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1

Smear positive pulmonary tuberculosis and its risk factors among tuberculosis suspect in South East Ethiopia; a hospital based cross-sectional study  

PubMed Central

Background Tuberculosis remains a deadly infectious disease, affecting millions of people worldwide. Ethiopia ranks seventh among the twenty two high tuberculosis burden countries. The aim of this study was to determine the prevalence of smear positive pulmonary tuberculosis and its associated risk factors in Goba and Robe hospitals of Bale zone. Methods A cross-sectional study was conducted on tuberculosis suspected patients from February-May 2012. Sputum samples were examined for acid fast bacilli using Ziehl-Neelsen staining and interview was conducted for each patient. Descriptive statistics, binary logistic and multivariable logistic regression analyses were employed to identify factors associated with pulmonary tuberculosis infection. Result The prevalence of smear positive tuberculosis was 9.2%. Age >36 (AOR?=?3.54, 95% CI?=?1. 3–9.82), marital status (AOR?=?8.40, 95% CI?=?3.02-23.20), family size (AOR?=?4. 10, 95% CI?=?1.60-10.80), contact with active tuberculosis patient (AOR?=?5. 90; 95% CI?=?2. 30–15.30), smoking cigarette regularly (AOR?=?3. 90; 95% CI?=?1. 20–12.40), and human immunodeficiency virus sero-status (AOR?=?11. 70; 95% CI?=?4. 30–31.70) were significantly associated with smear positive pulmonary tuberculosis. Conclusion The prevalence of smear positive pulmonary tuberculosis was high in the study area. Age, marital status, family size, history of contact with active tuberculosis patient, smoking cigarettes, and HIV sero-status were among the risk factors significantly associated with acquiring tuberculosis. Hence, strict pulmonary tuberculosis screening of HIV patients and intensification of health education to avoid risk factors identified are recommended. PMID:24884870

2014-01-01

2

Draft Genome Sequence of Multidrug-Resistant Mycobacterium tuberculosis Strain CWCFVRF MDRTB 670, Isolated from the Sputum of a Patient from Chennai, India, with Clinically Suspected Tuberculosis  

PubMed Central

We announce the draft genome sequence of a multidrug-resistant Mycobacterium tuberculosis strain (CWCFVRF MDRTB 670) isolated from sputum from a patient with clinically suspected tuberculosis. PMID:24855307

Lakshmipathy, Dhanurekha; Vetrivel, Umashankar; Ramasubban, Gayathri; Madhavan, H. N.; Sridhar, R.; Meenakshi, N.

2014-01-01

3

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

PubMed Central

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

2012-01-01

4

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

PubMed Central

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

2014-01-01

5

Validity of a decision tree for predicting active pulmonary tuberculosis.  

PubMed

The recent outbreaks of multidrug-resistant strains of M. tuberculosis in health care facilities has increased concern over its transmission in health care facilities. Isolation has been recommended for all patients suspected to have tuberculosis even though the feasibility and the cost of this recommendation can be substantial. We have developed a classification tree using clinical and radiographic data from 277 isolation episodes in patients admitted between August 1992 and March 1994 who required isolation for suspicion of tuberculosis. The classification tree was developed with a sensitivity and negative predictive value of 100% by binary recursive partitioning to predict those patients who are unlikely to require isolation. The predictor variables were upper zone disease on chest radiograph, a history of fever, weight loss, and CD4 count. The tree was validated in a separate cohort of 286 isolation episodes between April 1994 and December 1995. In this validation cohort, no erroneous prediction was made of not isolating a patient with active pulmonary tuberculosis. The classification tree had a sensitivity of 100% (95% confidence interval [CI]: 92.5 to 100%), a specificity of 48.1% (95% CI: 43.8 to 52.4%), and a negative predictive value of 100% (95% CI: 98.5 to 100%). We estimate that the use of the tree could have reduced the number of patients requiring isolation by more than 40% without increasing the risk of cross infection. PMID:9154881

El-Solh, A; Mylotte, J; Sherif, S; Serghani, J; Grant, B J

1997-05-01

6

The incremental cost-effectiveness of engaging private practitioners to refer tuberculosis suspects to DOTS services in Jogjakarta, Indonesia.  

