practices with plant extracts including garlic should be considered to decrease the burden of drug resistance and cost in the management of diseases. The use of garlic against MDR-TB may be of great importance regarding public health. PMID:21190924

  4. Tuberculosis (For Parents)

    MedlinePLUS

    ... Lessons? Visit KidsHealth in the Classroom What Other Parents Are Reading Measles: What to Know Vaccines: FAQs ... Pregnancy Precautions Checkups: What to Expect Tuberculosis KidsHealth > Parents > Infections > Bacterial & Viral Infections > Tuberculosis Print A A ...

  5. Tuberculosis in Blacks

    MedlinePLUS

    ... Share Compartir Fact Sheet ( PDF - 272k) Tuberculosis In Blacks Tuberculosis (TB) is a disease caused by a ... cases were reported in the United States; however, blacks continue to have a disproportionate share of TB. ...

  6. Play the Tuberculosis Game

    MedlinePLUS

    ... Questionnaire Tuberculosis Play Tuberculosis Experiments & Discoveries About the game Discover and experience some of the classic methods ... last will in Paris. Play the Blood Typing Game Try to save some patients and learn about ...

  7. Primary Thyroid Tuberculosis

    Microsoft Academic Search

    Sunita Sanehi; Chandrashekhar Dravid; Neena Chaudhary; A. K. Rai

    2007-01-01

    In India, it is estimated that more than 40% of the adults are infected with tuberculosis bacilli and every year 2 million\\u000a people develop tuberculosis and nearly 500,000 die from it1. But, tuberculosis of the thyroid gland occurs only rarely. Since\\u000a extra-pulmonary tuberculosis is now seen relatively more frequently, the existence of this condition should be recognized\\u000a when goitres are

  8. The Prevalence of Latent Tuberculosis Infection and Smear Positive Pulmonary Tuberculosis in People with Household Close Contact with Tuberculosis in North of Iran

    PubMed Central

    Moosazadeh, Mahmood; Khanjani, Narges; Parsaee, Mohammadreza

    2015-01-01

    One of the recommended strategies for preventing tuberculosis is to screen high-risk populations with respect to Mycobacterium tuberculosis (TB) infection. The aim of the present study was to investigate latent infection and active tuberculosis in people with close household contact. It was a cross-sectional descriptive, analytical study with the sample size of 668 people from homes with one infected resident. In order to diagnose tuberculosis latent infection, the PPD test was done. To determine patients with smear-positive pulmonary tuberculosis, three sputum samples were taken from every patient and were examined using direct microscopy and culture. Data was analyzed by SPSS20 software. The prevalence of latent tuberculosis infection and smear-positive pulmonary tuberculosis were 42.8% and 0.9% respectively. The prevalence of latent tuberculosis infection and smear-positive pulmonary tuberculosis in people with close household contact were less than that of other studies. However, smear-positive pulmonary tuberculosis in people with close household contact was 199.5 times more than that of the general population.

  9. Alcohol use as a risk factor for tuberculosis – a systematic review

    PubMed Central

    Lönnroth, Knut; Williams, Brian G; Stadlin, Stephanie; Jaramillo, Ernesto; Dye, Christopher

    2008-01-01

    Background It has long been evident that there is an association between alcohol use and risk of tuberculosis. It has not been established to what extent this association is confounded by social and other factors related to alcohol use. Nor has the strength of the association been established. The objective of this study was to systematically review the available evidence on the association between alcohol use and the risk of tuberculosis. Methods Based on a systematic literature review, we identified 3 cohort and 18 case control studies. These were further categorized according to definition of exposure, type of tuberculosis used as study outcome, and confounders controlled for. Pooled effect sizes were obtained for each sub-category of studies. Results The pooled relative risk across all studies that used an exposure cut-off level set at 40 g alcohol per day or above, or defined exposure as a clinical diagnosis of an alcohol use disorder, was 3.50 (95% CI: 2.01–5.93). After exclusion of small studies, because of suspected publication bias, the pooled relative risk was 2.94 (95% CI: 1.89–4.59). Subgroup analyses of studies that had controlled for various sets of confounders did not give significantly different results and did not explain the significant heterogeneity that was found across the studies. Conclusion The risk of active tuberculosis is substantially elevated in people who drink more than 40 g alcohol per day, and/or have an alcohol use disorder. This may be due to both increased risk of infection related to specific social mixing patterns associated with alcohol use, as well as influence on the immune system of alcohol itself and of alcohol related conditions. PMID:18702821

  10. Anti-Tuberculosis Policy of the Government General of Korea during Japanese-Colonial Period (1910-1945): From Simple Restriction to Active Enlightenment.

    PubMed

    Choi, Eun Kyung

    2013-12-01

    In this paper, I tried to examine the characteristic of anti-tuberculosis policy in colonial Korea and find out internal constraint of hygienic administration by Japanese government during Japanese-Colonial Period. Despite of high prevalence of tuberculosis among Japanese in Korea, the Japanese Government General of Korea had done almost nothing until 1936. Japan's hygienic administration was highly dependent upon hygienic police, and mainly with compulsory isolation and disinfection. It was inefficient in tuberculosis problem. In 1918, Japanese Government General enacted 'Ordinance of Prevention of Tuberculosis', solely based upon naive tuberculosis etiology in sputum; consisted of simple crackdown and isolation and had no effect due to the limit of anti-tuberculosis and health budget. Also the ordinance actually set limitation upon the tuberculosis facilities, only a few health care facilities could be affordable for tuberculosis patients. Since 1936, the Japanese Government General of Korea began tuberculosis prevention measures in earnest. Due to the Second Sino- Japanese War and World War II, there was urgent need to make Korean society and population as "safe, and healthy rear area". The Government organized 'Chosen Anti-tuberculosis Association' and highly pursued enlightment campaign. It was almost temporary measures of enlightenment and publicity. Also various types of health screening and tuberculosis prevalence research were introduced to Korean people. But it was not so effective to identify tuberculosis problem in Korea. Mass tuberculin test and X-ray test was introduced, but it was not well organized and scientifically designed. Besides, tuberculosis treatment facility was extremely rare because of strict isolation and high standard policy. Japanese Governemtn set numerous tuberculosis-counseling centers and mobilized public doctor for consulting tuberculosis, but the accessibility of centers was very low. Moreover, there was no source to establish facilities like sanatorium. The Japanese Government General of Korea was constantly suffered from limit of budget and a lot of Japanese in Korea had no inherent motive for installing sanatorium and anti-tuberculosis measures. As the result, the effort made by Japanese Government General of Korea to diminish tuberculosis in Korea failed during the wartime. PMID:24503920

  11. Structural activation of the transcriptional repressor EthR from Mycobacterium tuberculosis by single amino acid change mimicking natural and synthetic ligands

    PubMed Central

    Carette, Xavier; Blondiaux, Nicolas; Willery, Eve; Hoos, Sylviane; Lecat-Guillet, Nathalie; Lens, Zoé; Wohlkönig, Alexandre; Wintjens, René; Soror, Sameh H.; Frénois, Frédéric; Dirié, Bertrand; Villeret, Vincent; England, Patrick; Lippens, Guy; Deprez, Benoit; Locht, Camille; Willand, Nicolas; Baulard, Alain R.

    2012-01-01

    Ethionamide is an antituberculous drug for the treatment of multidrug-resistant Mycobacterium tuberculosis. This antibiotic requires activation by the monooxygenase EthA to exert its activity. Production of EthA is controlled by the transcriptional repressor EthR, a member of the TetR family. The sensitivity of M. tuberculosis to ethionamide can be artificially enhanced using synthetic ligands of EthR that allosterically inactivate its DNA-binding activity. Comparison of several structures of EthR co-crystallized with various ligands suggested that the structural reorganization of EthR resulting in its inactivation is controlled by a limited portion of the ligand-binding-pocket. In silico simulation predicted that mutation G106W may mimic ligands. X-ray crystallography of variant G106W indeed revealed a protein structurally similar to ligand-bound EthR. Surface plasmon resonance experiments established that this variant is unable to bind DNA, while thermal shift studies demonstrated that mutation G106W stabilizes EthR as strongly as ligands. Proton NMR of the methyl regions showed a lesser contribution of exchange broadening upon ligand binding, and the same quenched dynamics was observed in apo-variant G106W. Altogether, we here show that the area surrounding Gly106 constitutes the molecular switch involved in the conformational reorganization of EthR. These results also shed light on the mechanistic of ligand-induced allosterism controlling the DNA binding properties of TetR family repressors. PMID:22156370

  12. Guidelines for identifying suspect/counterfeit material

    SciTech Connect

    NONE

    1995-09-01

    These guidelines are intended to assist users of products in identifying: substandard, misrepresented, or fraudulently marked items. The guidelines provide information about such topics as: precautions, inspection and testing, dispositioning identified items, installed inspection and reporting suspect/counterfeit materials. These guidelines apply to users who are developing procurement documents, product acceptance/verification methods, company procedures, work instructions, etc. The intent of these SM guidelines in relation to the Quality Assurance Program Description (QAPD) and implementing company Management Control Procedures is not to substitute or replace existing requirements, as defined in either the QAPD or company implementing instructions (Management Control Procedures). Instead, the guidelines are intended to provide a consolidated source of information addressing the issue of Suspect/Counterfeit materials. These guidelines provide an extensive suspect component listing and suspect indications listing. Users can quickly check their suspect items against the list of manufacturers products (i.e., type, LD. number, and nameplate information) by consulting either of these listings.

  13. The Phenomenology of Specialization of Criminal Suspects

    PubMed Central

    Tumminello, Michele; Edling, Christofer; Liljeros, Fredrik; Mantegna, Rosario N.; Sarnecki, Jerzy

    2013-01-01

    A criminal career can be either general, with the criminal committing different types of crimes, or specialized, with the criminal committing a specific type of crime. A central problem in the study of crime specialization is to determine, from the perspective of the criminal, which crimes should be considered similar and which crimes should be considered distinct. We study a large set of Swedish suspects to empirically investigate generalist and specialist behavior in crime. We show that there is a large group of suspects who can be described as generalists. At the same time, we observe a non-trivial pattern of specialization across age and gender of suspects. Women are less prone to commit crimes of certain types, and, for instance, are more prone to specialize in crimes related to fraud. We also find evidence of temporal specialization of suspects. Older persons are more specialized than younger ones, and some crime types are preferentially committed by suspects of different ages. PMID:23691257

  14. EVALUATION OF AN INTERMITTENT SIX-MONTH REGIMEN IN NEW PULMONARY TUBERCULOSIS PATIENTS WITH DIABETES MELLITUS

    Microsoft Academic Search

    Rani Balasubramanian; Usha Ramanathan; K. Thyagarajan; Rajeswari Ramachandran; K. Rajaram; D Bhaskar; R. S. Hariharan; P. R. Narayanan

    Summary Background: The treatment of tuberculosis (TB) with category I regimen of the Revised National Tuberculosis Control Programme (RNTCP) for patients with diabetes mellitus (DM) needs evaluation. Objective: To assess the cure and relapse rates in 3 years, among the new smear-positive TB patients with Type-2 DM (DMTB) treated with CAT-I regimen (2E3H3R3Z3\\/4R3H3) of RNTCP. Methodology: TB suspects attending the

  15. Whole-Genome Sequencing and Mutation Analysis of Two Extensively Drug-Resistant Sputum Isolates of Mycobacterium tuberculosis (VRFCWCF XDRTB 232 and VRFCWCF XDRTB 1028) from Chennai, India

    PubMed Central

    Lakshmipathy, Dhanurekha; Ramasubban, Gayathri; Vetrivel, Umashankar; Rao, Madhavan Hajib Narahari; Rathinam, Sridhar; Narasimhan, Meenakshi

    2014-01-01

    We announce the draft genome sequence of two extensively drug-resistant Mycobacterium tuberculosis strains, VRFCWCF XDRTB 232 and VRFCWCF XDRTB 1028, isolated from the sputum samples of a patient clinically suspected to have tuberculosis, and we also report novel mutations that confer drug resistance. PMID:25395642

  16. Comparison of Sputum Induction with Fiberoptic Bronchoscopy in the Diagnosis of Tuberculosis Experience at an Acquired Immune Deficiency Syndrome Reference Center in Rio de Janeiro, Brazil

    Microsoft Academic Search

    MARCUS B. CONDE; SERGIO L. M. SOARES; FERNANDA C. Q. MELLO; VALERIA M. REZENDE; LUCIANA L. ALMEIDA; ARTHUR L. REINGOLD; CHARLES L. DALEY; AFRANIO L. KRITSKI

    Many patients with suspected pulmonary tuberculosis (PTB) do not produce sputum spontaneously or are smear-negative for acid-fast bacilli (AFB). We prospectively compared the yield of sputum in- duction (SI) and fiberoptic bronchoscopy with bronchoalveolar la- vage (BAL) for the diagnosis of PTB in a region with a high preva- lence of tuberculosis and human immunodeficiency virus (HIV) infection. Fifty seven

  17. 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

  18. High resolution computed tomographic findings in pulmonary tuberculosis.

    PubMed Central

    Hatipo?lu, O. N.; Osma, E.; Manisali, M.; Uçan, E. S.; Balci, P.; Akkoçlu, A.; Akpinar, O.; Karlikaya, C.; Yüksel, C.

    1996-01-01

    BACKGROUND: Although chest radiographs usually provide adequate information for the diagnosis of active pulmonary tuberculosis, minimal exudative tuberculosis can be overlooked on standard chest radiographs. The aim of the present study was to assess the findings of active pulmonary tuberculosis on high resolution computed tomographic (HRCT) scans, and to evaluate their possible use in determining disease activity. METHODS: Thirty two patients with newly diagnosed active pulmonary tuberculosis and 34 patients with inactive pulmonary tuberculosis were examined. The diagnosis of active pulmonary tuberculosis was based on positive acid fast bacilli in sputum and bronchial washing smears or cultures and/or changes on serial radiographs obtained during treatment. RESULTS: With HRCT scanning centrilobular lesions (n = 29), "tree-in-bud" appearance (n = 23), and macronodules 5-8 mm in diameter (n = 22) were most commonly seen in cases of active pulmonary tuberculosis. HRCT scans showed fibrotic lesions (n = 34), distortion of bronchovascular structures (n = 32), emphysema (n = 28), and bronchiectasis (n = 24) in patients with inactive tuberculosis. CONCLUSIONS: Centrilobular densities in and around the small airways and "tree-in-bud" appearances were the most characteristic CT features of disease activity. HRCT scanning clearly differentiated old fibrotic lesions from new active lesions and demonstrated early bronchogenic spread. These findings may be of value in decisions on treatment. Images PMID:8733492

  19. Structures of Mycobacterium tuberculosis DosR and DosR?DNA Complex Involved in Gene Activation during Adaptation to Hypoxic Latency

    SciTech Connect

    Wisedchaisri, Goragot; Wu, Meiting; Rice, Adrian E.; Roberts, David M.; Sherman, David R.; Hol, Wim G.J. (UWASH)

    2010-07-20

    On encountering low oxygen conditions, DosR activates the transcription of 47 genes, promoting long-term survival of Mycobacterium tuberculosis in a non-replicating state. Here, we report the crystal structures of the DosR C-terminal domain and its complex with a consensus DNA sequence of the hypoxia-induced gene promoter. The DosR C-terminal domain contains four {alpha}-helices and forms tetramers consisting of two dimers with non-intersecting dyads. In the DNA-bound structure, each DosR C-terminal domain in a dimer places its DNA-binding helix deep into the major groove, causing two bends in the DNA. DosR makes numerous protein-DNA base contacts using only three amino acid residues per subunit: Lys179, Lys182, and Asn183. The DosR tetramer is unique among response regulators with known structures.

  20. 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.

  1. PERSPECTIVE Candidate Mycobacterium tuberculosis genes

    E-print Network

    Wu, Jane Y.

    PERSPECTIVE Candidate Mycobacterium tuberculosis genes targeted by human microRNAs WeiRui Guo1-wu@northwestern.edu (J. Y. Wu), weilp@mail.cbi.pku.edu.cn (L. Wei) Tuberculosis (TB) remains a major health issue in 1882, Mycobacterium tuberculosis (M. tuberculosis), the causative agent for tuberculosis, remains one

  2. Peritoneal carcinomatosis mimicking a peritoneal tuberculosis

    PubMed Central

    Jung, Eun Young; Hur, Yun Jung; Lee, Yoon Jung; Han, Hyo Sang; Sang, Jae Hong

    2015-01-01

    Symptoms of a peritoneal progression from ovarian cancer are nonspecific such as abdominal pain, abdominal distention and more. Many imaging studies and serum CA-125 help diagnosis. However, it is difficult to exclude the instances of the diffuse peritoneal diseases that mimic carcinomatosis. The elevated CA-125 level usually correlates with the peritoneal carcimatosis, but it is often found in other peritoneal diseases. Therefore, the pathologic confirmation is necessary because of other mimicking diseases. In our case, CA-125 levels were elevated. Abdominal computed tomography finding was suspected a peritoneal tuberculosis but the pathologic result was the peritoneal carcimatosis, eventually. PMID:25629022

  3. Mycobacterium tuberculosis ESAT-6 exhibits a unique membrane-interacting activity that is not found in its ortholog from non-pathogenic Mycobacterium smegmatis.

    PubMed

    De Leon, Joaquin; Jiang, Guozhong; Ma, Yue; Rubin, Eric; Fortune, Sarah; Sun, Jianjun

    2012-12-28

    Mycobacterium tuberculosis ESAT-6 (MtbESAT-6) reportedly shows membrane/cell-lysis activity, and recently its biological roles in pathogenesis have been implicated in rupture of the phagosomes for bacterial cytosolic translocation. However, molecular mechanism of MtbESAT-6-mediated membrane interaction, particularly in relation with its biological functions in pathogenesis, is poorly understood. In this study, we investigated the pH-dependent membrane interaction of MtbESAT-6, MtbCFP-10, and the MtbESAT-6/CFP-10 heterodimer, by using liposomal model membranes that mimic phagosomal compartments. MtbESAT-6, but neither MtbCFP-10 nor the heterodimer, interacted with the liposomal membranes at acidic conditions, which was evidenced by release of K(+) ions from the liposomes. Most importantly, the orthologous ESAT-6 from non-pathogenic Mycobacterium smegmatis (MsESAT-6) was essentially inactive in release of K(+). The differential membrane interactions between MtbESAT-6 and MsESAT-6 were further confirmed in an independent membrane leakage assay using the dye/quencher pair, 8-aminonapthalene-1,3,6 trisulfonic acid (ANTS)/p-xylene-bis-pyridinium bromide (DPX). Finally, using intrinsic and extrinsic fluorescence approaches, we probed the pH-dependent conformational changes of MtbESAT-6 and MsESAT-6. At acidic pH conditions, MtbESAT-6 underwent a significant conformational change, which was featured by an increased solvent-exposed hydrophobicity, while MsESAT-6 showed little conformational change in response to acidification. In conclusion, we have demonstrated that MtbESAT-6 possesses a unique membrane-interacting activity that is not found in MsESAT-6 and established the utility of rigorous biochemical approaches in dissecting the virulence of M. tuberculosis. PMID:23150662

  4. Mycobacterium tuberculosis Modulates the Gene Interactions to Activate the HIV Replication and Faster Disease Progression in a Co-Infected Host

    PubMed Central

    Toor, Jaideep S.; Singh, Sukhvinder; Sharma, Aman; Arora, Sunil K.

    2014-01-01

    Understanding of the chronic immune activation, breakdown of immune defense and synergistic effect between HIV and Mycobacterium tuberculosis (Mtb) may provide essential information regarding key factors involved in the pathogenesis of HIV disease. In this study, we aimed to highlight a few of the immunological events that may influence and accelerate the progression of HIV disease in the presence of co-infecting Mtb. A cross-sectional study was performed on cohorts, including anti-tubercular therapy (ATT) naïve active pulmonary tuberculosis (PTB) patients, antiretroviral therapy (ART) naïve HIV-1 infected individuals at different stages of disease, ATT and ART naïve HIV-PTB co-infected individuals and healthy controls. A significantly higher T-regulatory cell (Treg) frequency coupled with the high FoxP3 expression in the CD4 T-cells indicated an immunosuppressive environment in the advance stage of HIV-1 infection. This is further substantiated by high HO-1 expression favoring TB co-infection. Functionally, this change in Treg frequency in HIV-1 infected individuals correlated well with suppression of T-cell proliferation. Mtb infection seems to facilitate the expansion of the Treg pool along with increased expression of FoxP3, specifically the variant-1, as evident from the data in HIV-1 co-infected as well as in patients with only PTB. A significantly lower expression of HO-1 in co-infected individuals compared to patients with only HIV-infection having comparable CD4 count correlated well with increased expression of CCR5 and CxCR4 as well as NF-?B and inflammatory cytokines IL-6 and TNF-?, which collectively may contribute to enhanced viral replication and increased cell death, hence faster disease progression in co-infected individuals. PMID:25198707

  5. Suspected myotoxicity of edible wild mushrooms.

    PubMed

    Nieminen, Petteri; Kirsi, Markku; Mustonen, Anne-Mari

    2006-02-01

    Recently, the widely consumed yellow tricholoma Tricholoma flavovirens caused delayed rhabdomyolysis and fatalities in humans in France and Poland and triggered elevated plasma creatine kinase activities in mice. Furthermore, the highly appreciated king boletus (Boletus edulis) caused similar responses in experimental mice. Because of this, it was hypothesized that other fungi could also contain chemical compounds that would cause similar myotoxic effects. To test the suspected myotoxicity of other wild mushrooms consumed by tradition, 86 mice were exposed for 5 days to 3, 6, or 9 g/kg body mass/day of edible mushrooms representing diverse genera (Russula spp, Cantharellus cibarius, Albatrellus ovinus, and Leccinium versipelle) mixed with regular laboratory rodent diet. The plasma creatine kinase activity increased with all studied mushroom species at 9 g/kg body mass/day, whereas the histologic appearance of muscle and liver samples was unaffected. The results support the hypothesis that the previously observed toxic effects are not specific to T. flavovirens, but probably represent an unspecific response requiring individual sensitivity and a significant amount of ingested mushroom to manifest itself. PMID:16446499

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

    PubMed Central

    Connaghan, Kathryn P.; Moore, Christopher A.

    2014-01-01

    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 spastic cerebral palsy; n = 10) and controls (n = 11). Two measures were used to infer jaw tension: a kinematic index of mass-normalized stiffness and electromechanical delay (EMD). The kinematic index used video-based kinematics to obtain the slope of the peak velocity-displacement relationship. The EMD was derived from the interval between the onset of suprahyoid muscle activity and the onset of jaw depression. Results Neither measure differentiated the groups. The kinematic index revealed differences between stressed and unstressed syllables in 3-syllable productions by the participants with cerebral palsy and controls, but not in 2-syllable productions by the participants with Down syndrome and controls. Conclusion This preliminary investigation included the novel application of 2 measures to infer the jaw-muscle tension of children with suspected tone abnormalities. Although the results do not support the hypothesis that suspected muscle-tone abnormalities affect jaw movement sufficiently to influence speech production, considerations for interpreting the findings include methodological limitations and possible compensatory muscle coactivation. PMID:22653916

  7. Spectroscope: Fingerprinting the Luminous Suspects

    NSDL National Science Digital Library

    This is an activity about spectroscopy. Learners will build a spectroscope with a scale for measuring wavelength and use it to observe various light sources. They will identify spectral lines in more than one light source and analyze the collected data. This activity requires diffraction grating material, several light sources, and gas emission lamps and power sources.

  8. Clinical peculiarities of tuberculosis

    PubMed Central

    2014-01-01

    The ongoing spread of tuberculosis (TB) in poor resource countries and the recently increasing incidence in high resource countries lead to the need of updated knowledge for clinicians, particularly for pediatricians. The purpose of this article is to provide an overview on the most important peculiarities of TB in children. Children are less contagious than adults, but the risk of progression to active disease is higher in infants and children as compared to the subsequent ages. Diagnosis of TB in children is more difficult than in adults, because few signs are associated with primary infection, interferon-gamma release assays and tuberculin skin test are less reliable in younger children, M. tuberculosis is more rarely detected in gastric aspirates than in smears in adults and radiological findings are often not specific. Treatment of latent TB is always necessary in young children, whereas it is recommended in older children, as well as in adults, only in particular conditions. Antimycobacterial drugs are generally better tolerated in children as compared to adults, but off-label use of second-line antimycobacterial drugs is increasing, because of spreading of multidrug resistant TB worldwide. Given that TB is a disease which often involves more than one member in a family, a closer collaboration is needed between pediatricians and clinicians who take care of adults. PMID:24564419

  9. Four year longitudinal study of Mycobacterium tuberculosis complex isolates in a region of North-Eastern Italy.

    PubMed

    Fallico, Loredana; Couvin, David; Peracchi, Marta; Pascarella, Michela; Franchin, Elisa; Lavezzo, Enrico; Rassu, Mario; Manganelli, Riccardo; Rastogi, Nalin; Palù, Giorgio

    2014-08-01

    Recent reports have suggested a change of Mycobacterium tuberculosis complex genetic diversity in Western Europe due to an increasing proportion of imported cases of tuberculosis (TB). This study analyzed a total of 705 M. tuberculosis strains isolated from 2006 to 2009 in Veneto, a North-Eastern Italian region, to see the impact of foreign-born cases vs. Italian patients on prevailing TB epidemiology. Strains were genotyped using spoligotyping followed by comparison with international genotyping database SITVIT2. Six spoligotyping clusters with suspected phylogeographical specificity for imported cases, were typed by 15-loci MIRUs for a finer characterization. Overall, 410 (58.16%) strains were isolated from foreign-born patients, while 295 (41.84%) were isolated from Italian patients. Older patients (>70 years, i.e., 46.4% of cases) predominated among Italians while younger age groups prevailed among foreign-born patients. Our results suggest that despite a high proportion of reactivation of latent TB infection in elderly Italian-born patients, active TB transmission between foreign-born and Italian patients may be ongoing, and argue in favor of an increased TB surveillance among immigrants to combat TB epidemic in Italy. PMID:24820340

  10. Virulence factors of the Mycobacterium tuberculosis complex

    PubMed Central

    Forrellad, Marina A.; Klepp, Laura I.; Gioffré, Andrea; Sabio y García, Julia; Morbidoni, Hector R.; Santangelo, María de la Paz; Cataldi, Angel A.; Bigi, Fabiana

    2013-01-01

    The Mycobacterium tuberculosis complex (MTBC) consists of closely related species that cause tuberculosis in both humans and animals. This illness, still today, remains to be one of the leading causes of morbidity and mortality throughout the world. The mycobacteria enter the host by air, and, once in the lungs, are phagocytated by macrophages. This may lead to the rapid elimination of the bacillus or to the triggering of an active tuberculosis infection. A large number of different virulence factors have evolved in MTBC members as a response to the host immune reaction. The aim of this review is to describe the bacterial genes/proteins that are essential for the virulence of MTBC species, and that have been demonstrated in an in vivo model of infection. Knowledge of MTBC virulence factors is essential for the development of new vaccines and drugs to help manage the disease toward an increasingly more tuberculosis-free world. PMID:23076359

  11. Tuberculosis infection causing intestinal perforations in 2 patients with systemic lupus erythematosus.

    PubMed

    González, Luis A; Muñoz, Carolina; Restrepo, Mauricio; Vanegas, Adriana Lucía; Vásquez, Gloria

    2014-08-01

    Patients with systemic lupus erythematosus (SLE) have a higher incidence rate of tuberculosis and a more frequent extrapulmonary involvement than the general population. We present 2 SLE patients who developed gastrointestinal tuberculosis complicated with intestinal perforation, a rare but serious complication that could be confused with lupus-associated intestinal vasculitis. Opportunistic infections such as tuberculosis must be suspected in SLE patients with abdominal symptoms on immunosuppressive therapy because its early recognition could prevent catastrophic complications such as intestinal perforation and subsequent peritonitis. PMID:25036568

  12. 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

  13. Tuberculosis diagnosis: primary health care or emergency medical services?

    PubMed Central

    Andrade, Rubia Laine de Paula; Scatolin, Beatriz Estuque; Wysocki, Anneliese Domingues; Beraldo, Aline Ale; Monroe, Aline Aparecida; Scatena, Lúcia Marina; Villa, Tereza Cristina Scatena

    2013-01-01

    OBJECTIVE To assess primary health care and emergency medical services performance for tuberculosis diagnosis. METHODS Cross-sectional study were conducted with 90 health professionals from primary health care and 68 from emergency medical services, in Ribeirao Preto, SP, Southeastern Brazil, in 2009. A structured questionnaire based on an instrument of tuberculosis care assessment was used. The association between health service and the variables of structure and process for tuberculosis diagnosis was assessed by Chi-square test, Fisher's exact test (both with 5% of statistical significance) and multiple correspondence analysis. RESULTS Primary health care was associated with the adequate provision of inputs and human resources, as well as with the sputum test request. Emergencial medical services were associated with the availability of X-ray equipment, work overload, human resources turnover, insufficient availability of health professionals, unavailability of sputum collection pots and do not request sputum test. In both services, tuberculosis diagnosis remained as a physician's responsibility. CONCLUSIONS Emergencial medical services presented weaknesses in its structure to identify tuberculosis suspects. Gaps on the process were identified in both primary health care and emergencial medical services. This situation highlights the need for qualification of health services that are the main gateway to health system to meet sector reforms that prioritize the timely diagnosis of tuberculosis and its control. PMID:24626553

  14. Tuberculosis Facts - Exposure to TB

    MedlinePLUS

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

  15. Tuberculosis in the lung (image)

    MedlinePLUS

    Tuberculosis is caused by a group of organisms Mycobacterium tuberculosis, M. bovis, M. africanum and a few other rarer subtypes. Tuberculosis usually appears as a lung (pulmonary) infection. However, ...

  16. Tuberculosis Facts - Testing for TB

    MedlinePLUS

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

  17. Women and tuberculosis.

    PubMed

    Connolly, M; Nunn, P

    1996-01-01

    Tuberculosis is the leading infectious cause of death in women worldwide. The disease poses a major threat to women's health security. Population growth, the HIV epidemic, increasing poverty and rising levels of drug resistance will inevitably increase the burden of this disease in women. Women are at increased risk of progression to disease during their reproductive years. However, in most low-income countries, twice as many men are notified with tuberculosis as women. Biological mechanisms may account for most of this difference but socioeconomic and cultural factors leading to barriers in accessing health care may cause under-notification in women. Tuberculosis control programmes should be sensitive to the constraints faced by women in accessing health care, in order to empower women to commence and complete treatment. The fear and stigma associated with tuberculosis have a greater impact on women than on men, often leaving them in a more precarious social and economic position. Tuberculosis in women creates orphans, impoverished families and reduces the economic development of society. Tuberculosis is a major cause of preventable suffering and death in women. WHO's recommended tuberculosis control strategy, DOTS, represents a cost-effective response to the problem of tuberculosis in women. Tuberculosis is a major women's health issue. It is a global health priority that tuberculosis treatment be made available to women, particularly to those in low-income countries who are bearing the brunt of this epidemic. PMID:9050189

  18. Characterization of New Mutations in Pyrazinamide-Resistant Strains of Mycobacterium tuberculosis and Identification of Conserved Regions Important for the Catalytic Activity of the Pyrazinamidase PncA

    Microsoft Academic Search

    NADINE LEMAITRE; WLADIMIR SOUGAKOFF; CHANTAL TRUFFOT-PERNOT; VINCENT JARLIER

    1999-01-01

    Recently, the gene pncA, encoding the pyrazinamidase (PZase) of Mycobacterium tuberculosis, was identified (8); mu- tations in pncA have been shown to be associated with pyra- zinamide (PZA) resistance (1, 5, 9, 10). However, the muta- tions found in the amino acid sequence of the PZase from M. tuberculosis have not been investigated with respect to their locations in conserved

  19. Molecular dynamics simulation of the last step of a catalytic cycle: Product release from the active site of the enzyme chorismate mutase from Mycobacterium tuberculosis

    PubMed Central

    Choutko, Alexandra; van Gunsteren, Wilfred F

    2012-01-01

    The protein chorismate mutase MtCM from Mycobacterium tuberculosis catalyzes one of the few pericyclic reactions known in biology: the transformation of chorismate to prephenate. Chorismate mutases have been widely studied experimentally and computationally to elucidate the transition state of the enzyme catalyzed reaction and the origin of the high catalytic rate. However, studies about substrate entry and product exit to and from the highly occluded active site of the enzyme have to our knowledge not been performed on this enzyme. Crystallographic data suggest a possible substrate entry gate, that involves a slight opening of the enzyme for the substrate to access the active site. Using multiple molecular dynamics simulations, we investigate the natural dynamic process of the product exiting from the binding pocket of MtCM. We identify a dominant exit pathway, which is in agreement with the gate proposed from the available crystallographic data. Helices H2 and H4 move apart from each other which enables the product to exit from the active site. Interestingly, in almost all exit trajectories, two residues arginine 72 and arginine 134, which participate in the burying of the active site, are accompanying the product on its exit journey from the catalytic site. PMID:22898919

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

    PubMed Central

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

    2013-01-01

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

  1. Tuberculosis Prevention in Methadone Maintenance Clinics Effectiveness and Cost-Effectiveness

    Microsoft Academic Search

    DAVID C. SNYDER; E. ANTONIO PAZ; JANET C. MOHLE-BOETANI; ROBERT FALLSTAD; ROSA LEE BLACK; DANIEL P. CHIN

    To determine the effectiveness and cost-effectiveness of a program to provide screening for tubercu- losis infection and directly observed preventive therapy (DOPT) in methadone maintenance clinics, we determined completion rates of screening for tuberculosis infection, medical evaluation, and pre- ventive therapy, as well as the number of active tuberculosis cases and tuberculosis-related deaths prevented, in five clinics in San Francisco,

  2. Surveillance of pyrazinamide susceptibility among multidrug-resistant Mycobacterium tuberculosis isolates from Siriraj Hospital, Thailand

    Microsoft Academic Search

    Jirarut Jonmalung; Therdsak Prammananan; Manoon Leechawengwongs; Angkana Chaiprasert

    2010-01-01

    BACKGROUND: Susceptibility testing of pyrazinamide (PZA) against Mycobacterium tuberculosis is difficult to perform because the acidity of culture medium that is required for drug activity also inhibits the growth of bacteria. In Thailand, very limited information has been generated on PZA resistance, particularly among multidrug-resistant tuberculosis (MDR-TB) isolated from Thailand. Only two studies on PZA susceptibility among Thai M. tuberculosis

  3. EspR, a key regulator of Mycobacterium tuberculosis virulence, adopts a unique dimeric structure

    E-print Network

    Stroud, Robert

    EspR, a key regulator of Mycobacterium tuberculosis virulence, adopts a unique dimeric structureR is a transcriptional regulator that activates the ESX-1 secretion system during Mycobacterium tuberculosis infection Mycobacterium tuberculosis, an intracellular pathogen that ex- erts an enormous toll on global human health, has

  4. Unique Ligand-Protein Interactions in a New Truncated Hemoglobin from Mycobacterium tuberculosis

    E-print Network

    Yeh, Syun-Ru

    Unique Ligand-Protein Interactions in a New Truncated Hemoglobin from Mycobacterium tuberculosis hemoglobin (HbO) from Mycobacterium tuberculosis has been expressed and purified. Sequence alignment of Hb hemoglobin from M. tuberculosis. The distinct features in the heme active site structures and the temporal

  5. Tuberculosis: What We Don't Know Can, and Does, Hurt Us

    E-print Network

    Kirschner, Denise

    REVIEW Tuberculosis: What We Don't Know Can, and Does, Hurt Us David G. Russell,1 * Clifton E. Barry 3rd,2 JoAnne L. Flynn3 Mycobacterium tuberculosis has a penetrance of its host population-burden" countries account for more than 80% of the active tuberculosis cases in the world, which shows

  6. Tuberculosis: Hospitalization and Outpatient Treatment

    PubMed Central

    Wicks, C. A.

    1964-01-01

    Initial hospitalization terminated by discharge upon medical advice to continue with chemotherapy on an outpatient basis represents the treatment of choice for most patients with active pulmonary tuberculosis. Any departure from this plan for any patient should be accepted only after careful consideration of all the circumstances. Patients with active pulmonary tuberculosis who are to receive outpatient chemotherapy without adequate initial hospitalization should be carefully selected by the local or provincial department of public health. Approval in writing should be required from the appropriate public health authority before antituberculosis chemotherapy is provided at public expense for any such patient, except possibly for a limited period while awaiting formal approval. In all instances, the clinic which dispenses the antituberculosis drugs should have the patient under supervision with recall for follow-up examinations as required. Prophylactic antituberculosis chemotherapy may be provided to certain groups of persons without hospitalization. PMID:14179540

  7. miR-582-5p Is Upregulated in Patients with Active Tuberculosis and Inhibits Apoptosis of Monocytes by Targeting FOXO1

    PubMed Central

    Liu, Yanhua; Jiang, Jing; Wang, Xinjing; Zhai, Fei; Cheng, Xiaoxing

    2013-01-01

    Macrophage apoptosis is a host innate defense mechanism against tuberculosis (TB). In this study, we found that percentage of apoptotic cells in peripheral blood monocytes from patients with active TB was lower than that from healthy controls (p<0.001). To understand whether microRNAs can modulate apoptosis of monocytes, we investigated differentially expressed microRNAs in patients with active TB. miR-582-5p was mainly expressed in monocytes and was upregulated in patients with active TB. The apoptotic percentage of THP-1 cells transfected with miR-582-5p mimics was significantly lower than those transfected with negative control of microRNA mimics (p<0.001), suggesting that miR-582-5p could inhibit apoptosis of monocytes. To our knowledge, the role of miR-582-5p in regulating apoptosis of monocytes has not been reported so far. Systematic bioinformatics analysis indicated that FOXO1 might be a target gene for miR-582-5p and its 3?UTR contains potential binding sites for miR-582-5p. To determine whether miR-582-5p could influence FOXO1 expression, miR-582-5p mimics or negative control of microRNA mimics were transfected into THP-1 cells. RT-PCR and western blot analysis showed that the miR-582-5p could suppress both FOXO1 mRNA and protein expression. Co-transfection of miR-582-5p and FOXO1 3?UTR-luciferase reporter vector into cells demonstrated that significant decrease in luciferase activity was only found in reporter vector that contained a wild type sequence of FOXO1 3?UTR, suggesting that miR-582-5p could directly target FOXO1. In conclusion, miR-582-5p inhibited apoptosis of monocytes by down-regulating FOXO1 expression and might play an important role in regulating anti-M. tuberculosis directed immune responses. PMID:24205217

  8. Avian tuberculosis in pigs: miliary lesions in bacon pigs.

    PubMed Central

    Windsor, R. S.; Durrant, D. S.; Burn, K. J.; Blackburn, J. T.; Duncan, W.

    1984-01-01

    An outbreak of tuberculosis caused by Mycobacterium avium type 2 is described which resulted in the total condemnation of 26 carcasses and partial condemnation of tissues and organs of a further 200 animals. Circumstantial evidence is presented that hens running in the farmyard were the source of the infection. Examinations of the carcasses and organs of the diseased pigs suggested that the accepted pathogenesis of the disease is incorrect and a new hypothesis is presented. The problems for the meat inspector in differentiating tuberculosis from 'milk-spot liver' are discussed and recommendations made. The findings of the study are discussed in the light of 'The Meat Inspection Regulations 1963' and it is recommended that where tuberculosis is suspected there is no longer any necessity to split the carcasses. The public health implications of this study are discussed. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:6707466

  9. UPDATED Crime Alert: 2nd Robbery Suspect Arrested

    E-print Network

    UPDATED Crime Alert: 2nd Robbery Suspect Arrested UCPD sent a crime alert yesterday in reference********** Crime Alert: Robbery & Robbery Suspect Arrested on Campus On 3/3/13 at about 8:00pm a suspect committed

  10. Efficient Activation of Human T Cells of Both CD4 and CD8 Subsets by Urease-Deficient Recombinant Mycobacterium bovis BCG That Produced a Heat Shock Protein 70-M. tuberculosis-Derived Major Membrane Protein II Fusion Protein

    PubMed Central

    Mukai, Tetsu; Tsukamoto, Yumiko; Maeda, Yumi; Tamura, Toshiki

    2014-01-01

    For the purpose of obtaining Mycobacterium bovis bacillus Calmette-Guérin (BCG) capable of activating human naive T cells, urease-deficient BCG expressing a fusion protein composed of Mycobacterium tuberculosis-derived major membrane protein II (MMP-II) and heat shock protein 70 (HSP70) of BCG (BCG-DHTM) was produced. BCG-DHTM secreted the HSP70-MMP-II fusion protein and effectively activated human monocyte-derived dendritic cells (DCs) by inducing phenotypic changes and enhanced cytokine production. BCG-DHTM-infected DCs activated naive T cells of both CD4 and naive CD8 subsets, in an antigen (Ag)-dependent manner. The T cell activation induced by BCG-DHTM was inhibited by the pretreatment of DCs with chloroquine. The naive CD8+ T cell activation was mediated by the transporter associated with antigen presentation (TAP) and the proteosome-dependent cytosolic cross-priming pathway. Memory CD8+ T cells and perforin-producing effector CD8+ T cells were efficiently produced from the naive T cell population by BCG-DHTM stimulation. Single primary infection with BCG-DHTM in C57BL/6 mice efficiently produced T cells responsive to in vitro secondary stimulation with HSP70, MMP-II, and M. tuberculosis-derived cytosolic protein and inhibited the multiplication of subsequently aerosol-challenged M. tuberculosis more efficiently than did vector control BCG. These results indicate that the introduction of MMP-II and HSP70 into urease-deficient BCG may be useful for improving BCG for control of tuberculosis. PMID:24152387

  11. Bilateral Parotid Tuberculosis

    PubMed Central

    Thakur, JS; Thakur, A; Mohindroo, NK; Mohindroo, S; Sharma, DR

    2011-01-01

    Tuberculosis of parotid is a rare clinical entity, and cases of bilateral tubercular parotitis are even rarer. We present a case of bilateral primary parotid tuberculosis in a 49-year-old female. The patient received anti-tuberculosis treatment for six months, resulting in complete resolution of the disease. We also review the theories related to the pathogenesis of tubercular parotitis, and propose a novel hypothesis about greater involvement of parotid gland as compared to other salivary glands in primary tuberculosis. PMID:21887065

  12. Bilateral parotid tuberculosis.

    PubMed

    Thakur, Js; Thakur, A; Mohindroo, Nk; Mohindroo, S; Sharma, Dr

    2011-07-01

    Tuberculosis of parotid is a rare clinical entity, and cases of bilateral tubercular parotitis are even rarer. We present a case of bilateral primary parotid tuberculosis in a 49-year-old female. The patient received anti-tuberculosis treatment for six months, resulting in complete resolution of the disease. We also review the theories related to the pathogenesis of tubercular parotitis, and propose a novel hypothesis about greater involvement of parotid gland as compared to other salivary glands in primary tuberculosis. PMID:21887065

  13. Keratinocyte Growth Factor Administration Attenuates Murine Pulmonary Mycobacterium tuberculosis Infection through Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF)-dependent Macrophage Activation and Phagolysosome Fusion.

    PubMed

    Pasula, Rajamouli; Azad, Abul K; Gardner, Jason C; Schlesinger, Larry S; McCormack, Francis X

    2015-03-13

    Augmentation of innate immune defenses is an appealing adjunctive strategy for treatment of pulmonary Mycobacterium tuberculosis infections, especially those caused by drug-resistant strains. The effect of intranasal administration of keratinocyte growth factor (KGF), an epithelial mitogen and differentiation factor, on M. tuberculosis infection in mice was tested in prophylaxis, treatment, and rescue scenarios. Infection of C57BL6 mice with M. tuberculosis resulted in inoculum size-dependent weight loss and mortality. A single dose of KGF given 1 day prior to infection with 10(5) M. tuberculosis bacilli prevented weight loss and enhanced pulmonary mycobacterial clearance (compared with saline-pretreated mice) for up to 28 days. Similar effects were seen when KGF was delivered intranasally every third day for 15 days, but weight loss and bacillary growth resumed when KGF was withdrawn. For mice with a well established M. tuberculosis infection, KGF given every 3 days beginning on day 15 postinoculation was associated with reversal of weight loss and an increase in M. tuberculosis clearance. In in vitro co-culture experiments, M. tuberculosis-infected macrophages exposed to conditioned medium from KGF-treated alveolar type II cell (MLE-15) monolayers exhibited enhanced GM-CSF-dependent killing through mechanisms that included promotion of phagolysosome fusion and induction of nitric oxide. Alveolar macrophages from KGF-treated mice also exhibited enhanced GM-CSF-dependent phagolysosomal fusion. These results provide evidence that administration of KGF promotes M. tuberculosis clearance through GM-CSF-dependent mechanisms and enhances host defense against M. tuberculosis infection. PMID:25605711

  14. Functional characterization of Mycobacterium tuberculosis Rv2969c membrane protein.

    PubMed

    Patarroyo, Manuel A; Plaza, David F; Ocampo, Marisol; Curtidor, Hernando; Forero, Martha; Rodriguez, Luis E; Patarroyo, Manuel E

    2008-08-01

    Identifying Mycobacterium tuberculosis membrane proteins involved in binding to and invasion of host cells is important in designing subunit-based anti-tuberculosis vaccines. The Rv2969c gene sequence was identified by PCR in M. tuberculosis complex strains, being transcribed in M. tuberculosis H37Rv, M. tuberculosis H37Ra, and M. bovis BCG. Rabbits immunized with synthetic peptides from highly specific conserved regions of this protein produced antibodies recognizing 27 and 29 kDa bands in M. tuberculosis lysate, which is consistent with the molecular weight of the Rv2969c gene product in M. tuberculosis H37Rv. Immunoelectron microscopy revealed the protein was localized on the bacillus surface. Four and three specific high activity binding peptides (HABPs) to the A549 alveolar epithelial and U937 monocyte cell lines were found, respectively. Two of the HABPs found inhibited M. tuberculosis invasion of A549 cells, suggesting that these peptides might be good candidates to be included in a multiepitopic, subunit-based anti-tuberculosis vaccine. PMID:18539140

  15. [Tuberculosis in Asia].

    PubMed

    2002-10-01

    1. Philippines: The development, expansion and maintenance of pilot area activities: Cristina B. Giango (Technical Division, Cebu Provincial Health Office, the Philippines) In 1994, the Department of Health developed the new NTP policies based on WHO recommendations and started a pilot project in Cebu Province in collaboration with the Japan International Cooperation Agency. To test its feasibility and effectiveness, the new NTP policies were pre-tested in one city and one Rural Health Unit. The test showed a high rate of three sputum collection (90%), high positive rate (10%), and high cure rate (80%). Before the new guidelines were introduced, the new policy was briefed, a baseline survey of the facility was conducted, equipment was provided, and intensive training was given. Recording/Reporting forms and procedures were also developed to ensure accurate reporting. Supervision, an important activity to ensure effective performance, was institutionalized. Laboratory services were strengthened, and a quality-control system was introduced in 1995 to ensure the quality of the laboratory services. With the implementation of DOTS strategy, barangay health workers were trained as treatment partners. In partnership with the private sector, the TB Diagnostic Committee was organized to deliberate and assess sputum negative but X-ray positive cases. The implementation of the new NTP guidelines in Cebe Province has reached a satisfactory level, the cure rate and positive rate have increased, and laboratory services have improved. Because of its successful implementation, the new NTP guidelines are now being used nationwide. 2. Nepal: The DOTS Strategy in the area with hard geographic situation: Dirgh Singh Bam (National Tuberculosis Center, Nepal) Three groups of factors characterize the population of Nepal: 1) Socio-cultural factors, e.g. migration, poverty, language; 2) Environmental factors, e.g. geography and climate; and 3) Political factors, prisoners and refugee populations. These factors pose particular problems for implementing DOTS in various ways. Socio-cultural and environmental factors are particularly important in Nepal, and several measures have been developed to overcome these difficulties. One is active community participation through the DOTS committee. The committee consists of a group of motivated people, including social workers, political leaders, health services providers, journalists, teachers, students, representatives of local organizations, medical schools and colleges, industries, private practitioners, and TB patients. One DOTS committee is formed in every treatment center. A key role of the DOTS committee is to identify local problems and their solutions. It increases public awareness about TB and DOTS; supports people with TB in the community by providing treatment observers and tracing late patients; and encourages cooperation among health institutions, health workers, NGOs, and political leaders. The case finding rate is now 69%, and nearly 95% of diagnosed TB cases are being treated under DOTS. The treatment success rate of new smear-positive cases is nearly 90%. Thus, DOTS increases the case finding and treatment success. 3. Cambodia: HIV/TB and the health sector reform: Tan Eang Mao (National Center for Tuberculosis and Leprosy Control, Cambodia) Cambodia is one of the 23 high burden countries of tuberculosis in the world. Moreover, HIV/AIDS has been spreading rapidly since 1990s, which is worsening the tuberculosis epidemics. To cope with the burden, Cambodia has started implementation of DOTS in 1994 and has expanded it to most of public hospitals across the country by 1998. NTP of Cambodia is now enjoying high cure rate of more than 90%. However, due to the constraints such as weak infrastructure and the poverty, it is proved that many of TB sufferers do not have access to the TB services, resulting in still low case detection rate. It is for this reason that the NTP has decided to expand DOTS to health center and community level based on the new health system. Its pilot program that has been

  16. TUBERCULOSIS 1 Tuberculosis in Aboriginal Populations in Canada

    E-print Network

    Peak, Derek

    TUBERCULOSIS 1 Tuberculosis in Aboriginal Populations in Canada: The Role of Health Care, PhD March 27, 2013 #12;TUBERCULOSIS 2 Abstract The persistent presence of infectious and increasingly). Tuberculosis is an infectious disease which is far more common in the Aboriginal population than the Canadian

  17. Development of an ESI-LC-MS-Based Assay for Kinetic Evaluation of Mycobacterium tuberculosis Shikimate Kinase Activity and Inhibition.

    PubMed

    Simithy, Johayra; Gill, Gobind; Wang, Yu; Goodwin, Douglas C; Calderón, Angela I

    2015-02-17

    A simple and reliable liquid chromatography-mass spectrometry (LC-MS) assay has been developed and validated for the kinetic characterization and evaluation of inhibitors of shikimate kinase from Mycobacterium tuberculosis (MtSK), a potential target for the development of novel antitubercular drugs. This assay is based on the direct determination of the reaction product shikimate-3-phosphate (S3P) using electrospray ionization (ESI) and a quadrupole time-of-flight (Q-TOF) detector. A comparative analysis of the kinetic parameters of MtSK obtained by the LC-MS assay with those obtained by a conventional UV-assay was performed. Kinetic parameters determined by LC-MS were in excellent agreement with those obtained from the UV assay, demonstrating the accuracy, and reliability of this method. The validated assay was successfully applied to the kinetic characterization of a known inhibitor of shikimate kinase; inhibition constants and mode of inhibition were accurately delineated with LC-MS. PMID:25629762

  18. Breath-based biomarkers for tuberculosis

    NASA Astrophysics Data System (ADS)

    Kolk, Arend H. J.; van Berkel, Joep J. B. N.; Claassens, Mareli M.; Walters, Elisabeth; Kuijper, Sjoukje; Dallinga, Jan W.; van Schooten, Fredrik-Jan

    2012-06-01

    We investigated the potential of breath analysis by gas chromatography - mass spectrometry (GC-MS) to discriminate between samples collected prospectively from patients with suspected tuberculosis (TB). Samples were obtained in a TB endemic setting in South Africa where 28% of the culture proven TB patients had a Ziehl-Neelsen (ZN) negative sputum smear. A training set of breath samples from 50 sputum culture proven TB patients and 50 culture negative non-TB patients was analyzed by GC-MS. A classification model with 7 compounds resulted in a training set with a sensitivity of 72%, specificity of 86% and accuracy of 79% compared with culture. The classification model was validated with an independent set of breath samples from 21 TB and 50 non-TB patients. A sensitivity of 62%, specificity of 84% and accuracy of 77% was found. We conclude that the 7 volatile organic compounds (VOCs) that discriminate breath samples from TB and non-TB patients in our study population are probably host-response related VOCs and are not derived from the VOCs secreted by M. tuberculosis. It is concluded that at present GC-MS breath analysis is able to differentiate between TB and non-TB breath samples even among patients with a negative ZN sputum smear but a positive culture for M. tuberculosis. Further research is required to improve the sensitivity and specificity before this method can be used in routine laboratories.