PubMed

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

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

2010-06-01

7

Correlates of Delayed Diagnosis among Human Immunodeficiency Virus-Infected Pulmonary Tuberculosis Suspects in a Rural HIV Clinic, South Africa  

PubMed Central

Background. Delay in pulmonary tuberculosis (PTB) diagnosis is one of the major factors that affect outcome and threatens continued spread of tuberculosis. This study aimed at determining factors associated with delayed PTB diagnosis among human immunodeficiency virus (HIV) infected individuals. Methods. A retrospective observational study was done using clinic records of HIV-infected PTB suspects attending an HIV/AIDS clinic at Tintswalo rural hospital in South Africa (SA) between January 2006 and December 2007. Using routine clinic registers, 480 records were identified. Results. PTB diagnosis delay was found among 77/176 (43.8%) of the patients diagnosed with PTB. The mean delay of PTB diagnosis was 170.6 days; diagnosis delay ranged 1–30 days in 27 (35.1%) patients, 31–180 days in 24 (33.8%) patients; 24 (31.2%) patients remained undiagnosed for ?180 days. Independent factors associated with delayed diagnosis were: older age >40 years (Odds Ratio (OR) 3.43, 95% CI 1.45–8.08) and virological failure (OR 2.72, 95% CI 1.09–6.74). Conclusion. There is a considerable delayed PTB diagnosis among HIV-infected patients in rural SA. Older patients as well as patients with high viral load are at a higher risk of PTB diagnosis delay. Therefore efforts to reduce PTB diagnosis delay need to emphasised. PMID:22778946

Boniface, Respicious; Moshabela, Mosa; Zulliger, Rose; MacPherson, Peter; Nyasulu, Peter

2012-01-01

8

[Isolation rate of Mycobacterium tuberculosis complex from patients with suspected tuberculosis and identification of the strains with BACTEC™ NAP and immunochromatographic TB Ag MPT64 Rapid™ Tests].  

PubMed

Tuberculosis (TB) which is still one of the important infectious diseases in the world as well as Turkey, results in high morbidity and mortality. Clinical mycobacteriology laboratories have crucial roles in the identification, typing and susceptibility testing of Mycobacterium tuberculosis. The aims of this study were the investigation of the isolation rate of M.tuberculosis complex (MTC) from the clinical specimens of TB-suspected patients and to compare identification of mycobacteria isolated from solid and/or liquid media by using BACTEC NAP and immunochromatographic TB Ag MPT64 rapid test. A total of 1670 patients who were admitted to outpatients clinics of our hospital and prediagnosed as TB, have been included in the study. All the patients were anti-HIV seronegative. NALC-NaOH method were used for decontamination/ homogenization, and preparations from samples were stained with Erlich-Ziehl-Neelsen method to detect acid-resistant bacilli (ARB) in direct microscopy. All of the samples were inoculated into BACTEC™ MGIT-960 (Becton Dickinson, USA) and Löwenstein-Jensen (LJ) media for cultivation and incubated at 37°C for 6-8 weeks. Mycobacteria that were grown in the media have been identified by BACTEC™ NAP (Becton Dickinson, USA) and TB Ag MPT64 rapid test (SD Bioline Ag MPT64 Rapid™; Standard Diagnostics, Korea). The culture positivity in the samples of TB-suspected patients was found to be 3.7% (63/1670) with LJ and/or MGIT-960 methods, whereas ARB positivity rate was 1.6% (28/1670). Fifty-three (84%) out of culture positive 63 samples have been identified as MTC by BACTEC NAP test, while 61 (97%) were found as MTC by TB MPT64 test. Considering BACTEC NAP test as the reference method, TB MPT64 test identified all the MTC strains correctly (sensitivity: 100%), however the false positivity rate was estimated as 12.7% (specificity: 87%). Of 53 MTC positive samples, 36 were sputum, four were bronchoalveolar lavage, four were urine, three were gastric fluid, three were pleural fluid, and one of each were abscess, peritoneal fluid and cerebrospinal fluid samples. ARB positivity rate was detected as 41.5% (22/53) among MTC culture positive samples. Of the patients who were infected with MTC, 72% (38/53) were male and 98% (52/53) were adults (age range: 20-85 years). Our data indicating 3.1% (53/1670) isolation rate of MTC from TB-suspected patients in our region were in concordance with the other results reported from Turkey. In conclusion, immunochromatographic TB Ag MPT64 test which seemed to be useful for the rapid identification of mycobacteria grown on solid and/or liquid, was practical to perform and had high sensitivity, however further larger-scaled studies are needed to support our data in our country. PMID:21644069

Kurto?lu, Muhammet Güzel; Ozdemir, Mehmet; Ke?li, Recep; Ozkalp, Birol; Baysal, Bülent

2011-04-01

9

Comparative performance of urinary lipoarabinomannan assays and Xpert MTB/RIF in HIV-infected individuals with suspected tuberculosis in Uganda  