  19. 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

  20. Evaluation of a Rapid PCR-Based Epidemiological Typing Method for Routine Studies of Mycobacterium tuberculosis

    Microsoft Academic Search

    Malcolm D. Yates; Francis A. Drobniewski; Stuart M. Wilson

    Restriction fragment length polymorphism (RFLP) based on the insertion sequence IS6110 is used to investigate episodes of suspected transmission of infection of tuberculosis but usually takes a number of weeks from receipt of request to obtain a result. Often investigations would benefit from a more rapid method, possibly one containing an amplification step. The method employed uses a simple DNA

  1. Mycobacterium tuberculosis 19-kDa lipoprotein induces Toll-like receptor 2-dependent peroxisome proliferator-activated receptor ? expression and promotes inflammatory responses in human macrophages.

    PubMed

    Liu, Li; Liu, Jincheng; Niu, Guoqiang; Xu, Qianhong; Chen, Qiliang

    2015-04-01

    Mycobacterium tuberculosis (M.tb) enhances its survival in macrophages by suppressing immune responses, in part through its complex cell wall structures. M.tb 19?kDa lipoprotein (P19), a component of the complex cell wall structures of M.tb, is a Toll?like receptor (TLR) agonist, and may induce immune responses through TLR2. Furthermore, the activation of peroxisome proliferator?activated receptor ? (PPAR?) is also involved in M.tb?induced immune responses in macrophages. In the present study, specific agonists/antagonists and siRNA were used to investigate the role of PPAR? in P19?induced immune responses in human macrophages, including TLR2 activation, p38 phosphorylation and cytokine production. In the present study, PPAR? expression, p38 phosphorylation and cytokine production were upregulated following M.tb H37Rv infection or P19 treatment. By pretreating macrophages with a specific PPAR? agonist or antagonist, it was demonstrated that phosphorylation and IL?6 production are modulated in macrophages by PPAR? activity. Following TLR2 knockdown in macrophages, the expression of PPAR? was significantly decreased in the presence or absence of P19 treatment. Furthermore, p38 phosphorylation and cytokine production were significantly reduced in TLR2 knockdown macrophages following P19 treatment. It was demonstrated in the current study that PPAR? was induced and activated by M.tb infection and that P19?induced PPAR? expression, p38 phosphorylation and cytokine production in macrophages are dependent on TLR2. These findings suggest a role for PPAR? and TLR2 in P19?induced p38 phosphorylation and cytokine production, thereby potentially influencing M.tb pathogenesis. PMID:25504154

  2. "Tuberculosis Case Management" Training.

    ERIC Educational Resources Information Center

    Knebel, Elisa; Kolodner, Jennifer

    2001-01-01

    The need to isolated health providers with critical knowledge in tuberculosis (TB) case management prompted the development of "Tuberculosis Case Management" CD-ROM. Features include "Learning Center,""Examination Room," and "Library." The combination of audio, video, and graphics allows participants to practice acquired skills in a simulated…

  3. 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

  4. Psychiatry and Tuberculosis

    PubMed Central

    Fantl, Kurt

    1950-01-01

    Studies on the psychosomatic aspects of tuberculosis have not brought to light a clearcut correlation between a specific personality structure and susceptibility to the illness. The recommendation is made to look for several rather than for one personality type. It is suggested that people should be studied who react to stress with loss of appetite and loss of sleep. This character structure in contrast to that where the person withdraws into sleep and overeats might make a person prone to tuberculosis. The somatopsychic influence of tuberculosis needs to be interpreted in terms of the localization of the lesion as well as infectiousness and conspicuousness of the disease. Some common sociopsychological factors of tuberculosis have been mentioned. Reports on mental illness and tuberculosis and on diet were reviewed. PMID:14792351

  5. In vitro synergistic activity of clofazimine and other antituberculous drugs against multidrug-resistant Mycobacterium tuberculosis isolates.

    PubMed

    Zhang, Zhijian; Li, Tianzhi; Qu, Geping; Pang, Yu; Zhao, Yanlin

    2015-01-01

    Clofazimine (CLO) is a promising candidate drug for use in the management of multidrug-resistant tuberculosis (MDR-TB) patients. In this study, the minimum inhibitory concentration (MIC) method was used to investigate drug susceptibility to CLO as well as potential synergies between CLO and other antituberculous drugs, including ethambutol (EMB), levofloxacin (LEV), moxifloxacin (MOX), amikacin (AMK) and capreomycin (CAP), among MDR-TB isolates from China. A total of 195 MDR-TB isolates were collected from the national drug resistance survey conducted in China. Of the 195 MDR-TB isolates, 54 (27.7%) were classified as CLO-resistant, whilst 141 (72.3%) were CLO-susceptible with MICs of ? 1 ?g/mL. In addition, the prevalence of CLO-resistant isolates among the extensively drug-resistant (XDR)-TB group was 61.5% (8/13), which was significantly higher than that of the MDR-TB group (23.0%) (P = 0.006). When fractional inhibitory concentration indexes (FICIs) were calculated for 24 isolates, synergy was found in 11 isolates (45.8%) against the CLO/EMB combination, 6 (25.0%) against the CLO/LEV combination, 8 (33.3%) against the CLO/MOX combination, 4 (16.7%) against the CLO/AMK combination and 5 (20.8%) against the CLO/CAP combination. In addition, <15% of MDR-TB isolates showed antagonistic effects against these five combinations. In conclusion, these findings demonstrate that the combination of CLO and EMB shows better synergism than the other combinations containing CLO. The CLO/MOX combination is more likely to show synergy against MDR-TB isolates than the CLO/LEV combination. Taken together, we suggest that CLO, in combination with EMB or MOX, may be a promising drug regimen for the treatment of MDR-TB. PMID:25459737

  6. Discovery of Novel Isoxazolines as Anti-tuberculosis Agents

    PubMed Central

    Tangallapally, Rajendra P.; Sun, Dianqing; Rakesh; Budha, Nageshwar; Lee, Robin E. B.; Lenaerts, Anne J. M.; Meibohm, Bernd; Lee, Richard E.

    2007-01-01

    Nitrofuranyl isoxazolines with increased proteolytic stability over nitrofuranyl amides were designed and synthesized leading to discovery of several compounds with potent in vitro anti-tuberculosis activity. However, their in vivo activity was limited by high protein binding and poor distribution. Consequently, a series of non-nitrofuran containing isoxazolines was prepared to determine if the core had residual anti-tuberculosis activity. This led to the discovery of novel isoxazoline 12 as anti-tuberculosis agent with a MIC90 value of 1.56 ?g/mL. PMID:17937983

  7. Enzyme immunoassay using BCG in serodiagnosis of pulmonary tuberculosis.

    PubMed Central

    Garcia-Carreño, F. L.; Carvajal, R. E.; Hernandez, R.

    1986-01-01

    Amounts of Mycobacterium tuberculosis antibodies were determined in sera from patients with either active or inactive tuberculosis and in healthy subjects by an immunoenzymatic assay in which whole BCG cells attached covalently to polystyrene disks were used as antigen. Statistically significant differences (P less than 0.005) were found both between the active and inactive tuberculosis groups and between the active group and healthy controls. No significant differences were found between the inactive group and controls. Since this procedure is efficient (91%) and can be used in areas which lack laboratory equipment, it appears promising for individual serodiagnosis and for epidemiological surveys. PMID:3098836

  8. The role of Mycobacterium tuberculosis Rv3166c protein-derived high-activity binding peptides in inhibiting invasion of human cell lines.

    PubMed

    Ocampo, Marisol; Aristizábal-Ramírez, Daniel; Rodríguez, Diana M; Muñoz, Marina; Curtidor, Hernando; Vanegas, Magnolia; Patarroyo, Manuel A; Patarroyo, Manuel E

    2012-05-01

    Given the urgent need for designing a new antituberculosis vaccine conferring total protection on patients of all ages, following the line of research adopted by our institute, this work has identified Mycobacterium tuberculosis (Mtb) Rv3166c protein high-activity binding peptides (HABPs) which are able to inhibit bacterial invasion of U937 (monocyte-derived macrophages) and A549 (type II alveolar epithelial cells) cell lines. The presence and transcription of the rv3166c gene in the Mtb species complex was confirmed by polymerase chain reaction (PCR) and reverse transcriptase-PCR; Rv3166c expression was evaluated by western blot and cellular localisation confirmed by immunoelectron microscopy. Its presence was mainly determined on cell surface. Sixteen peptides covering its entire length were chemically synthesised and tested for their ability to bind to U937 and A549 cells. Two U937 HABPs were identified and three for A549, one of them being shared by both cell lines. The four HABPs found inhibited Mtb entry by 15.07-94.06%. These results led us to including Rv3166c HABPs as candidates for further studies contributing towards the search for a multiepitope, chemically synthesised, subunit-based antituberculosis vaccine. PMID:22427370

  9. [Determination of antimycobacterial activities of fluoroquinolones against clinical isolates of Mycobacterium tuberculosis: comparative determination with egg-based Ogawa and agar-based Middlebrook 7H10 media].

    PubMed

    Yamane, N; Chilima, B Z; Tosaka, M; Okazawa, Y; Tanno, K

    1996-08-01

    The minimum inhibitory concentrations (MICs) to the fluoroquinolones, ofloxacin (OFLX), ciprofloxacin (CPFX), sparfloxacin (SPFX), norfloxacin (NFLX), balofloxacin (BLFX) and CS-940, were determined in 100 clinical isolates of Mycobacterium tuberculosis. The MICs were determined with 1% egg-based Ogawa or agar-based Middlebrook 7H10 and each of them supplemented with oxidation-reduction color dye, 2,3-diphenyl-5-thienyl-(2)-tetrazolium chloride (STC) by using the microculture technique. The MICs determined with Ogawa medium were approximately two- to four-fold higher when compared to those determined with Middlebrook agar medium. The supplement with STC slightly increased the MICs, probably as a result of easily recognizing small initial colonies. Among the six fluoroquinolones, CS-940 and SPFX showed the greatest antimycobacterial activities with inhibition of 50% of all the isolates at the concentrations between 0.25 to 0.5 microgram/ml. OFLX, CPFX and BLFX followed in potency at 0.5 to 2.0 micrograms /ml. NFLX was less potent requiring 8 to 16 micrograms/ml to inhibit 50% of the isolates. PMID:8831190

  10. Control and prevention of tuberculosis in the United Kingdom: Code of Practice 1994. Joint Tuberculosis Committee of the British Thoracic Society.

    PubMed Central

    1994-01-01

    BACKGROUND--The guidelines on control and prevention of tuberculosis in the United Kingdom have been reviewed and updated. METHODS--A subcommittee was appointed by the Joint Tuberculosis Committee (JTC). Each member of this group drafted one or more sections of the guidelines, and drafts were made available to all members of the group. In the course of several meetings drafts were altered and incorporated into a final text. The guidelines were approved by the full JTC and by the Standards of Care Committee of the British Thoracic Society. In revising the guidelines the authors took account of new published evidence and recent concerns about drug resistance and possible effects of HIV on tuberculosis. CONCLUSIONS--(1) All cases of tuberculosis must be notified. (2) A few patients need hospital admission. (3) Patients with positive sputum smears and sensitive organisms should be considered infectious until they have received two weeks' chemotherapy. (4) Treatment of all tuberculosis patients should be supervised by a respiratory physician employing standard medication guidelines and monitoring compliance at least monthly. (5) Health care workers at risk should be protected by BCG vaccination and appropriate infection control measures, and evidence of infectious tuberculosis should be sought among prospective NHS staff, school teachers, and others. (6) Prison staff should be protected. (7) Tuberculosis should be considered in the elderly in long stay care with persistent chest symptoms. (8) Contact tracing should be vigorously pursued with chemoprophylaxis, BCG vaccination, or follow up where applicable. (9) Entrants to the UK from high risk countries (tuberculosis incidence more than 40/100,000 population per year) should be screened. (10) BCG vaccination should be offered where appropriate but not in subjects with known or suspected HIV infection. (11) The local organisation of tuberculosis services should be strengthened and should include adequate nursing and support staff. (12) Contracts between purchasers and providers should specify management of tuberculosis in line with this and other JTC guidelines. PMID:7878551

  11. Tuberculosis treatment and management-an update on treatment regimens, trials, new drugs, and adjunct therapies.

    PubMed

    Zumla, Alimuddin; Chakaya, Jeremiah; Centis, Rosella; D'Ambrosio, Lia; Mwaba, Peter; Bates, Matthew; Kapata, Nathan; Nyirenda, Thomas; Chanda, Duncan; Mfinanga, Sayoki; Hoelscher, Michael; Maeurer, Markus; Migliori, Giovanni Battista

    2015-03-01

    WHO estimates that 9 million people developed active tuberculosis in 2013 and 1·5 million people died from it. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis continue to spread worldwide with an estimated 480?000 new cases in 2013. Treatment success rates of MDR and XDR tuberculosis are still low and development of new, more effective tuberculosis drugs and adjunct therapies to improve treatment outcomes are urgently needed. Although standard therapy for drug-sensitive tuberculosis is highly effective, shorter, more effective treatment regimens are needed to reduce the burden of infectious cases. We review the latest WHO guidelines and global recommendations for treatment and management of drug-sensitive and drug-resistant tuberculosis, and provide an update on new drug development, results of several phase 2 and phase 3 tuberculosis treatment trials, and other emerging adjunct therapeutic options for MDR and XDR tuberculosis. The use of fluoroquinolone-containing (moxifloxacin and gatifloxacin) regimens have failed to shorten duration of therapy, and the new tuberculosis drug pipeline is sparse. Scale-up of existing interventions with increased investments into tuberculosis health services, development of new antituberculosis drugs, adjunct therapies and vaccines, coupled with visionary political leadership, are still our best chance to change the unacceptable status quo of the tuberculosis situation worldwide and the growing problem of drug-resistant tuberculosis. PMID:25773212

  12. Approach to the patient with suspected radiculopathy.

    PubMed

    Levin, Kerry H

    2012-05-01

    Radiculopathy is a common neurologic disorder. Electrodiagnosis can provide a physiologic assessment of the localization, degree of axon loss, severity, and chronicity of the intraspinal canal lesion, and distinguish it from other neuromuscular disorders. This article reviews electrodiagnostic aspects related to evaluating patients with suspected radiculopathies. PMID:22361375

  13. [A reevaluation of the criteria for initiating medical treatment of pulmonary tuberculosis patients].

    PubMed

    Toyota, M; Yasuda, N; Ohara, H; Tagami, T; Ishikawa, Y

    1994-01-01

    In Japan some registered tuberculosis (TB) patients have had medical treatment initiated for the purpose of preventing development of inactive TB into active stages, or due to differential diagnosis. A reevaluation of the necessity of commencing medical treatment was performed on 91 TB patients to elucidate the special characteristics of TB patients who do not necessarily need medical treatment. The results are as follows: 1) Among the 91 patients, 67 patients were judged to be 'confirmed cases', while 24 patients were judged to be 'suspect cases', with either inactive TB or possibly without TB. 2) The rates of 'suspect cases' were higher in the tubercle bacillus negative groups as well as the X-ray mild cases compared to the tubercle bacillus positive cases and X-ray severe cases. 3) The patient's self-diagnosed symptoms proved to be useful in evaluating the TB patient's severity. It is thought that this information should be used to judge the necessity of commencing medical treatment in TB patients. PMID:8111099

  14. Redox potential measurements of the Mycobacterium tuberculosis heme protein KatG and the isoniazid-resistant enzyme KatG(S315T): insights into isoniazid activation.

    PubMed

    Wengenack, N L; Lopes, H; Kennedy, M J; Tavares, P; Pereira, A S; Moura, I; Moura, J J; Rusnak, F

    2000-09-19

    Mycobacterium tuberculosis KatG is a multifunctional heme enzyme responsible for activation of the antibiotic isoniazid. A KatG(S315T) point mutation is found in >50% of isoniazid-resistant clinical isolates. Since isoniazid activation is thought to involve an oxidation reaction, the redox potential of KatG was determined using cyclic voltammetry, square wave voltammetry, and spectroelectrochemical titrations. Isoniazid activation may proceed via a cytochrome P450-like mechanism. Therefore, the possibility that substrate binding by KatG leads to an increase in the heme redox potential and the possibility that KatG(S315T) confers isoniazid resistance by altering the redox potential were examined. Effects of the heme spin state on the reduction potentials of KatG and KatG(S315T) were also determined. Assessment of the Fe(3+)/Fe(2+) couple gave a midpoint potential of ca. -50 mV for both KatG and KatG(S315T). In contrast to cytochrome P450s, addition of substrate had no significant effect on either the KatG or KatG(S315T) redox potential. Conversion of the heme to a low-spin configuration resulted in a -150 to -200 mV shift of the KatG and KatG(S315T) redox potentials. These results suggest that isoniazid resistance conferred by KatG(S315T) is not mediated through changes in the heme redox potential. The redox potentials of isoniazid were also determined using cyclic and square wave voltammetry, and the results provide evidence that the ferric KatG and KatG(S315T) midpoint potentials are too low to promote isoniazid oxidation without formation of a high-valent enzyme intermediate such as compounds I and II or oxyferrous KatG. PMID:10985797

  15. Crystal Structure of Full-length Mycobacterium tuberculosis H37Rv Glycogen Branching Enzyme; Insights of N-Terminal [beta]-Sandwich in Sustrate Specifity and Enzymatic Activity

    SciTech Connect

    Pal, Kuntal; Kumar, Shiva; Sharma, Shikha; Garg, Saurabh Kumar; Alam, Mohammad Suhail; Xu, H. Eric; Agrawal, Pushpa; Swaminathan, Kunchithapadam (NU Sinapore); (Van Andel); (IMT-India)

    2010-07-13

    The open reading frame Rv1326c of Mycobacterium tuberculosis (Mtb) H37Rv encodes for an {alpha}-1,4-glucan branching enzyme (MtbGlgB, EC 2.4.1.18, Uniprot entry Q10625). This enzyme belongs to glycoside hydrolase (GH) family 13 and catalyzes the branching of a linear glucose chain during glycogenesis by cleaving a 1 {yields} 4 bond and making a new 1 {yields} 6 bond. Here, we show the crystal structure of full-length MtbGlgB (MtbGlgBWT) at 2.33-{angstrom} resolution. MtbGlgBWT contains four domains: N1 {beta}-sandwich, N2 {beta}-sandwich, a central ({beta}/{alpha}){sub 8} domain that houses the catalytic site, and a C-terminal {beta}-sandwich. We have assayed the amylase activity with amylose and starch as substrates and the glycogen branching activity using amylose as a substrate for MtbGlgBWT and the N1 domain-deleted (the first 108 residues deleted) Mtb{Delta}108GlgB protein. The N1 {beta}-sandwich, which is formed by the first 105 amino acids and superimposes well with the N2 {beta}-sandwich, is shown to have an influence in substrate binding in the amylase assay. Also, we have checked and shown that several GH13 family inhibitors are ineffective against MtbGlgBWT and Mtb{Delta}108GlgB. We propose a two-step reaction mechanism, for the amylase activity (1 {yields} 4 bond breakage) and isomerization (1 {yields} 6 bond formation), which occurs in the same catalytic pocket. The structural and functional properties of MtbGlgB and Mtb{Delta}108GlgB are compared with those of the N-terminal 112-amino acid-deleted Escherichia coli GlgB (EC{Delta}112GlgB).

  16. Tuberculosis in Thailand.

    PubMed

    Palwatwichai, A

    2001-03-01

    Tuberculosis (TB) was expected to be eradicated by the end of this century. However, an increasing incidence of tuberculosis in many parts of the world has led to renewed interest in the disease. The pandemic of HIV infection has changed TB, an endemic disease, to an epidemic worldwide. In Thailand, tuberculosis cases and deaths reduced year after year, until 1992 when the cases began to increase as a result of HIV infection. The annual risk of infection in 1997 was estimated at 1.4%, with approximately 100 000 new TB cases developing each year. Fifteen per cent of tuberculosis patients are seropositive for HIV infection. Increasing antituberculosis drug resistance has been correlated with the high prevalence of HIV infection in some parts of the country. In 1995, cure rate of this disease was approximately 50% and, since 1996, in order to cope with the worsening situation, the National Tuberculosis Programme (NTP) has adopted Directly Observed Treatment, Short-course (DOTS). Despite the current economic turmoil of the country, the programme has now been expanded to cover over 400 of the 810 districts of Thailand. Also, the economic effects of tuberculosis at the household level in Thailand were recently studied. Tuberculosis is a chronic disease that commonly affects the lower socioeconomic classes. Some patients were unable to follow the treatment regimens because of the financial burden. The low case detection and treatment completion rates are, in part, due to the inability of poor patients to cope with the expenditure. PMID:11264766

  17. Tuberculosis: burning issues: multidrug resistance and HIV-coinfection.

    PubMed

    Janbaz, Khalid Hussain; Qadir, M Imran; Ahmad, Bashir; Sarwar, Abida; Yaqoob, Nazish; Masood, Muhammad Irfan

    2012-11-01

    Tuberculosis is an infection of respiratory tract and Mycobacterium tuberculosis is the causative agent. Multidrug resistance and HIV-coinfection are the burning issues for tuberculosis. The management of drug resistance to tuberculosis is the necessity of the day so by taking effective and controlled measures and giving high doses of 2nd line drugs, we can minimize the death rate in TB. For the HIV-related TB infection, it is necessary to treat TB infection first so that effectiveness of antiretroviral therapy may not be altered and the transmission of M. tuberculosis to other healthy individuals of community could be prevented. All HIV positive individuals who are at a greater risk of acquiring TB infection, either due to suppressed immune system or unhealthy circumstances, must be investigated and if indicated must be treated effectively at immediate basis so that latent TB infection may not progress to active TB. PMID:22421086

  18. Transforming the fight against tuberculosis: targeting catalysts of transmission.

    PubMed

    Dowdy, David W; Azman, Andrew S; Kendall, Emily A; Mathema, Barun

    2014-10-15

    The global tuberculosis control community has committed itself to ambitious 10-year targets. To meet these targets, biomedical advances alone will be insufficient; a more targeted public health tuberculosis strategy is also needed. We highlight the role of "tuberculosis transmission catalysts," defined as variabilities in human behavior, bacillary properties, and host physiology that fuel the propagation of active tuberculosis at the local level. These catalysts can be categorized as factors that increase contact rates, infectiousness, or host susceptibility. Different catalysts predominate in different epidemiological and sociopolitical settings, and public health approaches are likely to succeed only if they are tailored to target the major catalysts driving transmission in the corresponding community. We argue that global tuberculosis policy should move from a country-level focus to a strategy that prioritizes collection of data on key transmission catalysts at the local level followed by deployment of "catalyst-targeted" interventions, supported by strengthened health systems. PMID:24982034

  19. 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

  20. The Human Antibody Response to the Surface of Mycobacterium tuberculosis

    PubMed Central

    Perley, Casey C.; Frahm, Marc; Click, Eva M.; Dobos, Karen M.; Ferrari, Guido; Stout, Jason E.; Frothingham, Richard

    2014-01-01

    Background Vaccine-induced human antibodies to surface components of Haemophilus influenzae and Streptococcus pneumonia are correlated with protection. Monoclonal antibodies to surface components of Mycobacterium tuberculosis are also protective in animal models. We have characterized human antibodies that bind to the surface of live M. tuberculosis. Methods Plasma from humans with latent tuberculosis (TB) infection (n?=?23), active TB disease (n?=?40), and uninfected controls (n?=?9) were assayed by ELISA for reactivity to the live M. tuberculosis surface and to inactivated M. tuberculosis fractions (whole cell lysate, lipoarabinomannan, cell wall, and secreted proteins). Results When compared to uninfected controls, patients with active TB disease had higher antibody titers to the surface of live M. tuberculosis (??=?0.72 log10), whole cell lysate (??=?0.82 log10), and secreted proteins (??=?0.62 log10), though there was substantial overlap between the two groups. Individuals with active disease had higher relative IgG avidity (??=?1.4 to 2.6) to all inactivated fractions. Surprisingly, the relative IgG avidity to the live M. tuberculosis surface was lower in the active disease group than in uninfected controls (??=?–1.53, p?=?0.004). Patients with active disease had higher IgG than IgM titers for all inactivated fractions (ratios, 2.8 to 10.1), but equal IgG and IgM titers to the live M. tuberculosis surface (ratio, 1.1). Higher antibody titers to the M. tuberculosis surface were observed in active disease patients who were BCG-vaccinated (??=?0.55 log10, p?=?0.008), foreign-born (??=?0.61 log10, p?=?0.004), or HIV-seronegative (??=?0.60 log10, p?=?0.04). Higher relative IgG avidity scores to the M. tuberculosis surface were also observed in active disease patients who were BCG-vaccinated (??=?1.12, p<0.001) and foreign-born (??=?0.87, p?=?0.01). Conclusions/Significance Humans with active TB disease produce antibodies to the surface of M. tuberculosis with low avidity and with a low IgG/IgM ratio. Highly-avid IgG antibodies to the M. tuberculosis surface may be an appropriate target for future TB vaccines. PMID:24918450

  1. MMPs in tuberculosis: granuloma creators and tissue destroyers

    PubMed Central

    Salgame, Padmini

    2011-01-01

    Most individuals infected with Mycobacterium tuberculosis develop a latent infection, which does not progress to active tuberculosis (TB). This occurs, in part, because infected macrophages recruit immune cells to form a granuloma, isolating the bacteria and preventing its spread. In some individuals, granulomas undergo necrosis and tissue destruction occurs, releasing the bacteria and allowing the development of active disease. In this issue of the JCI, Elkington et al. provide evidence that M. tuberculosis drives the expression of MMP-1, which in turn promotes the collagen breakdown that leads to alveolar destruction in TB. These findings identify putative therapeutic targets for the prevention of TB. PMID:21519148

  2. 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.

  3. 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

  4. Molecular epidemiology of bovine tuberculosis in wild animals in Spain: A first approach to risk factor analysis

    Microsoft Academic Search

    A. Parra; J. Larrasa; A. García; J. M. Alonso; J. Hermoso de Mendoza

    2005-01-01

    In human tuberculosis (Mycobacterium tuberculosis), molecular epidemiology has accurately indicated the risk factors involved in active transmission of the disease, by comparing individuals whose isolates belong to a cluster with patients whose strains are considered unique. Nevertheless, this application has not been used in bovine tuberculosis (Mycobacterium bovis). Our study describes the integration of epidemiological data into molecular classification data

  5. Parotid tuberculosis associated with cutaneous tuberculosis on a medial epicanthus.

    PubMed

    Demirci, Gulsen Tukenmez; Altunay, Ilknur Kivanç; Merto?lu, Eda; Sakiz, Damlanur

    2012-01-01

    An 83-year-old woman presented with a 2-month history of a gradually enlarging, reddish, crusted papule on her left medial epicanthus. Her medical history did not reveal any systemic disease. She gave no personal history of tuberculosis or any systemic symptoms, such as night sweat, weight loss, and pulmonary abnormalities. Her husband had been treated for pulmonary tuberculosis 30 years ago. A dermatologic examination revealed a 2.5 x 1.2-cm nontender, erythematous plaque with fine, white adherent scales on the left medial epicanthus (figure 1A). All laboratory values were within the normal range. Results from a tuberculin skin test were initially negative. A skin biopsy was performed, and a pathological examination demonstrated multiple noncaseating granulomas with various diameters in the reticular dermis and an infiltrate of neutrophils and lymphocytes in the surrounding dermis (figure 2). Periodic acid-Schiff, Ziehl-Nilsen, gram, and giemsa stains were negative for any microorganism. Leishman-Donovan-like bodies were observed within the epitheloid histiocytes that formed the granulomas. The pathological diagnosis was granulomatous dermatitis. The patient was diagnosed with cutaneous leishmaniasis (CL) based on her clinical appearance and histopathological findings, although the parasite was not detected in the tissue specimens. Treatment with intralesional glucantime for 5 consecutive weeks did not improve her condition. By the end of the fifth week, the patient developed asymptomatic facial swelling and a 1.5 x 1.2-cm erythematous plaque in the left parotid area (figure 1B). An ultrasonographic examination demonstrated a 13 x 11 x 17-mm hypoechoic mass, which suggested pleomorphic adenoma. In addition, lymph nodes, the largest of which were 9 x 10 mm, were noted in the left cervical area. A skin biopsy from the erythematous plaque of the left parotid area demonstrated diffuse neutrophilic infiltration with formation of focal granulomas. Tuberculosis was suspected, and mycobacterium tuberculosis (MT) was isolated from the culture. A tuberculin skin test was performed again, which was positive (12 mm). The erythrocyte sedimentation rate was 35 mm/h, and all other laboratory tests were within normal limits. Pulmonary radiography and thoracic computerized tomography findings were normal. Fine needle aspiration biopsy and ultrasonographic examination of the parotid mass were performed, which revealed necrotic material with neutrophils and lymphocytes (figure 3). We treated the patient with a standard antituberculous regimen, comprising isoniazid 300 mg/d, rifampin 600 mg/d, ethambutol 1200 mg/d, and pyrazinamide 1500 mg/d. By the end of the second month of treatment, the patient improved considerably. There was a marked reduction in facial swelling, and the lesion on the left medial epicanthus regressed dramatically (Figure 4A and Figure 4B). No adverse effects of the medication occurred. An additional 7 months of therapy with isoniazid and rifampin was planned. PMID:23163079

  6. Accurate mapping of mutations of pyrazinamide-resistant Mycobacterium tuberculosis strains with a scanning-frame oligonucleotide microarray

    Microsoft Academic Search

    Mary Margaret Wade; Dmitriy Volokhov; Mike Peredelchuk; Vladimir Chizhikov; Ying Zhang

    2004-01-01

    The increasing emergence of drug-resistant Mycobacterium tuberculosis poses significant threat to the treatment of tuberculosis. Conventional susceptibility testing for the front-line tuberculosis drug pyrazinamide (PZA) is difficult, because of the requirement for acid pH for the drug to show activity. Resistance to PZA in M. tuberculosis is caused by mutations in the pncA gene, and detection of pncA mutations can

  7. Suspected fibrocartilaginous embolism in a cat.

    PubMed

    Coradini, M; Johnstone, I; Filippich, L J; Armit, S

    2005-09-01

    A 12-year-old cat was presented to the University of Queensland's Small Animal Teaching Hospital with a 1-day history of left hemiparesis of acute onset, with no evidence of trauma or toxin exposure. Neurological examination findings were consistent with a lesion in the caudal left cervical spinal cord (C6 to C8), which was non-painful and had not progressed since the onset of clinical signs. No other abnormalities were found, although myelography showed a mild swelling involving the caudal cervical and cranial thoracic spinal segments. A diagnosis of suspected fibrocartilaginous embolism was made on the basis of the history, clinical presentation and diagnostic tests results, making this case the first report of a suspected fibrocartilaginous embolism in a cat that returned to normal function. PMID:16164143

  8. Suspect burial excavation procedure: a cautionary tale.

    PubMed

    Ruffell, Alastair; Donnelly, Colm; Carver, Naomi; Murphy, Eileen; Murray, Emily; McCambridge, James

    2009-01-10

    Geographic location, time of reporting and need for rapid evaluation contributed to a lack of intelligence concerning a suspect burial site in scrub woodland (approximately 15 km from the last known location of a missing person) in Northern Ireland. Police received reports of a subsiding 'grave', which was evaluated positively using GPR and victim recovery dogs (VRD). After 24h work, archaeological excavation showed a vertical-sided, stepped excavation on undisturbed clay with no inhumation. Subsequent research showed the feature to be an engineering trial pit. The GPR response was a water table and rocks, VRD were possibly reacting to disturbed ground. The work serves as a demonstration of good archaeological practice in suspect burial excavation, following a lack of landscape evaluation and poor overall intelligence. PMID:19081213

  9. Tuberculosis and HIV control in sub-Saharan African prisons: "thinking outside the prison cell".

    PubMed

    Reid, Stewart E; Topp, Stephanie M; Turnbull, Eleanor R; Hatwiinda, Sisa; Harris, Jennifer B; Maggard, Katie R; Roberts, Sarah T; Krüüner, Annika; Morse, Jill C; Kapata, Nathan; Chisela, Chileshe; Henostroza, German

    2012-05-15

    Tuberculosis is one of the fastest-growing epidemics in prison populations in sub-Saharan Africa (SSA), constituting a threat to both inmates and the wider community. Various factors have contributed to the breakdown of tuberculosis control in prison facilities in SSA, including slow and insensitive diagnostics, failing prison infrastructure, inadequate funding, and weak prevention and treatment interventions for human immunodeficiency virus (HIV). In this article, we describe the challenges inherent in current approaches to tuberculosis control in prisons and consider the alternatives. We argue that although improved implementation of conventional tuberculosis control activities is necessary, considerable investment in a broader range of public health interventions, including infrastructure and staffing upgrades, cutting-edge tuberculosis diagnostics, and combination prevention for HIV, will be equally critical. This combination response to tuberculosis in prisons will be essential for tackling existing and nascent prison tuberculosis epidemics and will require high-level political support and financing. PMID:22448015

  10. 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

  11. 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 ...

  12. 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 ...

  13. Update on cutaneous tuberculosis*

    PubMed Central

    Dias, Maria Fernanda Reis Gavazzoni; Bernardes Filho, Fred; Quaresma, Maria Victória; do Nascimento, Leninha Valério; Nery, José Augusto da Costa; Azulay, David Rubem

    2014-01-01

    Tuberculosis continues to draw special attention from health care professionals and society in general. Cutaneous tuberculosis is an infection caused by M. tuberculosis complex, M. bovis and bacillus Calmette-Guérin. Depending on individual immunity, environmental factors and the type of inoculum, it may present varied clinical and evolutionary aspects. Patients with HIV and those using immunobiological drugs are more prone to infection, which is a great concern in centers where the disease is considered endemic. This paper aims to review the current situation of cutaneous tuberculosis in light of this new scenario, highlighting the emergence of new and more specific methods of diagnosis, and the molecular and cellular mechanisms that regulate the parasite-host interaction. PMID:25387498

  14. Evolution of Mycobacterium tuberculosis.

    PubMed

    Behr, Marcel A

    2013-01-01

    Genomic studies have provided a refined understanding of the genetic diversity within the Mycobacterium genus, and more specifically within Mycobacterium tuberculosis. These results have informed a new perspective on the macro- and micro-evolution of the tubercle bacillus. In the first step, a M. kansasii-like opportunistic pathogen acquired new genes, through horizontal gene transfer, that enabled it to better exploit an intracellular niche and ultimately evolve into a professional pathogen. In the second step, different subspecies and strains of the M. tuberculosis complex emerged through mutation and deletion of unnecessary DNA. Understanding the differences between M. tuberculosis and related less pathogenic mycobacteria is expected to reveal key bacterial virulence mechanisms and provide opportunities to understand host resistance to mycobacterial infection. Understanding differences within the M. tuberculosis complex and the evolutionary forces shaping these differences is important for investigating the basis of its success as both a symbiont and a pathogen. PMID:23468104

  15. Screening Strategies for Tuberculosis Prevalence Surveys: The Value of Chest Radiography and Symptoms

    PubMed Central

    van’t Hoog, Anna H.; Meme, Helen K.; Laserson, Kayla F.; Agaya, Janet A.; Muchiri, Benson G.; Githui, Willie A.; Odeny, Lazarus O.; Marston, Barbara J.; Borgdorff, Martien W.

    2012-01-01

    Background We conducted a tuberculosis (TB) prevalence survey and evaluated the screening methods used in our survey, to assess if screening in TB prevalence surveys could be simplified, and to assess the accuracy of screening algorithms that may be applicable for active case finding. Methods All participants with a positive screen on either a symptom questionnaire, chest radiography (CXR) and/or sputum smear microscopy submitted sputum for culture. HIV status was obtained from prevalent cases. We estimated the accuracy of modified screening strategies with bacteriologically confirmed TB as the gold standard, and compared these with other survey reports. We also assessed whether sequential rather than parallel application of symptom, CXR and HIV screening would substantially reduce the number of participants requiring CXR and/or sputum culture. Results Presence of any abnormality on CXR had 94% (95%CI 88–98) sensitivity (92% in HIV-infected and 100% in HIV-uninfected) and 73% (95%CI 68–77) specificity. Symptom screening combinations had significantly lower sensitivity than CXR except for ‘any TB symptom’ which had 90% (95%CI 84–95) sensitivity (96% in HIV-infected and 82% in HIV-uninfected) and 32% (95%CI 30–34) specificity. Smear microscopy did not yield additional suspects, thus the combined symptom/CXR screen applied in the survey had 100% (95%CI 97–100) sensitivity. Specificity was 65% (95%CI 61–68). Sequential application of first a symptom screen for ‘any symptom’, followed by CXR-evaluation and different suspect criteria depending on HIV status would result in the largest reduction of the need for CXR and sputum culture, approximately 36%, but would underestimate prevalence by 11%. Conclusion CXR screening alone had higher accuracy compared to symptom screening alone. Combined CXR and symptom screening had the highest sensitivity and remains important for suspect identification in TB prevalence surveys in settings where bacteriological sputum examination of all participants is not feasible. PMID:22792158

  16. Libyan Suspects Detained in Lockerbie Case

    NSDL National Science Digital Library

    Osmond, Andrew.

    1994-01-01

    This week's In the News covers the long-awaited detainment and extradition of two Libyans accused of bombing a commercial airliner. On December 21, 1988, Pan Am Flight 103, en route from London to New York, exploded over the small town of Lockerbie, Scotland, killing 270 people, including 189 Americans, in an alleged act of terrorism. Yesterday in Tripoli, after ten years of legal squabbling among the US, UK, and Libya, Libyan officials finally surrendered the Lockerbie bombing suspects into the custody of United Nations representatives. Accompanied by their legal advisers, the two suspects, Libyan intelligence agents Abdel Basset Ali al-Megrahi and Lamen Khalifa Fhimah, were taken to Camp Zeist, near the city of Utrecht, the Netherlands, to stand trial. Libyan officials and the suspects agreed to a trial in a neutral location "to prove their innocence to the world." The transfer of the accused occurred as part of an extradition deal between Libyan leader Col. Moammar Gadhafi and the UN, a deal brokered by South African President Nelson Mandela and Crown Prince Abdullah of Saudi Arabia. If the extradition deal is conducted smoothly, UN Secretary-General Kofi Annan is expected to ask the UN Security Council to lift the punitive economic sanctions that it imposed on Libya in 1992. The UN sanctions were the first ever imposed on a sovereign state to force it to remit its citizens for an international trial. Although the venue for this unique international trial is Dutch, it will be governed by Scots law before a bench of three Scottish judges with no jury. If convicted, the suspects will serve life sentences in Scotland under UN supervision. Because of the complex legal issues involved in this case, the trial is predicted to last for several months. The eight resources discussed provide news, analysis, government reports, and background information on the Lockerbie incident.

  17. Therapy of suspected intrathoracic parathyroid adenomas

    Microsoft Academic Search

    Kenko Cupisti; Cornelia Dotzenrath; Dietmar Simon; Hans-Dietrich Röher; Peter E. Goretzki

    2002-01-01

    Background and aims: Ectopic mediastinal parathyroid adenoma as a cause of primary hyperparathyroidism (pHPT) can normally be resected from conventional collar incision. In rare cases with adenomas deeper in the chest, a transthoracic approach is necessary. Patients\\/methods: We report our experience of 19 patients with suspected mediastinal parathyroid adenomas from a total of 1035 patients with pHPT who were operated

  18. 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

  19. Zoonotic transmission of tuberculosis between pastoralists and their livestock in South-East Ethiopia.

    PubMed

    Gumi, Balako; Schelling, Esther; Berg, Stefan; Firdessa, Rebuma; Erenso, Girume; Mekonnen, Wondale; Hailu, Elena; Melese, Ermias; Hussein, Jemal; Aseffa, Abraham; Zinsstag, Jakob

    2012-06-01

    Despite huge global efforts in tuberculosis (TB) control, pastoral areas remain under-investigated. During two years sputum and fine needle aspirate (FNA) specimens were collected from 260 Ethiopian pastoralists of Oromia and Somali Regional States with suspected pulmonary TB and from 32 cases with suspected TB lymphadenitis. In parallel, 207 suspected tuberculous lesions were collected from cattle, camels and goats at abattoirs. All specimens were processed and cultured for mycobacteria; samples with acid-fast stained bacilli (AFB) were further characterized by molecular methods including genus and deletion typing as well as spoligotyping. Non-tuberculous mycobacteria (NTM) were sequenced at the 16S rDNA locus. Culturing of AFB from human sputum and FNA samples gave a yield of 174 (67%) and 9 (28%) isolates, respectively. Molecular typing was performed on 173 of these isolates and 160 were confirmed as Mycobacterium tuberculosis, three as M. bovis, and the remaining 10 were typed as NTMs. Similarly, 48 AFB isolates (23%) yielded from tuberculous lesions of livestock, of which 39 were molecular typed, including 24 M. bovis and 4 NTMs from cattle, 1 M. tuberculosis and 1 NTM from camels and 9 NTMs from goats. Isolation of M. bovis from humans and M. tuberculosis from livestock suggests transmission between livestock and humans in the pastoral areas of South-East Ethiopia. PMID:22526748

  20. Tuberculosis: Getting Healthy, Staying Healthy

    MedlinePLUS

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

  1. Screening and brief interventions for hazardous and harmful alcohol use among patients with active tuberculosis attending primary care clinics in South Africa: a cluster randomized controlled trial protocol

    PubMed Central

    2011-01-01

    Background In 2008 the World Health Organization (WHO) reported that South Africa had the highest tuberculosis (TB) incidence in the world. This high incidence rate is linked to a number of factors, including HIV co-infection and alcohol use disorders. The diagnosis and treatment package for TB and HIV co-infection is relatively well established in South Africa. However, because alcohol use disorders may present more insidiously, making it difficult to diagnose, those patients with active TB and misusing alcohol are not easily cured from TB. With this in mind, the primary purpose of this cluster randomized controlled trial is to provide screening for alcohol misuse and to test the efficacy of brief interventions in reducing alcohol intake in those patients with active TB found to be misusing alcohol in primary health care clinics in three provinces in South Africa. Methods/Design Within each of the three selected health districts with the highest TB burden in South Africa, 14 primary health care clinics with the highest TB caseloads will be selected. Those agreeing to participate will be stratified according to TB treatment caseload and the type of facility (clinic or community health centre). Within strata from 14 primary care facilities, 7 will be randomly selected into intervention and 7 to control study clinics (42 clinics, 21 intervention clinics and 21 control clinics). At the clinic level systematic sampling will be used to recruit newly diagnosed TB patients. Those consenting will be screened for alcohol misuse using the AUDIT. Patients who screen positive for alcohol misuse over a 6-month period will be given either a brief intervention based on the Information-Motivation-Behavioural Skills (IMB) Model or an alcohol use health education leaflet. A total sample size of 520 is expected. Discussion The trial will evaluate the impact of alcohol screening and brief interventions for patients with active TB in primary care settings in South Africa. The findings will impact public health and will enable the health ministry to formulate policy related to comprehensive treatment for TB and alcohol misuse, which will result in reduction in alcohol use and ultimately improve the TB cure rates. Trial registration number PACTR: PACTR201105000297151 PMID:21615934

  2. [Renal abscess in patients diagnosed with AIDS and disseminated tuberculosis].

    PubMed

    Jara, J; Moncada, I; Verdú, F; Herranz, F; Díez-Cordero, J M; Escribano, G; Durán, R; Hernández, C

    1993-06-01

    Presentation of two cases of renal abscess formation in patients with stage IV C-1 AIDS and active associated tuberculosis. The microorganism isolated in the first case was S. aureus. Culture of the second cases was artefacted since antibiotic administration had already been started. Also, both patients showed abdominal abscesses, at spleen and liver level in the first case, and prostatic level in the second case, both compatible with Mycobacterium tuberculosis dissemination. Both cases showed a lethal evolution. The role played by the immunodeficiency as a precipitating agent in the extrapulmonary tuberculosis and in the formation of renal abscesses is analyzed. PMID:8368105

  3. Childhood Tuberculosis, Still with Us...

    ERIC Educational Resources Information Center

    Chaulet, Pierre; And Others

    1992-01-01

    The first section of this report on childhood tuberculosis in developed and developing countries discusses the epidemiology of tuberculosis in children. Information is presented on: (1) sources and prevalence of infection; (2) risks, frequency, and types of tuberculosis; (3) mortality rates; and (4) the relation of poverty and AIDS to…

  4. Tuberculosis: A Problem for Lifeguards?

    ERIC Educational Resources Information Center

    Skaros, Susan

    1996-01-01

    Lifeguards run the risk of workplace infection by tuberculosis-carrying swimmers. Even if they work in ventilated, sunlit areas (which reduces risk), they can contract tuberculosis when performing respiratory resuscitation. Without appropriate precautions, lifeguards may be unnecessarily exposed. A tuberculosis infection control plan is needed in…

  5. What cannot be measured cannot be done; risk factors for childhood tuberculosis: a case control study.

    PubMed

    Karim, M R; Rahman, M A; Mamun, S A A; Alam, M A; Akhter, S

    2012-04-01

    Childhood tuberculosis is one of the major causes of childhood mortality and morbidity though much neglected within our National Tuberculosis Control Program. This case control study was carried out to identify the risk factors for tuberculosis among children. Cases (n=95) and controls (n=94) were selected from Directly Observed Treatment Short Course (DOTS) centers of four upazillas of Dhaka and Gazipur districts. Cases were childhood tuberculosis patient, who were test positive by sputum microscopy from January to May, 2011 and controls were children who visited DOTS laboratory suspecting tuberculosis infection but were sputum negative. Both cases and controls were selected from the sputum examination registers and were traced at home for exposure data. The study showed more girls were infected than boys. Several socio demographic and environmental factors were found to be associated with the development of childhood tuberculosis. Logistic regression model was constructed to find out the important predictors which revealed age, education of the respondents, indoor environment and contact pattern were significantly associated with childhood tuberculosis. Children more than 14 years of age had 6.25 times higher risk of developing childhood tuberculosis; (Odds ratio=6.25; 95% CI for OR=2.00 to 19.55), Children completed primary education had 3.12 times lower risk of developing childhood tuberculosis, (Odds ratio=.32; 95% CI for OR=.10 to 1.00). Those who resided in better in-house environment had 4.35 times lower risk of developing childhood tuberculosis (Odds ratio=.23; 95% CI for OR=.06 to .95) and children came in contact with source tuberculosis cases who were their relatives or neighbors were 5.26 times lower risk of developing childhood tuberculosis than being in contact with family members with TB (Odds ratio=.19; 95% CI for OR=.07 to .49). Contact Screening should be incorporated in National TB program for early detection and effective treatment of tuberculosis. Improvement of indoor environment and ventilation status of the bedroom might reduce the risk of developing childhood tuberculosis. PMID:22545348

  6. Development of Extensively Drug-resistant Tuberculosis during Multidrug-resistant Tuberculosis Treatment

    E-print Network

    Cohen, Ted

    Development of Extensively Drug-resistant Tuberculosis during Multidrug-resistant Tuberculosis of Public Health, Boston, Massachusetts; 6 Tomsk Oblast Tuberculosis Services, Tomsk, Russian Federation; 7 Siberia State Medical University, Tomsk, Russian Federation; 8 Tomsk Oblast Tuberculosis Hospital, Tomsk

  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. [Multidrug-resistant tuberculosis. 2. Mechanisms of drug-resistance in Mycobacterium tuberculosis--genetic mechanisms of drug-resistance].

    PubMed

    Ohno, H; Koga, H; Kohno, S

    1998-11-01

    Multidrug-resistant Mycobacterium tuberculosis infection is now world wide health problem. However, according to the recent advances of molecular biological technics, some of the genetic mechanisms of drug-resistance of M. tuberculosis has been uncovered. Generally, drug-resistance of M. tuberculosis was caused by point mutations in chromosomal gene. In isoniazid (INH) resistant M. tuberculosis, mutations and genetic deletions in catalase-peroxidase gene (katG), inhA gene, or alkyl hydroperoxide reductase gene were reported. We also found that about 15% of INH-resistant M. tuberculosis isolates lacked katG gene, and these isolates showed highly resistance to INH with MIC > or = 64 micrograms/ml. On the other hand, mutations and other genetic alterations in RNA polymerase beta subunit gene (rpoB) were the major mechanisms of resistance to rifampicin (RFP) with high frequencies of 90% or more. Our evaluation of the relationship between RFP susceptibility and genetic alteration in rpoB gene also showed that 95% of RFP-resistant M. tuberculosis isolates involved genetic alterations in 69 bp core region of rpoB gene. Moreover, these genetic alterations in rpoB gene were suspected as the resistant mechanism to other rifamycin antituberculosis drugs, such as rifabutin and KRM-1648. In addition, it was reported that point mutations in 16S rRNA gene (rrs) and ribosomal protein S12 gene (rpsL) induced M. tuberculosis as streptomycin (SM) resistant phenotype. We analyzed genetic alternations in rpsL gene of clinically isolates of M. tuberculosis, about 60% of SM resistant isolates were shown point mutation in this gene ant they were all high SM-resistant with MIC > or = 256 micrograms/ml. Furthermore, nicotinamidase (pncA) gene, DNA gyrase A subunit (gyrA) gene, and embB gene were reported as the responsible gene to pyrazinamide-, quinolone- and ethambutol-resistance, respectively. Although all mechanisms of drug-resistance were still unclear, these informations are very useful and helpful for development of rapid diagnosis system of drug-resistant M. tuberculosis. PMID:9866928

  9. [Lessons learned from tuberculosis outbreak cases].