PubMed Central

Background Xpert MTB/RIF (‘Xpert’) and urinary lipoarabinomannan (LAM) assays offer rapid tuberculosis (TB) diagnosis, but have suboptimal sensitivity when used individually in HIV-positive patients. The yield of these tests used in combination for the diagnosis of active TB among HIV-infected TB suspects is unknown. Design Study of comparative diagnostic accuracy nested into a prospective study of HIV-infected individuals with signs and/or symptoms of TB in Uganda. Methods Xpert testing of archived sputum was conducted for culture-confirmed TB cases and TB suspects in whom a diagnosis of TB was excluded. Additional testing included sputum smear microscopy, sputum culture (solid and liquid media), mycobacterial blood culture, and urinary testing for LAM using a lateral flow test (‘LF-LAM’) and an enzyme-linked immunosorbance assay (‘ELISA-LAM’). Results Among 103 participants with culture-confirmed TB, sensitivity of Xpert was 76% (95% confidence interval, CI 0.66–0.84), and was superior to that of LF-LAM (49%, 95% CI 0.39–0.59, P <0.001). Specificity was greater than 97% for both tests among 105 individuals without TB. The combination of smear microscopy and LF-LAM identified 67% (95% CI 0.57–0.76) of culture-confirmed TB cases and approached sensitivity of Xpert testing alone (P =0.15). The sensitivity of the combination of Xpert and LF-LAM was 85% (88/103 95% CI 0.77–0.92), which was superior to either test alone (P <0.05) and approached sensitivity of sputum liquid culture testing (94%, 95% CI 0.88–0.98, P =0.17). Conclusion Sputum Xpert and urinary LAM assays were complementary for the diagnosis of active TB in HIV-infected patients, and sensitivity of the combination of these tests was superior to that of either test alone. PMID:24637544

Shah, Maunank; Ssengooba, Willy; Armstrong, Derek; Nakiyingi, Lydia; Holshouser, Molly; Ellner, Jerrold J.; Joloba, Moses; Manabe, Yukari C.; Dorman, Susan E.

2014-01-01

10

38 CFR 3.374 - Effect of diagnosis of active tuberculosis.  

Code of Federal Regulations, 2010 CFR

...Relative to Specific Diseases § 3.374 Effect...diagnosis of active pulmonary tuberculosis will... Diagnosis of active pulmonary tuberculosis by... Diagnosis of active pulmonary tuberculosis by private...accepted to show the disease was initially...

2010-07-01

11

38 CFR 3.374 - Effect of diagnosis of active tuberculosis.  

Code of Federal Regulations, 2012 CFR

...Relative to Specific Diseases § 3.374 Effect...diagnosis of active pulmonary tuberculosis will... Diagnosis of active pulmonary tuberculosis by... Diagnosis of active pulmonary tuberculosis by private...accepted to show the disease was initially...

2012-07-01

12

38 CFR 3.374 - Effect of diagnosis of active tuberculosis.  

Code of Federal Regulations, 2011 CFR

...Relative to Specific Diseases § 3.374 Effect...diagnosis of active pulmonary tuberculosis will... Diagnosis of active pulmonary tuberculosis by... Diagnosis of active pulmonary tuberculosis by private...accepted to show the disease was initially...

2011-07-01

13

38 CFR 3.374 - Effect of diagnosis of active tuberculosis.  

Code of Federal Regulations, 2013 CFR

...Relative to Specific Diseases § 3.374 Effect...diagnosis of active pulmonary tuberculosis will... Diagnosis of active pulmonary tuberculosis by... Diagnosis of active pulmonary tuberculosis by private...accepted to show the disease was initially...

2013-07-01

14

Isoxyl Activation Is Required for Bacteriostatic Activity against Mycobacterium tuberculosis?  

PubMed Central

Isoxyl (ISO), a thiourea derivative that was successfully used for the clinical treatment of tuberculosis during the 1960s, is an inhibitor of the synthesis of oleic and mycolic acids in Mycobacterium tuberculosis. Its effect on oleic acid synthesis has been shown to be attributable to its inhibitory activity on the stearoyl-coenzyme A desaturase DesA3, but its enzymatic target(s) in the mycolic acid pathway remains to be identified. With the goal of elucidating the mode of action of ISO, we have isolated a number of spontaneous ISO-resistant mutants of M. tuberculosis and undertaken their genotypic characterization. We report here the characterization of a subset of these strains carrying mutations in the monooxygenase gene ethA. Through complementation studies, we demonstrate for the first time that the EthA-mediated oxidation of ISO is absolutely required for this prodrug to inhibit its lethal enzymatic target(s) in M. tuberculosis. An analysis of the metabolites resulting from the in vitro transformation of ISO by purified EthA revealed the occurrence of a formimidamide allowing the formulation of an activation pathway in which the oxidation of ISO catalyzed by EthA is followed by chemical transformations involving extrusion or elimination and, finally, hydrolysis. PMID:17785510

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

2007-01-01

15

Does neutralization of gastric aspirates from children with suspected intrathoracic tuberculosis affect mycobacterial yields on MGIT culture?  