    PubMed

    Kato, Seiya; Kuwabara, Katsuhiro

    2014-02-01

    Most TB outbreaks were caused by exposure of many people to tuberculosis bacilli due to delayed detection of initial cases who had long-lasting severe coughs and excretion of massive tuberculosis bacilli. They were also affected by several other factors, such as socio-environmental factors of the initial case; time and place of infection; and host factors of the infected persons such as immune status, infectivity, and/or pathogenicity of the bacilli. In this symposium, we learned the seriousness of infection and disease among immune-suppressed groups, special environmental factors with regard to the spread of infection, disease after treatment of latent tuberculosis infection, diagnostic specification of IGRA, and bacteriological features including genotyping of the bacilli. We reaffirmed that countermeasures for the case are important, but outbreaks can provide excellent opportunities to learn important information about infection, disease progression, etc. 1. Tuberculosis outbreak in a cancer ward: Katsuhiro KUWABARA (Division of Respiratory Diseases, National Hospital Organization Nishi-Niigata Chuo National Hospital) There was an outbreak of tuberculosis in a cancer ward of a highly specialized medical center. Outbreak cases included eight hospitalized patients and two medical staff members over a 1.5-year observation period after initial contact. Three immune-compromised patients including the index patent died of cancer and tuberculosis. Community hospitals and highly specialized medical centers, such as cancer centers, should carefully prepare a proper system to prevent nosocomial transmission of tuberculosis. 2. Sixty-one cases of TB exposures in hospital settings and contact investigations of the hospital staff, with special reference to the application of QFT: Hiroko Yoshikawa NIGORIKAWA (The Division of Infectious Diseases, Tokyo Metropolitan Health and Medical Treatment Corporation, Toshima Hospital; present: Division of Infectious Diseases, Tokyo Teishin Hospital), Toru MORI (Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association) The index case was a patient who was admitted to a general hospital where she was treated with pulsed corticosteroid therapy and then put on a respirator. Soon after, she developed tuberculosis (TB) and died. Immediately after her death, the healthcare workers who had close contact with the index case were given the QuantiFERON TB Gold (QFT) test, which indicated that all staff except one were negative. However, a QFT test administered eight weeks later had a positive rate of 18.6%. Subsequently, a total of five workers, including a doctor, nurses, and radiology technicians, developed TB. The bacterial isolates from five of them exhibited an RFLP pattern identical to that of the index case. These secondary cases of TB included a case who had contact of less than 5 minutes, a case whose QFT was negative ("doubtful" in the Japanese criterion of the QFT), and a case who was QFT-positive but declined to be treated for latent TB infection (LTBI). No other workers nor hospitalized patients developed TB. The healthcare worker contacts were further examined with the QFT 6, 9 and 12 months after the contact. The QFT results revealed four additional positive reactors and four "doubtful" reactors who were indicated for LTBI treatment. Among them were seven subjects who turned positive six months after the contact. TB prevention in hospital settings and contact investigations were discussed with the hospital staff, with special reference to the application of QFT. 3. Summary and issues of concern relating to a tuberculosis outbreak in a prison: Mitsunobu HOMMA, Takefumi ITOH (Department of Respiratory Medicine, Akita City Hospital) We report a tuberculosis outbreak that occurred in a prison in the spring of 2011, resulting in 11 cases of active disease and 40 cases of infection. The primary cause of the outbreak is thought to be the delay in identifying the index case, where the screening result interpretation might have contributed to the delay. However, w

  10. Electrodiagnostic approach to patients with suspected radiculopathy.

    PubMed

    Dillingham, Timothy R

    2002-08-01

    This article reviews the electrodiagnostic testing for persons suspected of having radiculopathies and the expected sensitivities that different testing modalities provide. One cannot minimize the importance of the clinical evaluation and differential diagnosis formulation by the electrodiagnostician to guide testing. The needle EMG examination is the most useful electrodiagnostic test but is limited in sensitivity. Electromyographic screening examinations using six muscles are possible that optimize identification yet minimize patient discomfort. Electrodiagnostic findings must be interpreted relative to the patient's clinical presentation, and the consultant should tailor the electrodiagnostic study to the clinical situation. PMID:12380549

  11. Renal Tuberculosis in the Modern Era

    PubMed Central

    De Francesco Daher, Elizabeth; Bezerra da Silva Junior, Geraldo; Barros, Elvino José Guardão

    2013-01-01

    Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis. The disease remains as an important public health problem in developing countries. Extrapulmonary TB became more common with the advent of infection with human immunodeficiency virus and by the increase in the number of organ transplantation, which also leads to immunosuppression of thousand of persons. Urogenital TB represents 27% of extrapulmonary cases. Renal involvement in TB can be part of a disseminated infection or a localized genitourinary disease. Renal involvement by TB infection is underdiagnosed in most health care centers. Most patients with renal TB have sterile pyuria, which can be accompanied by microscopic hematuria. The diagnosis of urinary tract TB is based on the finding of pyuria in the absence of common bacterial infection. The first choice drugs include isoniazide, rifampicin, pirazinamide, ethambutol, and streptomycin. Awareness of renal TB is urgently needed by physicians for suspecting this disease in patients with unexplained urinary tract abnormalities, mainly in those with any immunosuppression and those coming from TB-endemic areas. PMID:23303798

  12. 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

  13. 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

  14. Tuberculosis of knee joint and tubercular pyomyositis of gastrocnemius muscle.

    PubMed

    Ahmed, S; Shahin, M A; Kader, M A; Banik, J; Azad, A K; Haq, S A

    2011-10-01

    Extra-spinal musculoskeletal tuberculosis (TB) is rare and tubercular pyomyositis is extremely rare. Tuberculosis of the knee-joint is a haematogenous infection secondary to a focus of active disease elsewhere in the body which may not be found. Tubercular pyomyositis usually caused by invasion from the adjacent structures rather than a secondary spread. Here we describe a 40 years old male patient who presented to us with pain in the right knee joint for one and half years and pain and swelling of right calf muscle for fifteen days. He was eventually diagnosed as a case of tuberculosis of the right knee joint and tubercular pyomyositis of right gastrocnemius muscle on the basis of fine needle aspiration from the right calf that showed caseation necrosis with clusters of epithelial cells despite absence of systemic symptoms, the absence of other foci of active tuberculosis and a normal chest radiograph. PMID:22081197

  15. Therapeutic management of endobronchial tuberculosis.

    PubMed

    Rikimaru, Toru

    2004-07-01

    Endobronchial tuberculosis (EBTB) is defined as tuberculous infection of the tracheobronchial tree. Common symptoms are cough, haemoptysis, sputum production, wheezing, chest pain and fever in active disease and dyspnoea and wheezing in the fibrous stage. This form of tuberculosis is difficult to diagnose because the lesion is not evident in the chest radiograph, frequently delaying treatment. Computed tomography is very useful in evaluating bronchial lesions such as stenosis or obstruction. The most important goal of treatment in active EBTB is eradication of tubercle bacilli. The second most important goal is prevention of bronchial stenosis. Corticosteroid therapy for the prevention of bronchial stenosis in EBTB remains controversial. However, the healing time of ulcerous lesions was shorter and bronchial stenosis was less severe, in patients treated with aerosol therapy, consisting of streptomycin 100 mg, a corticosteroid (dexamethasone 0.5 mg) and naphazoline 0.1 mg administered twice-daily along with conventional oral therapy. In inactive disease, treatment to restore full patency is appropriate. As steroids or other medications are unable to reverse stenosis from fibrous disease, airway patency must be restored mechanically by surgery or endobronchial intervention. Effectiveness and complications remain important issues with the mechanical techniques as use and evaluation continue. Corticosteroid therapy for prevention of bronchial stenosis in EBTB remains controversial. Our observations suggest that progression of bronchial stenosis can be prevented in patients who are treated with aerosol therapy with corticosteroids. PMID:15212597

  16. Synchronously detected secondary signet ring cell urinary bladder malignancy from the stomach masquerading as genitourinary tuberculosis.

    PubMed

    Kalra, Sidhartha; Manikandan, Ramanitharan; Dorairajan, Lalgudi Narayanan; Badhe, Bhavana

    2015-01-01

    Secondary bladder neoplasms are very rare and represent 1% of all malignant bladder tumours. Among secondary bladder tumours, metastasis from the stomach accounts for about 4% of cases. These secondary tumours are generally detected during follow-up of patients already treated for gastric cancer. We report a case of metastatic adenocarcinoma of the urinary bladder from an occult primary poorly differentiated signet ring cell type gastric carcinoma masquerading clinically as genitourinary tuberculosis. Our case illustrates the importance of obtaining a bladder biopsy in suspected chronic inflammatory conditions such as urinary tract tuberculosis before starting medical management to avoid the serious consequences of missing a bladder malignancy. PMID:25618874

  17. [Urogenital tuberculosis today].

    PubMed

    Zhukova, I I; Kul'chavenia, E V; Kholtobin, D P; Brizhatiuk, E V; Khomiakov, V T; Osadchi?, A V

    2013-01-01

    In order to analyze the structure of urogenital tuberculosis, retrospective analysis of medical records of 131 patients with newly diagnosed urogenital tuberculosis observed in the Novosibirsk Regional TB Dispensary from 2009 to 2011 was performed. The renal tuberculosis is main form in the structure is urotuberculosis, detected in 75% of patients, and widespread destructive forms of the disease were diagnosed in more than half of cases. Isolated nephrotuberculosis was more often diagnosed in women--56.8%. 15.9% of patients had asymptomatic nephrotuberculosis; one-third of patients complained of pain in the lumbar region and frequent painful urination (35.2 and 39.8%, respectively); symptoms of intoxication were present in 17% of patients, renal colic--in 9.1%, and gross hematuria--in 7.9% of patients. Mycobacteriuria in isolated nephrotuberculosis was detected in 31.8% of cases. Acute tuberculous orchiepididymitis developed in 35.7% of patients, hemospermia was observed in 7.1% of patients, dysuria was in 35.7% of patients. The pain in the perineum, frequent painful urination (both by 31.6%), hemospermia (26.3%) were main complaints in prostate tuberculosis. Mycobacteria was detected in 10.5% of cases. It was found that urogenital tuberculosis has no pathognomonic symptoms; the most alarming manifestations include long-term dysuria, hematuria, hemospermia. PMID:23662488

  18. 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

  19. Diagnostic accuracy of an integrated respiratory guideline in identifying patients with respiratory symptoms requiring screening for pulmonary tuberculosis: a cross-sectional study

    Microsoft Academic Search

    René G English; Max O Bachmann; Eric D Bateman; Merrick F Zwarenstein; Lara R Fairall; Angeni Bheekie; Bosielo P Majara; Carl Lombard; Robert Scherpbier; Salah Eddine Ottomani

    2006-01-01

    BACKGROUND: To evaluate the diagnostic accuracy of the integrated Practical Approach to Lung Health in South Africa (PALSA) guideline in identifying patients requiring bacteriological screening for tuberculosis (TB), and to determine which clinical features best predict suspected and bacteriologically-confirmed tuberculosis among patients with respiratory symptoms. METHODS: A prospective, cross-sectional study in which 1392 adult patients with cough and\\/or difficult breathing,

  20. Local immunodiagnosis of pulmonary tuberculosis by enzyme-linked immunospot

    Microsoft Academic Search

    C. Jafari; M. Ernst; A. Strassburg; U. Greinert; B. Kalsdorf; D. Kirsten; C. Lange

    2008-01-01

    Lymphocytes are crucial in the immune defence against Mycobacterium tuberculosis (MTB) infection. The aim of the present study was to ascertain whether or not MTB-specific lymphocytes are selectively compartmentalised in the lungs of patients with minimal active pulmonary tuberculosis (PTB). Patients with smear-negative MTB-culture-confirmed PTB were prospectively recruited. Differential cell counts, immunophenotyping with monoclonal antibodies directed against the cell surface

  1. Aetiology of Pulmonary Symptoms in HIV-Infected Smear Negative Recurrent PTB Suspects in Kampala, Uganda: A Cross-Sectional Study

    PubMed Central

    Okwera, Alphonse; Bwanga, Freddie; Najjingo, Irene; Mulumba, Yusuf; Mafigiri, David K.; Whalen, Christopher C.; Joloba, Moses L.

    2013-01-01

    Introduction Previously treated TB patients with pulmonary symptoms are often considered recurrent TB suspects in the resource-limited settings, where investigations are limited to microscopy and chest x-ray. Category II anti-TB drugs may be inappropriate and may expose patients to pill burden, drug toxicities and drug-drug interactions. Objective To determine the causes of pulmonary symptoms in HIV-infected smear negative recurrent pulmonary tuberculosis suspects at Mulago Hospital, Kampala. Methods Between March 2008 and December 2011, induced sputum samples of 178 consented HIV-infected smear negative recurrent TB suspects in Kampala were subjected to MGIT and LJ cultures for mycobacteria at TB Reference Laboratory, Kampala. Processed sputum samples were also tested by PCR to detect 18S rRNA gene of P.jirovecii and cultured for other bacteria. Results Bacteria, M. tuberculosis and Pneumocystis jirovecii were detected in 27%, 18% and 6.7% of patients respectively and 53.4% of the specimens had no microorganisms. S. pneumoniae, M. catarrhalis and H. influenzae were 100% susceptible to chloramphenicol and erythromycin but co-trimoxazole resistant. Conclusion At least 81.5% of participants had no microbiologically-confirmed TB. However our findings call for thorough investigation of HIV-infected smear negative recurrent TB suspects to guide cost effective treatment. PMID:24312650

  2. A randomized controlled trial of standard versus intensified tuberculosis diagnostics on treatment decisions by physicians in Northern Tanzania

    PubMed Central

    2014-01-01

    Background Routine tuberculosis culture remains unavailable in many high-burden areas, including Tanzania. This study sought to determine the impact of providing mycobacterial culture results over standard of care [unconcentrated acid-fast (AFB) smears] on management of persons with suspected tuberculosis. Methods Adults and children with suspected tuberculosis were randomized to standard (direct AFB smear only) or intensified (concentrated AFB smear and tuberculosis culture) diagnostics and followed for 8 weeks. The primary endpoint was appropriate treatment (i.e. antituberculosis therapy for those with tuberculosis, no antituberculous therapy for those without tuberculosis). Results Seventy participants were randomized to standard (n?=?37, 53%) or intensive (n?=?33, 47%) diagnostics. At 8 weeks, 100% (n?=?22) of participants in follow up randomized to intensive diagnostics were receiving appropriate care, vs. 22 (88%) of 25 participants randomized to standard diagnostics (p?=?0.14). Overall, 18 (26%) participants died; antituberculosis therapy was associated with lower mortality (9% who received antiuberculosis treatment died vs. 26% who did not, p?=?0.04). Conclusions Under field conditions in a high burden setting, the impact of intensified diagnostics was blunted by high early mortality. Enhanced availability of rapid diagnostics must be linked to earlier access to care for outcomes to improve. PMID:24552306

  3. [Evaluation of the management of tuberculosis in children in Madagascar. Results of a multicentric study].

    PubMed

    Rasamoelisoa, J M; Tovone, X G; Razoeliarinoro, H V; Rakotoarimanana, D R

    1999-01-01

    In Madagascar, tuberculosis remains an important cause of morbidity and letality with a Risk of Annual Tubercular Infection about 1% in 1996 in spite of a vaccination rate of 82.6% and tubercular drugs free of charge. In 1995, the National Tubercular Control Program detected 7,000 cases of pulmonary tuberculosis and expected more than 12,000 cases per year. This study was carried out in order to review the management and the treatment of the child tuberculosis in Madagascar. This retrospective study was conducted in four pediatric units of the General hospital of Befelatanana (A and B), Ambohimiandra Hospital and Regional Hospital Centre of Toliara for a twenty four months period from January 1997 to December 1998. All the less than 15-year-old children medical files were consulted. 214 cases were suspected of tuberculosis. 133 of them were treated upon clinical presumption basis and/or radiological exams (33 bacteriological and/or histopathological exams were only realized). 56% of the cases were vaccinated by BCG vaccine. Respiratory diseases with fever motive 46% of hospitalization. The majority of these children are living in poor conditions and 38% of them had malnutrition. Were found as clinical manifestations: 47% of pulmonary tuberculosis (among them 20% were smear-positive pulmonary tuberculosis), 12% had ganglionar tuberculosis, 10% peritoneal tuberculosis, 8% a tubercular meningitis, 5% a Pott-disease and 2% a miliary-disease. Mortality increases with suffocation. 18% of cases died, especially infants and in tubercular meningitis. The authors conclude that management and treatment of tuberculosis need an early diagnosis. But the diagnosis is difficult in front of non specific clinical manifestations in children and due to lack of means and national agreement which settle up diagnosis and therapy. A scoring system based upon clinical signs in agreement with complementary medical tests is desirable. PMID:12478966

  4. Isolated urethral tuberculosis in a middle-aged man: a case report

    PubMed Central

    2013-01-01

    Introduction Urogenital tuberculosis is a frequent disease in endemic countries. It is characterized by clinical polymorphism. The isolated urethral form is exceptional, even in countries with endemic tuberculosis. We present a rare case of urogenital tuberculosis in a man revealed by urethral narrowing and multiple urethro-scrotal fistulas. Case presentation The patient, a Moroccan man, was 40 years old. He visited our hospital for a urology consultation and presented with dysuria, purulent discharge and a meatic penoscrotal fistula. A retrograde and voiding urethrocystography was performed and revealed an extended narrowing of the whole anterior urethra associated with multiple fistulous portions toward the scrotum and perineum. At this stage, we reached a diagnosis of nonspecific sclero-inflammatory urethral stricture with complicating fistulas. We decided to perform a urethroplasty enlargement to clear the narrowing urethral sinus tracts. The evolution was marked by delayed wound healing associated with the persistence of fistulas extending into the corpus cavernosum with purulent discharge. It was at this point in the treatment that we suspected tuberculosis. Multiple biopsies were then performed on the periurethral tissue and fistula tracts. The histological examination confirmed urethral tuberculosis and showed the presence of giant cell epithelial lesions with caseous necrosis characteristic of tuberculosis. The treatment for tuberculosis was immediately established and the evolution was marked by a localized, rapid and significant improvement. A second-stage urethroplasty was scheduled for two months after the start of his antituberculous treatment. Conclusions Urogenital tuberculosis is common, but isolated urethral involvement is very rare even in countries with endemic tuberculosis. We urge practitioners, and especially urologists, to consider the disease in their investigation whenever given clinical signs are declared. PMID:23566379

  5. [The microbiological diagnosis of tuberculosis in areas under strict radiation control].

    PubMed

    Golyshevskaia, V I; Cheshek, V G; Shevchenko, N I

    1993-01-01

    Mycobacterial variability was studied in active tuberculosis patients from radioactive contamination area subject to close radiation control. For such areas it was noted that the patients discharge altered coccoid mycobacteria stained with routine luminescent dyes. Biological investigations of freshly isolated strains revealed potentiation of M. tuberculosis virulence in patients with respiratory tuberculosis. A large number of patients from the contaminated areas against control demonstrated primary resistance to rifampicin and isoniazid. PMID:8290527

  6. Induced sputum and bronchoscopy in the diagnosis of pulmonary tuberculosis

    PubMed Central

    McWilliams, T; Wells, A; Harrison, A; Lindstrom, S; Cameron, R; Foskin, E

    2002-01-01

    Background: Previous studies suggest that bronchoscopy and a single induced sputum sample are equally effective for diagnosing pulmonary tuberculosis. Methods: In a prospective study of subjects with possibly active pulmonary tuberculosis, the diagnostic yield of three induced sputum tests was compared with that of bronchoscopy. Subjects either produced no sputum or (acid fast) smear negative sputum. Bronchoscopy was only performed if at least two induced sputum samples were smear negative. Results: Of 129 subjects who completed all tests, 27 (21%) had smear negative and culture positive specimens, 14 (52%) on bronchoscopy and 26 (96%) on induced sputum (p<0.005). One patient was culture positive on bronchoscopy alone compared with 13 on induced sputum alone; 13 were culture positive on both tests. Induced sputum positivity was strikingly more prevalent when chest radiographic appearances showed any features of active tuberculosis (20/63, 32%) than when appearances suggested inactivity (1/44, 2%; p<0.005). Induced sputum costs were about one third those of bronchoscopy, and the ratio of costs of the two tests per case of tuberculosis diagnosed could be as much as 1:6. Conclusions: In subjects investigated for possibly active or inactive tuberculosis who produce no sputum or have smear negative sputum, the most cost effective strategy is to perform three induced sputum tests without bronchoscopy. Induced sputum testing carries a high risk of nosocomial tuberculosis unless performed in respiratory isolation conditions. The cost benefits shown could be lost if risk management measures are not observed. PMID:12454293

  7. LKB1 and lung cancer: more than the usual suspects.

    PubMed

    Shah, Usman; Sharpless, Norman E; Hayes, D Neil

    2008-05-15

    Often, the problem in cancer research is figuring out how a gene or pathway works in regulating cellular transformation. The question of what RAS activates or PTEN inhibits have been classic dilemmas of modern cancer biology. In these cases, biochemical and genetic studies have provided us with a fairly clear picture of the cancer relevant functions of these genes. For LKB1, a more recently identified human tumor suppressor gene, however, the problem is different. This serine-threonine kinase that is conserved from yeast to mammals seems to play a role in many diverse cellular pathways. Therefore, although elegant functional and genetic approaches have established critical roles for LKB1 in the regulation of metabolism, motility, polarity, and the cell cycle, the role(s) responsible for its true tumor suppressor function(s) is unknown. One is reminded of an Agatha Christie murder mystery where nearly every character in the book has reason to be suspected of committing the crime-there are too many suspects for how LKB1 might repress lung cancer. PMID:18483235

  8. Care seeking in tuberculosis: results from a countrywide cluster randomised survey in Bangladesh

    PubMed Central

    Hossain, Shahed; Zaman, K; Quaiyum, Abdul; Banu, Sayera; Husain, Ashaque; Islam, Akramul; Borgdorff, Martien; van Leth, Frank

    2014-01-01

    Objectives To explore systematically the care seeking trajectories of tuberculosis (TB) cases up to four subsequent places of care and to assess the type of services provided at each place. Methods TB cases detected actively during the 2007–2009 national TB prevalence survey and passively under the routine programme in the same period were interviewed by administering a standardised questionnaire. Care seeking and services provided up to four subsequent points were explored. Care seeking was further explored by categorising the providers into formal, informal and ‘self-care’ groups. Results A total of 273 TB cases were included in this study, of which 33 (12%) were detected during the survey and 240 (88%) from the TB registers. Out of the 118 passively detected cases who first sought care from an informal provider, 52 (44.1%) remained in the informal sector at the second point of care. Similarly, out of the 52, 17 (32.7%) and out of the 17, 5 (29.4%) remained in the informal sector at the third and fourth subsequent points of care, respectively. All the 33 actively detected cases had ‘self-care’ at the first point, and 27 (81.8%) remained with ’self-care’ up to the fourth point of care. Prescribing drugs (59–99%) was the major type of care provided by the formal and informal care providers at each point and was limited to the non-existent practice of investigation or referrals. Conclusions Free TB services are still underutilised by TB cases and informal caregivers remained the major care providers for such cases in Bangladesh. In order to improve case detection, it is necessary that the National Tuberculosis Programme immediately takes effective initiatives to engage all types of care providers, particularly informal providers who are the first point of care for the majority of the TB suspects. PMID:24871537

  9. Characterization of Mycobacterium tuberculosis nicotinamidase/pyrazinamidase.

    PubMed

    Zhang, Hua; Deng, Jiao-Yu; Bi, Li-Jun; Zhou, Ya-Feng; Zhang, Zhi-Ping; Zhang, Cheng-Gang; Zhang, Ying; Zhang, Xian-En

    2008-02-01

    The nicotinamidase/pyrazinamidase (PncA) of Mycobacterium tuberculosis is involved in the activation of the important front-line antituberculosis drug pyrazinamide by converting it into the active form, pyrazinoic acid. Mutations in the pncA gene cause pyrazinamide resistance in M. tuberculosis. The properties of M. tuberculosis PncA were characterized in this study. The enzyme was found to be a 20.89 kDa monomeric protein. The optimal pH and temperature of enzymatic activity were pH 7.0 and 40 degrees C, respectively. Inductively coupled plasma-optical emission spectrometry revealed that the enzyme was an Mn(2+)/Fe(2+)-containing protein with a molar ratio of [Mn(2+)] to [Fe(2+)] of 1 : 1; furthermore, the external addition of either type of metal ion had no apparent effect on the wild-type enzymatic activity. The activity of the purified enzyme was determined by HPLC, and it was shown that it possessed similar pyrazinamidase and nicotinamidase activity, by contrast with previous reports. Nine PncA mutants were generated by site-directed mutagenesis. Determination of the enzymatic activity and metal ion content suggested that Asp8, Lys96 and Cys138 were key residues for catalysis, and Asp49, His51, His57 and His71 were essential for metal ion binding. Our data show that M. tuberculosis PncA may bind metal ions in a manner different from that observed in the case of Pyrococcus horikoshii PncA. PMID:18201201

  10. Mycobacterium tuberculosis 10-kDa co-chaperonin regulates the expression levels of receptor activator of nuclear factor-?B ligand and osteoprotegerin in human osteoblasts

    PubMed Central

    ZHANG, YUANYU; LIU, XIA; LI, KUN; BAI, JINGPING

    2015-01-01

    The aim of the present study was to investigate the effect of recombinant Mycobacterium tuberculosis (r-Mt) 10-kDa co-chaperonin (cpn10) on the expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-?B ligand (RANKL) in third-generation cultured osteoblasts. The osteoblast-like cultures were isolated from bone fragments taken from patients undergoing surgery. Prior to stimulation with r-Mt cpn10, cells were incubated in serum-free medium for 24 h. r-Mt cpn10 was added into fresh serum-free medium, reaching final concentrations of 0.01–10 ?g/ml. The levels of OPG were determined using enzyme-linked immunosorbent assay. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis was performed to determine the levels of RANKL and OPG mRNA. For measurement of the protein levels of OPG and RANKL, a western blotting assay was performed. r-Mt cpn10 downregulated the protein levels of OPG in the third generation cultured osteoblasts at a dose of 10 ?g/ml. RT-qPCR revealed that the OPG mRNA level was decreased by 73% after 4 h and by 85.5% after 8 h following incubation with r-Mt cpn10 (10 ?g/ml). Western blot analysis demonstrated similar results for the OPG protein level. In the third-generation cultured osteoblasts, the levels of RANKL mRNA and protein were increased by 2.6- and 1-fold, respectively, following incubation with r-Mt cpn10 (10 ?g/ml). Furthermore, the RANKL/OPG ratio was markedly increased by r-Mt cpn10 (10 ?g/ml) treatment. In conclusion, the results of the current study demonstrated that r-Mt cpn10 decreased the levels of OPG and increased the levels of RANKL in a dose- and time-dependent manner. Notably, the present study indicated that r-Mt cpn10 exerts its effect on osteoblastic cells by increasing the RANKL/OPG ratio. PMID:25667654

  11. Tuberculosis and the Risk of Infection with Other Intracellular Bacteria: a Population-Based Study

    PubMed Central

    Huaman, M. A.; Fiske, C. T.; Jones, T. F.; Warkentin, J.; Shepherd, B. E.; Ingram, L.A.; Maruri, F.; Sterling, T. R.

    2014-01-01

    SUMMARY Persons who develop tuberculosis may have subtle immune defects that could predispose to other intracellular bacterial infections (ICBIs). We obtained data on tuberculosis and five ICBIs (Chlamydia trachomatis,Salmonella spp., Shigella spp., Yersinia spp., and Listeria monocytogenes) reported to the Tennessee Department of Health, USA, 2000–2011. Incidence rate ratios (IRRs) comparing ICBIs in persons who developed tuberculosis and ICBIs in the Tennessee population, adjusted for age, sex, race and ethnicity were estimated. IRRs were not significantly elevated for all ICBIs combined (IRR, 0.87, 95%CI: 0.71–1.06). C. trachomatis rate was lowest in the year post-tuberculosis diagnosis (IRR, 0.17; 95%CI, 0.04–0.70). More Salmonella infections occurred in extrapulmonary tuberculosis compared to pulmonary tuberculosis patients (IRR, 14.3, 95%CI: 1.67–122); however, this appeared to be related to HIV-coinfection. Tuberculosis was not associated with an increased risk of other ICBIs. In fact, fewer C. trachomatis infections occurred after recent tuberculosis diagnosis. Reasons for this association, including reduced exposure, protection conferred by anti-tuberculosis drugs or macrophage activation by M. tuberculosis infection warrant further investigation. PMID:25148655

  12. Detection of multidrug resistance in Mycobacterium tuberculosis.

    PubMed

    Sekiguchi, Jun-ichiro; Miyoshi-Akiyama, Tohru; Augustynowicz-Kope?, Ewa; Zwolska, Zofia; Kirikae, Fumiko; Toyota, Emiko; Kobayashi, Intetsu; Morita, Koji; Kudo, Koichiro; Kato, Seiya; Kuratsuji, Tadatoshi; Mori, Toru; Kirikae, Teruo

    2007-01-01

    We developed a DNA sequencing-based method to detect mutations in the genome of drug-resistant Mycobacterium tuberculosis. Drug resistance in M. tuberculosis is caused by mutations in restricted regions of the genome. Eight genome regions associated with drug resistance, including rpoB for rifampin (RIF), katG and the mabA (fabG1)-inhA promoter for isoniazid (INH), embB for ethambutol (EMB), pncA for pyrazinamide (PZA), rpsL and rrs for streptomycin (STR), and gyrA for levofloxacin, were amplified simultaneously by PCR, and the DNA sequences were determined. It took 6.5 h to complete all procedures. Among the 138 clinical isolates tested, 55 were resistant to at least one drug. Thirty-four of 38 INH-resistant isolates (89.5%), 28 of 28 RIF-resistant isolates (100%), 15 of 18 EMB-resistant isolates (83.3%), 18 of 30 STR-resistant isolates (60%), and 17 of 17 PZA-resistant isolates (100%) had mutations related to specific drug resistance. Eighteen of these mutations had not been reported previously. These novel mutations include one in rpoB, eight in katG, one in the mabA-inhA regulatory region, two in embB, five in pncA, and one in rrs. Escherichia coli isolates expressing individually five of the eight katG mutations showed loss of catalase and INH oxidation activities, and isolates carrying any of the five pncA mutations showed no pyrazinamidase activity, indicating that these mutations are associated with INH and PZA resistance, respectively. Our sequencing-based method was also useful for testing sputa from tuberculosis patients and for screening of mutations in Mycobacterium bovis. In conclusion, our new method is useful for rapid detection of multiple-drug-resistant M. tuberculosis and for identifying novel mutations in drug-resistant M. tuberculosis. PMID:17108078

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

    PubMed Central

    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

  14. Screening and brief interventions for hazardous and harmful alcohol use among patients with active tuberculosis attending primary care clinics in South Africa: a cluster randomized controlled trial protocol

    Microsoft Academic Search

    Karl K Peltzer; Pamela P Naidoo; Gladys G Matseke; Khangelani K Zuma

    2011-01-01

    Background  In 2008 the World Health Organization (WHO) reported that South Africa had the highest tuberculosis (TB) incidence in the\\u000a world. This high incidence rate is linked to a number of factors, including HIV co-infection and alcohol use disorders. The\\u000a diagnosis and treatment package for TB and HIV co-infection is relatively well established in South Africa. However, because\\u000a alcohol use disorders

  15. In an in vitro model of human tuberculosis, monocyte-microglial networks regulate matrix metalloproteinase-1 and -3 gene expression and secretion via a p38 mitogen activated protein kinase-dependent pathway

    PubMed Central

    2013-01-01

    Background Tuberculosis (TB) of the central nervous system (CNS) is characterized by extensive tissue inflammation, driven by molecules that cleave extracellular matrix such as matrix metalloproteinase (MMP)-1 and MMP-3. However, relatively little is known about the regulation of these MMPs in the CNS. Methods Using a cellular model of CNS TB, we stimulated a human microglial cell line (CHME3) with conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb). MMP-1 and MMP-3 secretion was detected using ELISAs confirmed with casein zymography or western blotting. Key results of a phospho-array profile that detects a wide range of kinase activity were confirmed with phospho-Western blotting. Chemical inhibition (SB203580) of microglial cells allowed investigation of expression and secretion of MMP-1 and MMP-3. Finally we used promoter reporter assays employing full length and MMP-3 promoter deletion constructs. Student’s t-test was used for comparison of continuous variables and multiple intervention experiments were compared by one-way ANOVA with Tukey’s correction for multiple pairwise comparisons. Results CoMTb up-regulated microglial MMP-1 and MMP-3 secretion in a dose- and time-dependent manner. The phospho-array profiling showed that the major increase in kinase activity due to CoMTb stimulation was in p38 mitogen activated protein kinase (MAPK), principally the ? and ? subunits. p38 phosphorylation was detected at 15 minutes, with a second peak of activity at 120 minutes. High basal extracellular signal-regulated kinase activity was further increased by CoMTb. Secretion and expression of MMP-1 and MMP-3 were both p38 dependent. CoMTb stimulation of full length and MMP-3 promoter deletion constructs demonstrated up-regulation of activity in the wild type but a suppression site between -2183 and -1612 bp. Conclusions Monocyte-microglial network-dependent MMP-1 and MMP-3 gene expression and secretion are dependent upon p38 MAPK in tuberculosis. p38 is therefore a potential target for adjuvant therapy in CNS TB. PMID:23978194

  16. Protective efficacy of piperine against Mycobacterium tuberculosis.

    PubMed

    Sharma, Sandeep; Kalia, Nitin Pal; Suden, Pankaj; Chauhan, Prashant Singh; Kumar, Manoj; Ram, Anshu Beulah; Khajuria, Anamika; Bani, Sarang; Khan, Inshad Ali

    2014-07-01

    Piperine a trans-trans isomer of 1-piperoyl-piperidine was evaluated for its immunomodulatory activity to enhance the efficacy of rifampicin in a murine model of Mycobacterium tuberculosis infection. In-vitro immunomodulation of piperine was tested on mouse splenocytes for lymphocyte proliferation, cytokine production and macrophage activation. Protective efficacy of piperine was tested in a mice infection model of M. tuberculosis for the activation of Th-1 response and synergistic combination efficacy with rifampicin. Murine splenocytes exposed to piperine exhibited proliferation of T and B cell, increased Th-1 cytokines and enhanced macrophage activation. Piperine (1 mg/kg) in mice infected with M. tuberculosis activated the differentiation of T cells into Th-1 sub-population (CD4+ / CD8+ subsets). There was an increase in secretion of Th-1 cytokines (IFN-? and IL-2) by these cells. The qRT-PCR studies revealed corresponding increases in the mRNA transcripts of IFN-? and IL-2 in the infected lung tissues. Combination of piperine and rifampicin (1 mg/kg) exhibited better efficacy of and resulted in additional 1.4 to 0.8 log reduction in lung cfu as compared to rifampicin alone. The up-regulation of Th1 immunity by piperine can be synergistically combined with rifampicin to improve its therapeutic efficacy in immune-compromised TB patients. PMID:24880706

  17. Evaluating the patient with suspected radiculopathy.

    PubMed

    Dillingham, Timothy R

    2013-05-01

    Persons with back, neck, and limb symptoms are commonly seen by health care providers. They constitute a major referral population to specialists in electrodiagnostic medicine. The evaluation of these patients involves consideration of both the common and less common disorders. The electrodiagnostic examination with needle electromyography is the most important means of testing for radiculopathy. This test has modest sensitivity but high specificity. It complements imaging of the spine. Electromyography in combination with nerve conduction testing is valuable in excluding entrapment neuropathies and polyneuropathy, conditions that frequently mimic radicular symptoms. A streamlined examination with 6 muscles, 1 of which is the paraspinal, has a high diagnostic yield, yet minimizes patient discomfort and examiner time. This article presents an overview of the electrodiagnostic evaluation for patients with suspected radiculopathy. PMID:23524070

  18. Observations of Suspected RR Lyrae Variable Stars

    NASA Astrophysics Data System (ADS)

    Smith, Stephanie; Powell, W. L.; Wilhelm, R. J.; De Lee, N. M.

    2014-01-01

    Our group is working on confirming variability of suspected RR Lyrae variables we have identified, and making follow-up observations of confirmed new variables. We developed a new method of detecting RR Lyrae variable stars using only a single epoch of both photometry and spectroscopy taken from the Sloan Digital Sky Survey (SDSS). The method takes advantage of clear departures from the template norm for stars that have photometry and spectroscopy taken out of phase. Over 1,000 stars have been identified as probable RR Lyrae stars, scattered across the halo and ranging from 14th to 20th magnitude. This paper describes observations taken at McDonald Observatory by undergraduate students as part of this project. We will discuss how and why the method works, and our McDonald observations to confirm variability and obtain full lightcurves.

  19. Exome Sequencing in Suspected Monogenic Dyslipidemias

    PubMed Central

    Stitziel, Nathan O.; Peloso, Gina M.; Abifadel, Marianne; Cefalu, Angelo B.; Fouchier, Sigrid; Motazacker, M. Mahdi; Tada, Hayato; Larach, Daniel B.; Awan, Zuhier; Haller, Jorge F.; Pullinger, Clive R.; Varret, Mathilde; Rabès, Jean-Pierre; Noto, Davide; Tarugi, Patrizia; Kawashiri, Masa-aki; Nohara, Atsushi; Yamagishi, Masakazu; Risman, Marjorie; Deo, Rahul; Ruel, Isabelle; Shendure, Jay; Nickerson, Deborah A.; Wilson, James G.; Rich, Stephen S.; Gupta, Namrata; Farlow, Deborah N.; Neale, Benjamin M.; Daly, Mark J.; Kane, John P.; Freeman, Mason W.; Genest, Jacques; Rader, Daniel J.; Mabuchi, Hiroshi; Kastelein, John J.P.; Hovingh, G. Kees; Averna, Maurizio R.; Gabriel, Stacey; Boileau, Catherine; Kathiresan, Sekar

    2015-01-01

    Background Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We utilized this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. Methods and Results We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein (LDL) cholesterol (after candidate gene sequencing excluded known genetic causes for high LDL cholesterol families) or high-density lipoprotein (HDL) cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual in order to account for their burden of common genetic variants known to influence lipid levels. In nine families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families despite follow-up analyses. We identified three factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. Conclusions We identified the genetic basis of disease in nine of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies. PMID:25632026

  20. Immunology studies in non-human primate models of tuberculosis.

    PubMed

    Flynn, JoAnne L; Gideon, Hannah P; Mattila, Joshua T; Lin, Philana Ling

    2015-03-01

    Non-human primates, primarily macaques, have been used to study tuberculosis for decades. However, in the last 15 years, this model has been refined substantially to allow careful investigations of the immune response and host-pathogen interactions in Mycobacterium tuberculosis infection. Low-dose challenge with fully virulent strains in cynomolgus macaques result in the full clinical spectrum seen in humans, including latent and active infection. Reagents from humans are usually cross-reactive with macaques, further facilitating the use of this model system to study tuberculosis. Finally, macaques develop the spectrum of granuloma types seen in humans, providing a unique opportunity to investigate bacterial and host factors at the local (lung and lymph node) level. Here, we review the past decade of immunology and pathology studies in macaque models of tuberculosis. PMID:25703552

  1. 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

  2. Tuberculosis Facts - You Can Prevent TB

    MedlinePLUS

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

  3. Tuberculosis Facts - TB and HIV/AIDS

    MedlinePLUS

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

  4. Tuberculosis Facts - TB Can Be Treated

    MedlinePLUS

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

  5. Electronic-Nose Technology Using Sputum Samples in Diagnosis of Patients with Tuberculosis ?

    PubMed Central

    Kolk, Arend; Hoelscher, Michael; Maboko, Leonard; Jung, Jutta; Kuijper, Sjoukje; Cauchi, Michael; Bessant, Conrad; van Beers, Stella; Dutta, Ritaban; Gibson, Tim; Reither, Klaus

    2010-01-01

    We investigated the potential of two different electronic noses (EN; code named “Rob” and “Walter”) to differentiate between sputum headspace samples from tuberculosis (TB) patients and non-TB patients. Only samples from Ziehl-Neelsen stain (ZN)- and Mycobacterium tuberculosis culture-positive (TBPOS) sputum samples and ZN- and culture-negative (TBNEG) samples were used for headspace analysis; with EN Rob, we used 284 samples from TB suspects (56 TBPOS and 228 TBNEG samples), and with EN Walter, we used 323 samples from TB suspects (80 TBPOS and 243 TBNEG samples). The best results were obtained using advanced data extraction and linear discriminant function analysis, resulting in a sensitivity of 68%, a specificity of 69%, and an accuracy of 69% for EN Rob; for EN Walter, the results were 75%, 67%, and 69%, respectively. Further research is still required to improve the sensitivity and specificity by choosing more selective sensors and type of sampling technique. PMID:20720034

  6. 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

  7. A Novel Murine Cytomegalovirus Vaccine Vector Protects against Mycobacterium tuberculosis

    PubMed Central

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

    2014-01-01

    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-2d–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

  8. 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

  9. Depletion of CD4 1 T Cells Causes Reactivation of Murine Persistent Tuberculosis Despite Continued Expression of Interferon g and Nitric Oxide Synthase 2

    Microsoft Academic Search

    Charles A. Scanga; V. P. Mohan; Keming Yu; Heather Joseph; Kathryn Tanaka; John Chan; JoAnne L. Flynn

    Tuberculosis is a major cause of death in much of the world. Current estimates are that one- third of the world's population is infected with Mycobacterium tuberculosis . Most infected persons control the infection but in many cases may not eliminate the organism. Reactivation of this clinically latent infection is responsible for a large proportion of active tuberculosis cases. A

  10. 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

  11. Risk factors for tuberculosis in contact investigations in Rotterdam, the Netherlands

    PubMed Central

    Verdier, Jesse Eduard; Jan de Vlas, Sake; Kidgell-Koppelaar, Inge D.; Richardus, Jan Hendrik

    2012-01-01

    Contact investigations around tuberculosis patients enable early detection of infection and disease, and prevention of secondary tuberculosis cases. We aim to identify risk factors for M. tuberculosis transmission to contacts of tuberculosis patients, based on unique data from routine contact investigations by the Public Health Service in Rotterdam, the Netherlands, collected between 2001 and 2006. Through logistic regression analysis, we determined the effect of various risk factors on the chance of finding a latent tuberculosis (TB) infection or overt tuberculosis case among contacts. A total of 1165 index patients with active tuberculosis were registered and at least one contact was investigated in 731, resulting in 21,540 contacts overall. Altogether, the contact investigations led to 91 cases of active tuberculosis. Of the 12,698 contacts eligible for screening by tuberculin skin test, 1091 (9%) were diagnosed with latent tuberculosis infections. Risk factors were old age of the contact, old age of the index patient, and the relationship to the index. A larger fraction of infected close contacts was strongly associated with infections among more distant contacts. Our findings emphasize the importance of including these personal and interpersonal risk factors in decision making in contact investigations. PMID:24470940

  12. Structures of the Michaelis-Complex (1.2 Å) and the Covalent Acyl-Intermediate (2.0 Å) of Cefamandole Bound in the Active Sites of the Mycobacterium tuberculosis ?-Lactamase K73A and E166A Mutants

    PubMed Central

    Tremblay, Lee W.; Xu, Hua; Blanchard, John S.

    2010-01-01

    The genome of Mycobacterium tuberculosis contains a gene that encodes a highly active ?-lactamase, BlaC that imparts TB with resistance to ?-lactam chemotherapy. The structure of covalent BlaC-?-lactam complexes suggests that active site residues K73 and E166 are essential for acylation and deacylation, respectively. We have prepared the K73A and E166A mutant forms of BlaC and have determined the structures of the Michaelis-complex of cefamandole, as well as the covalently bound acyl-intermediate of cefamandole at resolutions of 1.2 and 2.0 Å, respectively. These structures provide insight into the details of the catalytic mechanism. PMID:20961112

  13. Structures of the Michaelis Complex (1.2A) and the Covalent Acyl Intermediate (2.0A ) of Cefamandole Bound in the Active Sites of the Mycobacterium tuberculosis beta-Lactamase K72A and E166A Mutants

    SciTech Connect

    L Tremblay; h Xu; J Blanchard

    2011-12-31

    The genome of Mycobacterium tuberculosis (TB) contains a gene that encodes a highly active {beta}-lactamase, BlaC, that imparts TB with resistance to {beta}-lactam chemotherapy. The structure of covalent BlaC-{beta}-lactam complexes suggests that active site residues K73 and E166 are essential for acylation and deacylation, respectively. We have prepared the K73A and E166A mutant forms of BlaC and have determined the structures of the Michaelis complex of cefamandole and the covalently bound acyl intermediate of cefamandole at resolutions of 1.2 and 2.0 {angstrom}, respectively. These structures provide insight into the details of the catalytic mechanism.

  14. 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

  15. Role of laparoscopic peritoneal biopsy in the diagnosis of peritoneal tuberculosis. A seven-year experience.

    PubMed

    Abdelaal, A; Alfkey, R; Abdelaziem, S; Abunada, M; Alfaky, A; Ibrahim, W H; Toro, A; Di Carlo, I

    2014-01-01

    The diagnosis of asymptomatic abdominal tuberculosis,without characteristic laboratory and radiologic findings, is difficult. We therefore investigated the role of diagnostic laparoscopy in patients with suspected peritoneal tuberculosis(PTB). Patients admitted to Hamad General Hospital, Qatar,who underwent laparoscopic peritoneal biopsy for suspected PTB from January 2004 to December 2010 were retrospectively analysed. Factors assessed included patient age, sex, symptoms,clinical signs, CT scan findings, laparoscopic findings andhistopathological diagnosis. A total of 41 patients, 33 males(80.5%) and 8 females (19.5%), of mean age 31 years, underwent laparoscopic peritoneal biopsy for suspected PTB duringthe study period. Abdominal pain was the most common presenting symptom, observed in 33 (80.5%) patients.Computerized tomography (CT) of the abdomen showed as citesin 37 patients (90%), bowel nodules in 22 (54%), peritoneal thickening and nodules in 37 (90%) and enlarged mesenteric lymph nodes in 11 (27%). The classical gross laparoscopic appearance of peritoneal tuberculosis was observed in 38 patients (93%), whereas laparoscopic findings were normal in 3 patients (7%). Histopathological results confirmed granulomatous inflammation in 38 patients (93%). The sensitivity and specificity of gross laparoscopic appearance in diagnosing peritoneal TB were both 100%. Two patients experienced complications from laparoscopy (5%), but there were nolaparoscopy-related deaths. Laparoscopic peritoneal biopsy isa rapid and safe method of accurately diagnosing PTB. PMID:24956337

  16. Pharmacodynamic Evidence that Ciprofloxacin Failure against Tuberculosis Is Not Due to Poor Microbial Kill but to Rapid Emergence of Resistance

    Microsoft Academic Search

    Tawanda Gumbo; Arnold Louie; Mark R. Deziel; George L. Drusano

    2005-01-01

    Studies of early bactericidal activity provide a fast and economic way to evaluate the clinical efficacy of potential agents for the treatment of tuberculosis. Based on good early bactericidal activity data, ciprofloxacin entered further studies and is now recommended as part of treatment for multidrug-resistant tuberculosis. We examined the relationship between ciprofloxacin bactericidal activity and the emergence of resistance in

  17. Transient Loss of Resistance to Pulmonary Tuberculosis in p47phox-\\/- Mice

    Microsoft Academic Search

    ANDREA M. COOPER; BRAHM H. SEGAL; ANTHONY A. FRANK; STEVEN M. HOLLAND; IAN M. ORME

    2000-01-01

    Mycobacterium tuberculosis is an important respiratory pathogen the growth of which is controlled primarily by cytokine-activated macrophages. One of the principal mediators of this control is nitric oxide; however, superoxide has recently been shown to be protective in systemic mycobacterial infections. To determine whether superoxide is important in controlling M. tuberculosis during primary pulmonary infection, mice lacking the cytosolic p47phox

  18. Unusual presentation of tuberculosis in an elderly male: a case report

    PubMed Central

    Kandel, Ramesh; Bhattarai, Bhawana; Maharjan, Santosh

    2015-01-01

    Key Clinical Message Tuberculous liver abscess is an extremely rare condition, even in tuberculosis endemic countries. A 68-year-old male presented with 2 months of fever, significant weight loss, and hepatomegaly. Ultrasonography revealed a right hepatic lobe abscess. Guided aspiration of the fluid showed tubercular bacilli. He had no evidence of active Tuberculosis elsewhere. PMID:25678973

  19. Epidemiology of Pediatric Tuberculosis Using Traditional and Molecular Techniques: Houston, Texas

    Microsoft Academic Search

    Susan H. Wootton; Blanca E. Gonzalez; Rebecca Pawlak; Larry D. Teeter; Kim Connelly Smith; James M. Musser; Jeffrey R. Starke; Edward A. Graviss

    2010-01-01

    Objective. To investigate the transmis- sion dynamics of pediatric tuberculosis (TB) by analyz- ing the clinical characteristics with the molecular profiles of Mycobacterium tuberculosis isolates during a 5-year period. Methods. A retrospective review of a prospective population-based active surveillance and molecular epi- demiology project was conducted in private and public pediatric clinics within Houston and Harris County, Texas. The study

  20. Characterization of pncA mutations of pyrazinamide-resistant Mycobacterium tuberculosis in Turkey

    Microsoft Academic Search

    Pelin Yüksel; Özlem Tansel

    Mutations in the pyrazinamidase (PZase) gene (pncA) are considered the major mechanism of pyrazinamide (PZA) resistance in Mycobacterium tuberculosis. The aim of this study was designed to determine pncA mutations among ten PZA resistant and two PZA susceptible M. tuberculosis strains from Turkey and also to compare the PZase activity of them with the genotype. All isolates were identified by

  1. Novel inhibitors of Mycobacterium tuberculosis growth based on modified pyrimidine nucleosides and their analogues

    NASA Astrophysics Data System (ADS)

    Shmalenyuk, E. R.; Kochetkov, S. N.; Alexandrova, L. A.

    2013-09-01

    The review summarizes data on the synthesis and antituberculosis activity of pyrimidine nucleoside derivatives and their analogues. Enzymes from M. tuberculosis as promising targets for prototypes of new-generation drugs are considered. Nucleosides as inhibitors of drug-resistant M. tuberculosis strains are characterized. The bibliography includes 101 references.

  2. Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis

    Microsoft Academic Search

    S-J Ha; B-Y Jeon; J-I Youn; S-C Kim; S-N Cho; Y-C Sung

    2005-01-01

    Active disease of tuberculosis (TB) can be developed decades later by either a relapse of the initial infection (endogenous reactivation) or by an entrance of the secondary infection (exogenous reinfection), since the current chemotherapy cannot lead to complete elimination of tuberculosis. Although the immunotherapeutic approaches in conjunction with conventional chemotherapy were tried to prevent TB growth via boosting the immune

  3. 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

  4. Silymarin protects liver against toxic effects of anti-tuberculosis drugs in experimental animals

    Microsoft Academic Search

    Sude Eminzade; Fikriye Uras; Fikret V Izzettin

    2008-01-01

    BACKGROUND: The first line anti-tuberculosis drugs isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA) continues to be the effective drugs in the treatment of tuberculosis, however, the use of these drugs is associated with toxic reactions in tissues, particularly in the liver, leading to hepatitis. Silymarin, a standard plant extract with strong antioxidant activity obtained from S. marianum, is known to

  5. 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

  6. Measurement of Sputum Mycobacterium tuberculosis Messenger RNA as a Surrogate for Response to Chemotherapy

    Microsoft Academic Search

    LUCY E. DESJARDIN; MARK D. PERKINS; KATHY WOLSKI; SHIRLEY HAUN; LUCILÉIA TEIXEIRA; YING CHEN; JOHN L. JOHNSON; JERROLD J. ELLNER; REYNALDO DIETZE; JOSEPH BATES; M. DONALD CAVE; KATHLEEN D. EISENACH

    Effective treatment regimens for pulmonary tuberculosis are difficult to assess because of the slow growth rate of Mycobacterium tuberculosis in culture and its protracted clearance from sputum. A rapid method that reflects effective antimicrobial activity would markedly advance evaluation of treatment and promote the assessment of new antituberculosis drugs. Conventional methods mea- sure the progressive reduction of numbers of acid-fast

  7. Male genital tuberculosis in Siberians.

    PubMed

    Kulchavenya, Ekaterina; Khomyakov, Victor

    2006-02-01

    To study the epidemiology and the clinical picture of male genital tuberculosis in Siberia, Russia. Five hundred and fourteen patients with genitourinary tuberculosis were enrolled in the study: 414 had kidney tuberculosis only, 100 had genital involvement. The clinical picture and structure of genital tuberculosis were investigated: 42 had tuberculosis of scrotal organs and 58 had tuberculosis of the prostate. Urinary cultures, urinalysis, three-glass test, and investigation of the prostate secretion, Mycobacteria culture, and susceptibility testing were performed in all 514 patients. 33.6% of all patients earlier suffered from pulmonary or extrapulmonary tuberculosis and were successfully cured. In 61.9% nephrotuberculosis was diagnosed alongside with an orchiepididymitis. In 30.9% of patients bilateral epididymorchitis was diagnosed. Mycobacteriuria was present in 38.1%. Scrotal fistula was found in 11.9%. In 66.7% the symptoms appeared acutely. Half of the patients with prostate tuberculosis complained of dysuria, 23 (39.6%) had perineal pain, 34 (58.6%) had flank pain. Leucocytes in urine were present in 49 (84.5%) patients, and in prostatic secretion in 45 (77.6%) patients. Erythrocytes in urine were present in 31 (53.4%) patients, and in prostatic secretions in 17 (29.3%) patients. Male genital tuberculosis has no specific pathognomonic signs. Using a special algorithm for the management of patients with prostatitis or epididymitis is recommended. PMID:16429302

  8. Development of new vaccines and diagnostic reagents against tuberculosis.

    PubMed

    Mustafa, Abu Salim

    2002-09-01

    Tuberculosis (TB) is a major infectious disease problem with one-third of the world population infected, 8 million people developing the active disease and 2 million dying of TB each year. The attenuated Mycobacterium bovis Bacillus Calmette Guerin (BCG) is the only available vaccine against TB. However, the trials conducted in different parts of the world have shown that this vaccine doe not provide consistent protection against TB. The purified protein derivative (PPD) of Mycobacterium tuberculosis is the commonly used reagent for the diagnosis of TB. However, PPD lacks specificity because of the presence of antigens crossreactive with M. bovis BCG and other mycobacteria. The studies to identify M. tuberculosis antigens and epitopes as candidates for new protective vaccines and specific diagnostic reagents against TB have led to the identification and characterization of several major antigens of M. tuberculosis including heat shock proteins (hsp) and secreted antigens present in the culture filtrate (CF) of M. tuberculosis. Some of these antigens have shown promise as new candidate vaccines (hsp60, Ag85 and ESAT-6, etc.) and specific diagnostic reagents (ESAT-6 and CFP10, etc.) for TB. Moreover, in the mouse model of TB, vaccination with DNA-hsp60 has immunotheraputic effects and helps in eradication of persisters. In addition, identification of proper adjuvant and delivery systems has shown the promise to overcome the problem of poor immunogenicity associated with subunit and peptide based vaccines. More recently, the comparison of the genome sequence of M. tuberculosis with M. bovis BCG and other mycobacteria has led to the identification of M. tuberculosis-specific genomic regions. Evaluation of these regions for encoding proteins with immunological reactivity can lead to the identification of additional antigens of M. tuberculosis useful as new vaccines and reagents for specific diagnosis of TB. PMID:12213334

  9. The global emergency of tuberculosis: what is the cause?

    PubMed

    Grange, J M; Zumla, A

    2002-06-01

    The treatment of tuberculosis is cheap and highly effective, yet worldwide the disease remains a serious cause of illness and death; so serious as to have been declared a 'global emergency' in 1993. It is principally a disease of poverty, with 95% of cases and 98% of deaths occurring in developing countries. The incidence of tuberculosis is increasing worldwide, partly due to poverty and inequity and partly to the HIV/AIDS pandemic, which greatly increases the risk of infection proceeding to overt disease. Around 30% of AIDS-related deaths are due to tuberculosis. The emergence of multidrug resistant tuberculosis (MDRTB) is an increasing threat to tuberculosis control. Although treatable with alternative drugs, the cost is enormous and, accordingly, not undertaken in many poor nations. While the overall global incidence of MDRTB is low, it occurs in certain 'hotspots' including Russian prisons. Due to adverse socio-economic factors, London has not escaped the general rise in incidence and, without the introduction of active control strategies, there could be a serious epidemic as occurred in New York City ten years ago which required an enormous financial outlay for its control. In view of the global emergency of tuberculosis, the WHO 'Stop TB' campaign has called for the universal adoption of its directly observed therapy, short course (DOTS) strategy. Also, though the Massive Effort Against Diseases of Poverty, several international agencies are urging the establishment of effective control programmes worldwide. London should take the lead and set an example. PMID:12134771

  10. The Effect of HIV-Related Immunosuppression on the Risk of Tuberculosis Transmission to Household Contacts

    PubMed Central

    Huang, Chuan-Chin; Tchetgen, Eric Tchetgen; Becerra, Mercedes C.; Cohen, Ted; Hughes, Katherine C.; Zhang, Zibiao; Calderon, Roger; Yataco, Rosa; Contreras, Carmen; Galea, Jerome; Lecca, Leonid; Murray, Megan

    2014-01-01

    Background.?Coinfection with human immunodeficiency virus (HIV) may modify the risk of transmitting tuberculosis. Some previous investigations suggest that patients coinfected with HIV and tuberculosis are less likely to transmit infection, whereas others do not support this conclusion. Here, we estimated the relative risk of tuberculosis transmission from coinfected patients compared to HIV-negative patients with tuberculosis. Methods.?Between September 2009 and August 2012, we identified and enrolled 4841 household contacts of 1608 patients with drug-sensitive tuberculosis in Lima, Peru. We assessed the HIV status and CD4 counts of index patients, as well as other risk factors for infection specific to the index patient, the household, and the exposed individuals. Contacts underwent tuberculin skin testing to determine tuberculosis infection status. Results.?After adjusting for covariates, we found that household contacts of HIV-infected tuberculosis patients with a CD4 count ?250 cells/µL were less likely to be infected with tuberculosis (risk ratio = 0.49 [95% confidence interval, .24–.96]) than the contacts of HIV-negative tuberculosis patients. No children younger than 15 years who were exposed to HIV-positive patients with a CD4 count ?250 cells/µL were infected with tuberculosis, compared to 22% of those exposed to non-HIV-infected patients. There was no significant difference in the risk of infection between contacts of HIV-infected index patients with CD4 counts >250 cells/µL and contacts of index patients who were not HIV-infected. Conclusions.?We found a reduced risk of tuberculosis infection among the household contacts of patients with active tuberculosis who had advanced HIV-related immunosuppression, suggesting reduced transmission from these index patients. PMID:24368620

  11. [Adrenal tuberculosis: case report].

    PubMed

    Ouarssani, A; Atoini, F; Ait Lhou, F; Rguibi, M I

    2012-06-01

    Isolated adrenal tuberculosis is rare, and represents between 1-2% of the etiologies of adrenal masses called incidentalomas. A 32-year-old woman, without notable medical history, was hospitalized for pain in the left hypochondrium, lasting for two months in a context of apyrexia and weight loss amounted to 5 kg. Clinical examination was normal, but abdominopelvic CT objectified bilateral adrenal hypertrophy predominantly left with bilateral linear calcifications. The chest radiograph was normal, adrenal hormones were normal. The research of BK in sputum and urine were negative on direct examination and culture. The tuberculin was 12 mm and HIV status was negative. A left adrenal biopsy was done and histopathological study of tuberculous lesions was found confirming caseofolliculaire adrenal tuberculosis. The patient has been treated with antibacillaire with favorable evolution. In light of this observation, the authors make the point on this rare disease. PMID:22206787

  12. Tuberculosis and BCG

    Microsoft Academic Search

    Marina Gheorghiu; Micheline Lagranderie; Anne-Marie Balazuc

    \\u000a Tuberculosis occurred in humans probably as early as 8,000 bc in its sporadic form. Indeed, it is mentioned in India’s Vedas, the most sacred texts of Hinduism, and later by Hippocrates,\\u000a Celse D’Aretée de Cappadoce (170 bc), and Avicene (Calmette 1923; Calmette et al. 1928). Recently, genetic studies of the tubercle bacillus have found its progenitor\\u000a to come into existence

  13. Sensing the Killer - Tuberculosis

    NSDL National Science Digital Library

    2010-01-04

    Thirty-fourth monthly installment of our "What A Year!" website project, introducing life science breakthroughs to middle and high school students and their teachers. About 2 billion people are walking around infected by tuberculosis. But they don't it, because they don't have any symptoms of this terrible disease. The trick with TB is to catch it early and prevent ever-widening circles of infection.

  14. Cutaneous tuberculosis: a rare presentation in an immigrant.

    PubMed

    Gulisano, G; Mariani, L

    1998-09-01

    The increased incidence of tubercular diseases in industrialized countries appears to be due to several factors, including development of resistance to the most commonly used specific chemotherapeutic substances, unsuitable control programmes, HIV infection, the increased influx of immigrants, and homelessness. Different forms of cutaneous tuberculosis are caused by different species of mycobacteria (e.g., Mycobacterium tuberculosis, M. bovis, M. avium). Determining the species of mycobacteria is relevant when disease is suspected to be linked to the type of employment of the patient, mainly because the clinical features do not always indicate which species is the cause of the infection. Mycobacterium tuberculosis (MT) usually infects through the lung, but in rare cases can penetrate the skin or mucous membranes. Skin transmission can be exogenous by inoculation, or endogenous by diffusion (lymphatic or hematic) or by contiguity. The immunologic status of the patient is a crucial factor which influences the clinical variants and the course of disease itself. Here we report a case of an illegal immigrant who presented with a bilateral, symmetrical ulcer on the neck. PMID:9772331

  15. The human immune response to tuberculosis and its treatment: a view from the blood

    PubMed Central

    Cliff, Jacqueline M; Kaufmann, Stefan H E; McShane, Helen; van Helden, Paul; O'Garra, Anne

    2015-01-01

    The immune response upon infection with the pathogen Mycobacterium tuberculosis is poorly understood, hampering the discovery of new treatments and the improvements in diagnosis. In the last years, a blood transcriptional signature in tuberculosis has provided knowledge on the immune response occurring during active tuberculosis disease. This signature was absent in the majority of asymptomatic individuals who are latently infected with M. tuberculosis (referred to as latent). Using modular and pathway analyses of the complex data has shown, now in multiple studies, that the signature of active tuberculosis is dominated by overexpression of interferon-inducible genes (consisting of both type I and type II interferon signaling), myeloid genes, and inflammatory genes. There is also downregulation of genes encoding B and T-cell function. The blood signature of tuberculosis correlates with the extent of radiographic disease and is diminished upon effective treatment suggesting the possibility of new improved strategies to support diagnostic assays and methods for drug treatment monitoring. The signature suggested a previously under-appreciated role for type I interferons in development of active tuberculosis disease, and numerous mechanisms have now been uncovered to explain how type I interferon impedes the protective response to M. tuberculosis infection. PMID:25703554

  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. 21 CFR 866.3370 - Mycobacterium tuberculosis immunofluorescent reagents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...2013-04-01 false Mycobacterium tuberculosis immunofluorescent reagents... § 866.3370 Mycobacterium tuberculosis immunofluorescent reagents...Identification. Mycobacterium tuberculosis immunofluorescent...

  18. 21 CFR 866.3370 - Mycobacterium tuberculosis immunofluorescent reagents.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...2012-04-01 false Mycobacterium tuberculosis immunofluorescent reagents... § 866.3370 Mycobacterium tuberculosis immunofluorescent reagents...Identification. Mycobacterium tuberculosis immunofluorescent...

  19. 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...

  20. Synthesis, crystal, computational study and in vitro anti-tuberculosis activity of N-(furan-2-yl-methyl)- N-(phenyl(quinolin-3-yl)methyl) acetamide derivatives

    NASA Astrophysics Data System (ADS)

    Bai, Yuefei; Wang, Lijuan; Chen, Yu; Yuan, Lei; Xu, Wei; Sun, Tiemin

    2011-11-01

    A one-pot synthesis of N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methyl)- N-(furan-2-yl-methyl)-2-morpholinoacetamide ( 1) and N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methyl)- N-(furan-2-yl-methyl)-2-adamantylacetamide ( 2) was achieved in good yield for the first time. Compounds 1 and 2·H 2O were characterized by single crystal X-ray diffraction in solid state. The structures of two new derivatives have been confirmed by typical spectroscopic techniques, namely IR, 1H and 13C NMR. The optimized geometric bond lengths and bond angles obtained by using density functional theory (DFT) have been compared with X-ray diffraction values. The experimental molecular structures are well reproduced by the computation. The geometrical parameters of the title compounds are similar to those of some reported derivatives. In addition, in vitro anti-tuberculosis activities of derivatives 1 and 2 were also investigated.

  1. Tuberculosis in Tanzanian wildlife.

    PubMed

    Cleaveland, S; Mlengeya, T; Kazwala, R R; Michel, A; Kaare, M T; Jones, S L; Eblate, E; Shirima, G M; Packer, C

    2005-04-01

    Bovine tuberculosis, caused by Mycobacterium bovis, is a pathogen of growing concern in free-ranging wildlife in Africa, but little is known about the disease in Tanzanian wildlife. Here, we report the infection status of Mycobacterium bovis in a range of wildlife species sampled from protected areas in northern Tanzania. M. bovis was isolated from 11.1% (2/18) migratory wildebeest (Connochaetes taurinus) and 11.1% (1/9) topi (Damaliscus lunatus) sampled systematically in 2000 during a meat cropping program in the Serengeti ecosystem, and from one wildebeest and one lesser kudu (Tragelaphus imberbis) killed by sport hunters adjacent to Tarangire National Park. A tuberculosis antibody enzyme immunoassay (EIA) was used to screen serum samples collected from 184 Serengeti lions (Panthera leo) and 19 lions from Ngorongoro Crater sampled between 1985 and 2000. Samples from 212 ungulates collected throughout the protected area network between 1998 and 2001 also were tested by EIA. Serological assays detected antibodies to M. bovis in 4% of Serengeti lions; one positive lion was sampled in 1984. Antibodies were detected in one of 17 (6%) buffalo (Syncerus caffer) in Tarangire and one of 41 (2%) wildebeest in the Serengeti. This study confirms for the first time the presence of bovine tuberculosis in wildlife of northern Tanzania, but further investigation is required to assess the impact on wildlife populations and the role of different wildlife species in maintenance and transmission. PMID:16107683

  2. Novel targets for tuberculosis drug discovery.

    PubMed

    Mdluli, Khisimuzi; Spigelman, Melvin

    2006-10-01

    Since the determination of the Mycobacterium tuberculosis genome sequence, various groups have used the genomic information to identify and validate targets as the basis for the development of new anti-tuberculosis agents. Validation might include many components: demonstration of the biochemical activity of the enzyme, determination of its crystal structure in complex with an inhibitor or a substrate, confirmation of essentiality, and the identification of potent growth inhibitors either in vitro or in an infection model. If novel target validation and subsequent inhibition are matched by an improved understanding of disease biology, then new antibiotics could have the potential to shorten the duration of therapy, prevent resistance development and eliminate latent disease. PMID:16904376

  3. Tuberculosis immunity: opportunities from studies with cattle.

    PubMed

    Waters, W Ray; Palmer, Mitchell V; Thacker, Tyler C; Davis, William C; Sreevatsan, Srinand; Coussens, Paul; Meade, Kieran G; Hope, Jayne C; Estes, D Mark

    2011-01-01

    Mycobacterium tuberculosis and M. bovis share >99% genetic identity and induce similar host responses and disease profiles upon infection. There is a rich history of codiscovery in the development of control measures applicable to both human and bovine tuberculosis (TB) including skin-testing procedures, M. bovis BCG vaccination, and interferon-? release assays. The calf TB infection model offers several opportunities to further our understanding of TB immunopathogenesis. Recent observations include correlation of central memory immune responses with TB vaccine efficacy, association of SIRP?(+) cells in ESAT-6:CFP10-elicited multinucleate giant cell formation, early ?? T cell responses to TB, antimycobacterial activity of memory CD4(+) T cells via granulysin production, association of specific antibody with antigen burden, and suppression of innate immune gene expression in infected animals. Partnerships teaming researchers with veterinary and medical perspectives will continue to provide mutual benefit to TB research in man and animals. PMID:21197095

  4. Tuberculosis Immunity: Opportunities from Studies with Cattle

    PubMed Central

    Waters, W. Ray; Palmer, Mitchell V.; Thacker, Tyler C.; Davis, William C.; Sreevatsan, Srinand; Coussens, Paul; Meade, Kieran G.; Hope, Jayne C.; Estes, D. Mark

    2011-01-01

    Mycobacterium tuberculosis and M. bovis share >99% genetic identity and induce similar host responses and disease profiles upon infection. There is a rich history of codiscovery in the development of control measures applicable to both human and bovine tuberculosis (TB) including skin-testing procedures, M. bovis BCG vaccination, and interferon-? release assays. The calf TB infection model offers several opportunities to further our understanding of TB immunopathogenesis. Recent observations include correlation of central memory immune responses with TB vaccine efficacy, association of SIRP?+ cells in ESAT-6:CFP10-elicited multinucleate giant cell formation, early ?? T cell responses to TB, antimycobacterial activity of memory CD4+ T cells via granulysin production, association of specific antibody with antigen burden, and suppression of innate immune gene expression in infected animals. Partnerships teaming researchers with veterinary and medical perspectives will continue to provide mutual benefit to TB research in man and animals. PMID:21197095

  5. 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…

  6. Selecting foils for identification lineups: matching suspects or descriptions?

    PubMed

    Tunnicliff, J L; Clark, S E

    2000-04-01

    Two experiments directly compare two methods of selecting foils for identification lineups. The suspect-matched method selects foils based on their match to the suspect, whereas the description-matched method selects foils based on their match to the witness's description of the perpetrator. Theoretical analyses and previous results predict an advantage for description-matched lineups both in terms of correctly identifying the perpetrator and minimizing false identification of innocent suspects. The advantage for description-matched lineups should be particularly pronounced if the foils selected in suspect-matched lineups are too similar to the suspect. In Experiment 1, the lineups were created by trained police officers, and in Experiment 2, the lineups were constructed by undergraduate college students. The results of both experiments showed higher suspect-to-foil similarity for suspect-matched lineups than for description-matched lineups. However, neither experiment showed a difference in correct or false identification rates. Both experiments did, however, show that there may be an advantage for suspect-matched lineups in terms of no-pick and rejection responses. From these results, the endorsement of one method over the other seems premature. PMID:10810840

  7. REPORTING SUSPECTED CHILD ABUSE AND NEGLECT Policy Statement

    E-print Network

    Shahriar, Selim

    Page 1 REPORTING SUSPECTED CHILD ABUSE AND NEGLECT Policy Statement Northwestern University places with the provisions of this policy. Furthermore, the Illinois Abused and Neglected Child Reporting Act specifies that all University employees are mandated reporters of suspected cases of child abuse and/or neglect

  8. Report of Suspected Identity Theft Page 1 of 3

    E-print Network

    Oliver, Douglas L.

    Report of Suspected Identity Theft Page 1 of 3 University of Connecticut Health Center Report of Suspected Identity Theft Part I-Initial Report Background Information: Your Name: ____________________ Incident Description: Include all indicators that signal possible identity theft or other fraudulent

  9. Guidelines for Investigating Suspected Financial Fraud November 26, 2013

    E-print Network

    Simaan, Nabil

    Guidelines for Investigating Suspected Financial Fraud November 26, 2013 Introduction Safeguarding to a manager or employee who suspects fraud is being committed. Overview of Fraud Occupational fraud is defined or misapplication of the employing organization's resources or assets." In general terms a fraud takes place when

  10. Targeted exome sequencing of suspected mitochondrial disorders

    PubMed Central

    Lieber, Daniel S.; Calvo, Sarah E.; Shanahan, Kristy; Slate, Nancy G.; Liu, Shangtao; Hershman, Steven G.; Gold, Nina B.; Chapman, Brad A.; Thorburn, David R.; Berry, Gerard T.; Schmahmann, Jeremy D.; Borowsky, Mark L.; Mueller, David M.; Sims, Katherine B.

    2013-01-01

    Objective: To evaluate the utility of targeted exome sequencing for the molecular diagnosis of mitochondrial disorders, which exhibit marked phenotypic and genetic heterogeneity. Methods: We considered a diverse set of 102 patients with suspected mitochondrial disorders based on clinical, biochemical, and/or molecular findings, and whose disease ranged from mild to severe, with varying age at onset. We sequenced the mitochondrial genome (mtDNA) and the exons of 1,598 nuclear-encoded genes implicated in mitochondrial biology, mitochondrial disease, or monogenic disorders with phenotypic overlap. We prioritized variants likely to underlie disease and established molecular diagnoses in accordance with current clinical genetic guidelines. Results: Targeted exome sequencing yielded molecular diagnoses in established disease loci in 22% of cases, including 17 of 18 (94%) with prior molecular diagnoses and 5 of 84 (6%) without. The 5 new diagnoses implicated 2 genes associated with canonical mitochondrial disorders (NDUFV1, POLG2), and 3 genes known to underlie other neurologic disorders (DPYD, KARS, WFS1), underscoring the phenotypic and biochemical overlap with other inborn errors. We prioritized variants in an additional 26 patients, including recessive, X-linked, and mtDNA variants that were enriched 2-fold over background and await further support of pathogenicity. In one case, we modeled patient mutations in yeast to provide evidence that recessive mutations in ATP5A1 can underlie combined respiratory chain deficiency. Conclusion: The results demonstrate that targeted exome sequencing is an effective alternative to the sequential testing of mtDNA and individual nuclear genes as part of the investigation of mitochondrial disease. Our study underscores the ongoing challenge of variant interpretation in the clinical setting. PMID:23596069

  11. 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

  12. Tuberculosis endometritis presenting as a leiomyoma.

    PubMed

    Shirazi, Mahboobeh; Shahbazi, Fatemeh; Pirzadeh, Leila; Mohammadi, Seyed Rahim; Ghaffari, Parisa; Eftekhar, Tahereh

    2015-01-01

    Genitourinary tuberculosis is a common extrapulmonary manifestation of tuberculosis. Taking into consideration that genitourinary tuberculosis may be associated with a diversity of presentations, its diagnoses may be difficult. A young woman with an initial presumptive diagnosis of a uterine leiomyoma presented with abdominal pain and a pelvic mass that after further investigations, she was diagnosed with genital tuberculosis. PMID:25780530

  13. ORIGINAL ARTICLE Mycobacterium tuberculosis secretory proteins

    E-print Network

    Cai, Long

    ORIGINAL ARTICLE Mycobacterium tuberculosis secretory proteins CFP-10, ESAT-6 and the CFP10:ESAT6, Dinakar M Salunke2 and Pawan Sharma1 Mycobacterium tuberculosis (Mtb) causes death of 2­3 million people; lipopolysaccharide; NF-kB; ROS Tuberculosis is a global health problem caused by Mycobacterium tuberculosis (Mtb

  14. Multidrug-Resistant Mycobacterium tuberculosis: Molecular Perspectives

    Microsoft Academic Search

    Ashok Rattan; Awdhesh Kalia; Nishat Ahmad

    1998-01-01

    Multidrug-resistant strains of Mycobacterium tuberculosis seriously threaten tuberculosis (TB) control and prevention efforts. Molecular studies of the mechanism of action of antitubercular drugs have elucidated the genetic basis of drug resistance in M. tuberculosis. Drug resistance in M. tuberculosis is attributed primarily to the accumulation of mutations in the drug target genes; these mutations lead either to an altered target

  15. Schiffert Health Center TUBERCULOSIS RISK ASSESSMENT FORM

    E-print Network

    Virginia Tech

    Schiffert Health Center TUBERCULOSIS RISK ASSESSMENT FORM Name that tuberculosis skin testing (PPD) be performed on all individuals who may be at increased risk of tuberculosis tuberculosis · Use of illegal injected drugs · At risk of being infected with HIV (Human Immunodeficiency Virus

  16. Tuberculosis Endometritis Presenting as A Leiomyoma

    PubMed Central

    Shirazi, Mahboobeh; Shahbazi, Fatemeh; Pirzadeh, Leila; Mohammadi, Seyed Rahim; Ghaffari, Parisa; Eftekhar, Tahereh

    2015-01-01

    Genitourinary tuberculosis is a common extrapulmonary manifestation of tuberculosis. Taking into consideration that genitourinary tuberculosis may be associated with a diversity of presentations, its diagnoses may be difficult. A young woman with an initial presumptive diagnosis of a uterine leiomyoma presented with abdominal pain and a pelvic mass that after further investigations, she was diagnosed with genital tuberculosis.

  17. An Unconventional Hexacoordinated Flavohemoglobin from Mycobacterium tuberculosis*

    PubMed Central

    Gupta, Sanjay; Pawaria, Sudesh; Lu, Changyuan; Hade, Mangesh Dattu; Singh, Chaahat; Yeh, Syun-Ru; Dikshit, Kanak L.

    2012-01-01

    Being an obligate aerobe, Mycobacterium tuberculosis faces a number of energetic challenges when it encounters hypoxia and environmental stress during intracellular infection. Consequently, it has evolved innovative strategies to cope with these unfavorable conditions. Here, we report a novel flavohemoglobin (MtbFHb) from M. tuberculosis that exhibits unique features within its heme and reductase domains distinct from conventional FHbs, including the absence of the characteristic hydrogen bonding interactions within the proximal heme pocket and mutations in the FAD and NADH binding regions of the reductase domain. In contrast to conventional FHbs, it has a hexacoordinate low-spin heme with a proximal histidine ligand lacking imidazolate character and a distal heme pocket with a relatively low electrostatic potential. Additionally, MtbFHb carries a new FAD binding site in its reductase domain similar to that of d-lactate dehydrogenase (d-LDH). When overexpressed in Escherichia coli or Mycobacterium smegmatis, MtbFHb remained associated with the cell membrane and exhibited d-lactate:phenazine methosulfate reductase activity and oxidized d-lactate into pyruvate by converting the heme iron from Fe3+ to Fe2+ in a FAD-dependent manner, indicating electron transfer from d-lactate to the heme via FAD cofactor. Under oxidative stress, MtbFHb-expressing cells exhibited growth advantage with reduced levels of lipid peroxidation. Given the fact that d-lactate is a byproduct of lipid peroxidation and that M. tuberculosis lacks the gene encoding d-LDH, we propose that the novel d-lactate metabolizing activity of MtbFHb uniquely equips M. tuberculosis to balance the stress level by protecting the cell membrane from oxidative damage via cycling between the Fe3+/Fe2+ redox states. PMID:22437825

  18. 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

  19. [Surgical treatment of obstructive urinary tract diseases in patients with pulmonary tuberculosis].

    PubMed

    Iagafarova, R K; Zuban', O N; Iashkin, D V; Levashev, Iu N

    2004-01-01

    The paper presents the data of an examination of 92 patients [males (59-64.1%) and females (33-35.9%)] with active pulmonary tuberculosis concurrent with obstructive urinary tract diseases of various etiology. The patients' age ranged from 39 to 90 years (mean 58.2 +/- 2.5 years). Seventy-six (82.0%) patients suffered from infiltrative tuberculosis; 12 (13.0%) and 4 (4.3%) patients had cavernous and fibrocavernous tuberculosis, respectively. A relationship was found between pulmonary tuberculosis and obstructive urinary tract diseases leading to uniform changes in the upper urinary tract. The use of currently available methods for examination and treatment to eliminate infra- and supravesical obstruction permits performance of surgical interventions in patients with active pulmonary tuberculosis. PMID:15532465

  20. Tuberculosis: a problem with persistence

    Microsoft Academic Search

    Graham R. Stewart; Brian D. Robertson; Douglas B. Young

    2003-01-01

    Mycobacterium tuberculosis is one of most successful pathogens of mankind, infecting one-third of the global population and claiming two million lives every year. The ability of the bacteria to persist in the form of a long-term asymptomatic infection, referred to as latent tuberculosis, is central to the biology of the disease. The persistence of bacteria in superficially normal tissue was

  1. Transcriptional Blood Signatures Distinguish Pulmonary Tuberculosis, Pulmonary Sarcoidosis, Pneumonias and Lung Cancers

    PubMed Central

    Bloom, Chloe I.; Graham, Christine M.; Berry, Matthew P. R.; Rozakeas, Fotini; Redford, Paul S.; Wang, Yuanyuan; Xu, Zhaohui; Wilkinson, Katalin A.; Wilkinson, Robert J.; Kendrick, Yvonne; Devouassoux, Gilles; Ferry, Tristan; Miyara, Makoto; Bouvry, Diane; Dominique, Valeyre; Gorochov, Guy; Blankenship, Derek; Saadatian, Mitra; Vanhems, Phillip; Beynon, Huw; Vancheeswaran, Rama; Wickremasinghe, Melissa; Chaussabel, Damien; Banchereau, Jacques; Pascual, Virginia; Ho, Ling-pei; Lipman, Marc; O’Garra, Anne

    2013-01-01

    Rationale New approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations. Objectives To determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases. Methods We compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations. Measurements and Main Results An Interferon-inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls. Conclusions Tuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the heterogeneity of their profiles and their transcriptional response to treatment. PMID:23940611

  2. Reflections on the immunology of tuberculosis: will we ever unravel the skein?

    PubMed Central

    2014-01-01

    Many and large dumps exist in our knowledge about Mycobacterium tuberculosis infection and disease in infants and children. We still do not understand why some individuals do acquire and others do not acquire the infection in the presence of the same risk factors. We do not understand why some individuals convert from latent to active tuberculosis and why other individuals convert from active to inactive tuberculosis even without treatment. As a matter of fact the immune system mounts a bouncing, robust and polyedral defence against Mycobacterium tuberculosis, but the bacillus is so much artful and dextrous that it has ahead from this immunological fierce accoutrements. Mycobacterium tuberculosis survival, multiplication, and transmission are largely favoured by the immune mechanisms. The granuloma itself is more bacillus- than host-protective. These abilities make Mycobacterium tuberculosis one of more successful human pathogens, but dumps in our knowledge and the counterproductive immunity hinder development of new diagnostics, therapies and vaccines. This occurs in front of an infection which engages one third of the world population and a disease which kills in a year about 1.5 million individuals worldwide. Understanding mechanisms and meaning of immune response in tuberculosis marks out the foundations of strategies with a view to prepare effective vaccines and reliable diagnostic tools as well as to build up therapeutic weapons. To gain these objectives is vital and urgent considering that tuberculosis is a common cause of morbidity and is a leading cause of death. PMID:24564297

  3. Latent Variable Assessment of Outcomes in a Nurse-Managed Intervention to Increase Latent Tuberculosis Treatment Completion in Homeless Adults

    Microsoft Academic Search

    Adeline Nyamathi; Judith A. Stein; Anja Schumann; Darlene Tyler

    2007-01-01

    Objective: To assess predictors of latent tuberculosis infection (LTBI) completion by using structural equation modeling (SEM) among homeless adults, a group at great risk for LTBI and active tuberculosis (TB). LTBI therapy is effective in stemming the progression to active TB, yet treatment adherence among homeless persons is difficult to attain. Design: By using SEM, the authors assessed predictors of

  4. Atypical DNA recognition mechanism used by the EspR virulence regulator of Mycobacterium tuberculosis.

    PubMed

    Blasco, Benjamin; Stenta, Marco; Alonso-Sarduy, Livan; Dietler, Giovanni; Peraro, Matteo Dal; Cole, Stewart T; Pojer, Florence

    2011-10-01

    The human pathogen Mycobacterium tuberculosis requires the ESX-1 secretion system for full virulence. EspR plays a key role in ESX-1 regulation via direct binding and transcriptional activation of the espACD operon. Here, we describe the crystal structures of EspR, a C-terminally truncated form, EspR?10, as well as an EspR-DNA complex. EspR forms a dimer with each monomer containing an N-terminal helix-turn-helix DNA binding motif and an atypical C-terminal dimerization domain. Structural studies combined with footprinting experiments, atomic force microscopy and molecular dynamic simulations allow us to propose a model in which a dimer of EspR dimers is the minimal functional unit with two subunits binding two consecutive major grooves. The other two DNA binding domains are thus free to form higher-order oligomers and to bridge distant DNA sites in a cooperative way. These features are reminiscent of nucleoid-associated proteins and suggest a more general regulatory role for EspR than was previously suspected. PMID:21883526

  5. 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

  6. Rapid Detection of Mycobacterium tuberculosis and Rifampin Resistance by Use of On-Demand, Near-Patient Technology? † ‡

    PubMed Central

    Helb, Danica; Jones, Martin; Story, Elizabeth; Boehme, Catharina; Wallace, Ellen; Ho, Ken; Kop, JoAnn; Owens, Michelle R.; Rodgers, Richard; Banada, Padmapriya; Safi, Hassan; Blakemore, Robert; Lan, N. T. Ngoc; Jones-López, Edward C.; Levi, Michael; Burday, Michele; Ayakaka, Irene; Mugerwa, Roy D.; McMillan, Bill; Winn-Deen, Emily; Christel, Lee; Dailey, Peter; Perkins, Mark D.; Persing, David H.; Alland, David

    2010-01-01

    Current nucleic acid amplification methods to detect Mycobacterium tuberculosis are complex, labor-intensive, and technically challenging. We developed and performed the first analysis of the Cepheid Gene Xpert System's MTB/RIF assay, an integrated hands-free sputum-processing and real-time PCR system with rapid on-demand, near-patient technology, to simultaneously detect M. tuberculosis and rifampin resistance. Analytic tests of M. tuberculosis DNA demonstrated a limit of detection (LOD) of 4.5 genomes per reaction. Studies using sputum spiked with known numbers of M. tuberculosis CFU predicted a clinical LOD of 131 CFU/ml. Killing studies showed that the assay's buffer decreased M. tuberculosis viability by at least 8 logs, substantially reducing biohazards. Tests of 23 different commonly occurring rifampin resistance mutations demonstrated that all 23 (100%) would be identified as rifampin resistant. An analysis of 20 nontuberculosis mycobacteria species confirmed high assay specificity. A small clinical validation study of 107 clinical sputum samples from suspected tuberculosis cases in Vietnam detected 29/29 (100%) smear-positive culture-positive cases and 33/39 (84.6%) or 38/53 (71.7%) smear-negative culture-positive cases, as determined by growth on solid medium or on both solid and liquid media, respectively. M. tuberculosis was not detected in 25/25 (100%) of the culture-negative samples. A study of 64 smear-positive culture-positive sputa from retreatment tuberculosis cases in Uganda detected 63/64 (98.4%) culture-positive cases and 9/9 (100%) cases of rifampin resistance. Rifampin resistance was excluded in 54/55 (98.2%) susceptible cases. Specificity rose to 100% after correcting for a conventional susceptibility test error. In conclusion, this highly sensitive and simple-to-use system can detect M. tuberculosis directly from sputum in less than 2 h. PMID:19864480

  7. Structural and functional characterization of Mycobacterium tuberculosis triosephosphate isomerase

    SciTech Connect

    Connor, Sean E.; Capodagli, Glenn C.; Deaton, Michelle K.; Pegan, Scott D. (Oregon)

    2012-04-18

    Tuberculosis (TB) is a major infectious disease that accounts for over 1.7 million deaths every year. Mycobacterium tuberculosis, the causative agent of tuberculosis, enters the human host by the inhalation of infectious aerosols. Additionally, one third of the world's population is likely to be infected with latent TB. The incidence of TB is on the rise owing in part to the emergence of multidrug-resistant strains. As a result, there is a growing need to focus on novel M. tuberculosis enzyme targets. M. tuberculosis triosephosphate isomerase (MtTPI) is an essential enzyme for gluconeogenetic pathways, making it a potential target for future therapeutics. In order to determine its structure, the X-ray crystal structure of MtTPI has been determined, as well as that of MtTPI bound with a reaction-intermediate analog. As a result, two forms of the active site were revealed. In conjunction with the kinetic parameters obtained for the MtTPI-facilitated conversion of dihydroxyacetone phosphate (DHAP) to D-glyceraldehyde-3-phosphate (D-GAP), this provides a greater structural and biochemical understanding of this enzyme. Additionally, isothermal titration calorimetry was used to determine the binding constant for a reaction-intermediate analog bound to the active site of MtTPI.

  8. Sarcoid-like pattern in a patient with tuberculosis.

    PubMed

    Chokoeva, A A; Tchernev, G; Tana, C; Ananiev, J; Wollina, U

    2014-01-01

    For several decades the ?mystery? of sarcoidosis has continued to evade revelation. Nowadays, due to medical progress and the opportunity of performing highly specialized tests which assist the identification of this condition as a separate disease, the understanding of the eternal mystery appears closer. Nevertheless, many contemporary studies focus on the putative link between sarcoidosis and infectious antigens isolated from skin lesions. On the other hand, a golden rule to differentiate sarcoidosis from other conditions such as tuberculosis and sarcoid-like reactions is the sterility of granulomas. However, there are hypotheses which state that sarcoidosis could be related to tuberculosis and, in particular, to the Mycobacterium species. The similarities that many authors identify between the genetic signatures of the two conditions definitely raise concerns regarding: i) the inability to categorize every single case in a clear-cut way, namely in inflammatory/autoimmune or infectious; ii) the need of new criteria to clearly differentiate sarcoid-type reactions in the context of infectious diseases from sarcoidosis as an autonomous disease. We report the case of a 35-year-old male patient with histopathological evidence of sarcoid-like granulomas in cutaneous lesions on the face and imaging studies consistent with a systemic form of sarcoidosis. However, a positive QuantiFERON-TB Gold test and Ziehl-Neelsen staining was found, leading to the diagnosis of a rare case of TBC with histopathological evidence of sarcoid-like lesions. The following are also discussed: i) the potential role of tuberculosis antigens in the context of occult tuberculosis as generators of sarcoid-type of reaction; and ii) the necessity of additional diagnostic panels as a standard procedure in patients with suspected sarcoid granulomas of unknown origin. PMID:25620187

  9. Development of cell-based tuberculosis vaccines: genetically modified dendritic cell vaccine is a much more potent activator of CD4 and CD8 T cells than peptide- or protein-loaded counterparts.

    PubMed

    Malowany, Janet I; McCormick, Sarah; Santosuosso, Michael; Zhang, Xizhong; Aoki, Naoko; Ngai, Patricia; Wang, Jun; Leitch, Jaina; Bramson, Jonathan; Wan, Yonghong; Xing, Zhou

    2006-04-01

    Genetically modified dendritic cell (DC)-based vaccines have not been explored for immunization against tuberculosis. A gene-modified DC vaccine expressing Mycobacterium tuberculosis (M.tb) antigen 85A (Ag85A) was developed by using a recombinant replication-deficient adenoviral gene transfer vector (AdAg85A). AdAg85A-transduced DC vaccine (AdAg85/DC) expressed higher levels of IL-12 and was much more immunogenic than Ag85 protein-loaded (pro/DC) or CD4/CD8 T cell peptide-loaded (pep/DC) DC vaccines. Compared to pro/DC or pep/DC, AdAg85/DC elicited a remarkably higher level of ex vivo IFN-gamma production by CD4 and CD8 T cells at weeks 2, 6, and 12 postimmunization, which was coupled with higher frequencies of antigen-specific T cells. By an in vivo CD8 or CD4 T cell cytotoxicity (CTL) assay, AdAg85/DC was shown to provoke much higher and more sustained levels of CD8 and CD4 CTL activity up to 12 weeks postimmunization. Intramuscular (im) AdAg85/DC immunization was more potent than the iv route of AdAg85/DC immunization. Such stronger immunogenicity of im AdAg85/DC vaccination was corroborated with better protection from M.tb challenge. Our results thus suggest that genetically modified DC-based TB vaccine is superior to subunit DC vaccines and has the potential for therapeutic applications. PMID:16343993

  10. Selective BCG vaccination in a country with low incidence of tuberculosis.

    PubMed

    Romanus, V

    2006-01-01

    In 1975 the BCG vaccination policy in Sweden changed from routine vaccination of all newborn infants to selective vaccination of groups at higher risk. This report aims to evaluate the present BCG policy, with focus on the tuberculosis situation in Sweden during the period from 1989 to 2005. The population structure in Sweden has changed, with increasing numbers and proportions of people who were born outside Sweden, especially in countries with high prevalence of tuberculosis. BCG vaccination coverage fell from more than 95% before 1975 to less than 2% in 1976 to 1980, and then again increased to around 16% (corresponding to about 88% of the risk group recommended for vaccination). The increasing proportion of foreign born tuberculosis patients among all tuberculosis cases of illness in Sweden, and the high age-specific incidence of tuberculosis in the childbearing age groups in the foreign-born population, indicate the need to continue selective vaccination of children in families originating from countries with high tuberculosis incidence. The cumulative incidence of tuberculosis in the 30 cohorts born in Sweden after 1974 and observed to the end of 2004 was estimated at 0.5 cases per 100 000 person-years. Sweden still has one of the lowest incidences of tuberculosis in the world, which means a minimal average risk of infection for the majority of children born to Swedish parents. The observed increase of tuberculosis in 2005, partly attributed to an outbreak at a day nursery, is a reminder of the serious consequences of delayed diagnosis. Intensified active case finding is the most important action to prevent childhood tuberculosis, by means of eliminating the sources of infection to prevent transmission to the child population. Early detection and treatment of infected children is necessary to prevent development of serious disseminated tuberculosis. PMID:16567880

  11. Risk factors of multi-drug-resistant tuberculosis in Bangladeshi population: a case control study.

    PubMed

    Flora, M S; Amin, M N; Karim, M R; Afroz, S; Islam, S; Alam, A; Hossain, M

    2013-04-01

    Despite success in tuberculosis control, multi-drug resistant tuberculosis in Bangladesh is increasing and currently multi-drug-resistant tuberculosis rate is 3.6% in new cases and 19% in re-treatment cases. This study focused on determination of multi-drug-resistant tuberculosis which is warranted for effective prevention strategy. An unmatched case control study was conducted in 2010. Purposively recruited 136 culture-proved multi-drug-resistant- tuberculosis cases and 152 cured tuberculosis patients were interviewed. Associations between exposure and outcome variables were initially tested by chi2-test, t-test. A result was considered significant at p value < 0.05. Effects of exposure variables were also assessed after adjusting for other variables by binary logistic regression models. Crude and adjusted Odds Ratio with 95% Confidence Interval was computed. Younger age (p = 0.008) and, peri-urban locality (p = 0.002) were associated with multi-drug-resistant tuberculosis. History of contact (p < 0.001) and tuberculosis in the past (p < 0.001) were four and eight times, respectively, more likely to influence multi-drug-resistant tuberculosis. Regularity [Odds Ratio 0.05; 95% Confidence Interval (0.01 to 0.39)] and always observation of treatment [Odds Ratio 0.25; 95% Confidence Interval (0.10 to 0.61)], sputum conversion [Odds Ratio 0.02; 95% Confidence Interval (0.01 to 0.08)] negatively associated with multi-drug-resistant tuberculosis. Gender and socio-economic status did not show any influence. Treatment course and sputum conversion was the best predictors. Like other developing countries adequacy of treatment is the most important exposure variable. Strengthening of control activities might contribute in preventing development of resistance in tuberculosis patients. PMID:23923410

  12. 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

  13. 78 FR 1718 - Approved Tests for Bovine Tuberculosis in Cervids

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-09

    ...Approved Tests for Bovine Tuberculosis in Cervids AGENCY...antibodies to bovine tuberculosis in certain species...has waived its review under Executive...tests as official tuberculosis tests for captive...tuberculosis tests for bovine...

  14. 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

  15. B Plant/WESF suspect/counterfeit parts identification program

    SciTech Connect

    Mertz, D.W.

    1996-01-12

    This document describes a suspect/counterfeit parts inspection program required by DOE conducted in accordance with Internal Memo 16710-94-DWM-048, J.A. O`Brien to J. N. Nansen, B Plant Suspect/ Counterfeit Parts Action Plan, dated May 24, 1994. The program included: physical inspection of all spare parts inventories within the plant; screening of installed B Plant/WESF (Waste Encapsulation and Storage Facility) systems for applications where the use and subsequent potential failure of suspect/counterfeit parts could have critical consequences; and a physical inspection based upon this screening.

  16. Some Nigerian Anti-Tuberculosis Ethnomedicines: A Preliminary Efficacy Assessment

    PubMed Central

    Ibekwe, Nneka N.; Nvau, John B.; Oladosu, Peters O.; Usman, Auwal M.; Ibrahim, Kolo; Boshoff, Helena I.; Dowd, Cynthia S.; Orisadipe, Abayomi T.; Aiyelaagbe, Olapeju; Adesomoju, Akinbo A.; Barry, Clifton E.; Okogun, Joseph I.

    2014-01-01

    Ethnopharmacological significance Nigerian herbalists possess indigenous ethnomedicinal recipes for the management of tuberculosis and related ailments. Aim of the study To carry out a collaborative preliminary modern scientific evaluation of the efficacy of some Nigerian ethnomedicines used by traditional medicine practitioners (TMPs) in the management of tuberculosis and related ailments Materials and methods Ethnomedicinal recipes (ETMs) were collected from TMPs from locations in various ecological zones of Nigeria under a collaborative understanding. The aqueous methanolic extracts of the ETMs were screened against Mycobacterium bovis, BCG and Mycobacterium tuberculosis (M. tb.) strain H37Rv using the broth microdilution method. Results Extracts of ETMs screened against BCG showed 69% activity against the organism. The activities varied from weak, ? 2500?g /mL to highly active, 33?g /mL 64% of the extracts were active against M. tb. The activities of the extracts against M.tb. varied from weak, ? 2500?g /mL to highly active, 128?g/mL. There was 77% agreement in results obtained using BCG or M. tb. as test organisms Conclusion The results show clear evidence for the efficacy of the majority of indigenous Nigerian herbal recipes in the ethnomedicinal management of tuberculosis and related ailments. BCG may be effectively used, to a great extent, as the organism for screening for potential anti-M. tb. agents. A set of prioritization criteria for the selection of plants for initial further studies for the purpose of antituberculsis drug discovery research is proposed. PMID:24911338

  17. Killer Cell Lectin-Like Receptor G1 Deficiency Significantly Enhances Survival after Mycobacterium tuberculosis Infection

    PubMed Central

    Cyktor, Joshua C.; Carruthers, Bridget; Stromberg, Paul; Flaño, Emilio; Pircher, Hanspeter

    2013-01-01

    The expression of T cell differentiation markers is known to increase during Mycobacterium tuberculosis infection, and yet the biological role of such markers remains unclear. We examined the requirement of the T cell differentiation marker killer cell lectin-like receptor G1 (KLRG1) during M. tuberculosis infection using mice deficient in KLRG1. KLRG1?/? mice had a significant survival extension after M. tuberculosis infection compared to wild-type controls, and maintained a significantly lower level of pulmonary M. tuberculosis throughout chronic infection. Improved control of M. tuberculosis infection was associated with an increased number of activated pulmonary CD4+ T cells capable of secreting gamma interferon (IFN-?). Our report is the first to show an in vivo impact of KLRG1 on disease control. PMID:23340310

  18. 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.

  19. Dysregulation of inflammatory and hemostatic markers in sepsis and suspected disseminated intravascular coagulation.

    PubMed

    Hoppensteadt, Debra; Tsuruta, Kazuhisa; Hirman, Joe; Kaul, Inder; Osawa, Yutaka; Fareed, Jawed

    2015-03-01

    Inflammatory mediators and hemostatic markers were evaluated in patients enrolled in a phase-2b study evaluating the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with sepsis and suspected disseminated intravascular coagulation (DIC). In contrast to controls, patients with sepsis and suspected DIC showed an increase in the circulating levels of inflammatory and fibrinolytic markers. The levels of procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), anaphylatoxin C5a, plasminogen activator inhibitor 1 (PAI-1), and myeloperoxidase were higher in the patients with sepsis and suspected DIC, whereas protein C (PrC) exhibited a significant decrease. When the patients with overt and nonovert DIC were compared, the PrC level was lower, and PCT, PAI-1, IL-6, and IL-10 levels were higher in the patients with overt DIC. These results indicate that inflammation is elevated in sepsis and suspected DIC, and inflammation, impairment of fibrinolysis, and overconsumption of PrC may play a key role in the pathogenesis of DIC. PMID:24254894

  20. PCR colorimetric dot-blot assay and clinical pretest probability for diagnosis of Pulmonary Tuberculosis in Smear-Negative patients

    PubMed Central

    Scherer, Luciene Cardoso; Sperhacke, Rosa Dea; Jarczewski, Carla; Cafrune, Patrícia I; Minghelli, Simone; Ribeiro, Marta Osório; Mello, Fernanda CQ; Ruffino-Netto, Antonio; Rossetti, Maria LR; Kritski, Afrânio L

    2007-01-01

    Background Smear-negative pulmonary tuberculosis (SNPTB) accounts for 30% of Pulmonary Tuberculosis (PTB) cases reported annually in developing nations. Polymerase chain reaction (PCR) may provide an alternative for the rapid detection of Mycobacterium tuberculosis (MTB); however little data are available regarding the clinical utility of PCR in SNPTB, in a setting with a high burden of TB/HIV co-infection. Methods To evaluate the performance of the PCR dot-blot in parallel with pretest probability (Clinical Suspicion) in patients suspected of having SNPTB, a prospective study of 213 individuals with clinical and radiological suspicion of SNPTB was carried out from May 2003 to May 2004, in a TB/HIV reference hospital. Respiratory specialists estimated the pretest probability of active disease into high, intermediate, low categories. Expectorated sputum was examined by direct microscopy (Ziehl-Neelsen staining), culture (Lowenstein Jensen) and PCR dot-blot. Gold standard was based on culture positivity combined with the clinical definition of PTB. Results In smear-negative and HIV subjects, active PTB was diagnosed in 28.4% (43/151) and 42.2% (19/45), respectively. In the high, intermediate and low pretest probability categories active PTB was diagnosed in 67.4% (31/46), 24% (6/25), 7.5% (6/80), respectively. PCR had sensitivity of 65% (CI 95%: 50%–78%) and specificity of 83% (CI 95%: 75%–89%). There was no difference in the sensitivity of PCR in relation to HIV status. PCR sensitivity and specificity among non-previously TB treated and those treated in the past were, respectively: 69%, 43%, 85% and 80%. The high pretest probability, when used as a diagnostic test, had sensitivity of 72% (CI 95%:57%–84%) and specificity of 86% (CI 95%:78%–92%). Using the PCR dot-blot in parallel with high pretest probability as a diagnostic test, sensitivity, specificity, positive and negative predictive values were: 90%, 71%, 75%, and 88%, respectively. Among non-previously TB treated and HIV subjects, this approach had sensitivity, specificity, positive and negative predictive values of 91%, 79%, 81%, 90%, and 90%, 65%, 72%, 88%, respectively. Conclusion PCR dot-blot associated with a high clinical suspicion may provide an important contribution to the diagnosis of SNPTB mainly in patients that have not been previously treated attended at a TB/HIV reference hospital. PMID:18096069