PubMed

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

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

2013-06-01

16

Evaluation of Two Line Probe Assays for Rapid Detection of Mycobacterium tuberculosis, Tuberculosis (TB) Drug Resistance, and Non-TB Mycobacteria in HIV-Infected Individuals with Suspected TB  

PubMed Central

Limited performance data from line probe assays (LPAs), nucleic acid tests used for the rapid diagnosis of tuberculosis (TB), nontuberculosis mycobacteria (NTM), and Mycobacterium tuberculosis drug resistance are available for HIV-infected individuals, in whom paucibacillary TB is common. In this study, the strategy of testing sputum with GenoType MTBDRplus (MTBDR-Plus) and GenoType Direct LPA (Direct LPA) was compared to a gold standard of one mycobacterial growth indicator tube (MGIT) liquid culture. HIV-positive (HIV+) individuals with suspected TB from southern Africa and South America with <7 days of TB treatment had 1 sputum specimen tested with Direct LPA, MTBDR-Plus LPA, smear microscopy, MGIT, biochemical identification of mycobacterial species, and culture-based drug-susceptibility testing (DST). Of 639 participants, 59.3% were MGIT M. tuberculosis culture positive, of which 276 (72.8%) were acid-fast bacillus (AFB) smear positive. MTBDR-Plus had a sensitivity of 81.0% and a specificity of 100%, with sensitivities of 44.1% in AFB smear-negative versus 94.6% in AFB smear-positive specimens. For specimens that were positive for M. tuberculosis by MTBDR-Plus, the sensitivity and specificity for rifampin resistance were 91.7% and 96.6%, respectively, and for isoniazid (INH) they were 70.6% and 99.1%. The Direct LPA had a sensitivity of 88.4% and a specificity of 94.6% for M. tuberculosis detection, with a sensitivity of 72.5% in smear-negative specimens. Ten of 639 MGIT cultures grew Mycobacterium avium complex or Mycobacterium kansasii, half of which were detected by Direct LPA. Both LPA assays performed well in specimens from HIV-infected individuals, including in AFB smear-negative specimens, with 72.5% sensitivity for M. tuberculosis identification with the Direct LPA and 44.1% sensitivity with MTBDR-Plus. LPAs have a continued role for use in settings where rapid identification of INH resistance and clinically relevant NTM are priorities. PMID:24430455

Kendall, Michelle A.; Wu, Xingye; Lourenco, Maria Cristina; Jentsch, Ute; Swindells, Susan; Qasba, Sarojini S.; Sanchez, Jorge; Havlir, Diane V.; Grinsztejn, Beatriz; Sanne, Ian M.; Firnhaber, Cynthia

2014-01-01

17

New tools and emerging technologies for the diagnosis of tuberculosis: Part II. Active tuberculosis and drug resistance.  

E-print Network

of drug resistance. These include simplified nucleic aciddrug resistance. Diagnostics for active tuberculosis Nucleic aciddrug resistance. For diagnosis, new tools include newer versions of nucleic acid

Pai, Madhukar; Kalantri, Shriprakash; Dheda, Keertan

2006-01-01

18

Indoleamides are active against drug-resistant Mycobacterium tuberculosis.  

PubMed

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 antimycobacterial 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

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

2013-01-01

19

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

PubMed

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

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

2013-08-01

20

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

Code of Federal Regulations, 2011 CFR

...2011-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378...Rating Considerations Relative to Specific Diseases § 3.378 Changes from activity in pulmonary tuberculosis pension...

2011-07-01

21

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

Code of Federal Regulations, 2011 CFR

...Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray...active service. (a) Active disease. X-ray evidence alone...direct service connection for pulmonary tuberculosis....

2011-07-01

22

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

Code of Federal Regulations, 2012 CFR

...2012-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378...Rating Considerations Relative to Specific Diseases § 3.378 Changes from activity in pulmonary tuberculosis pension...

2012-07-01

23

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

Code of Federal Regulations, 2013 CFR

...Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray...active service. (a) Active disease. X-ray evidence alone...direct service connection for pulmonary tuberculosis....

2013-07-01

24

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

Code of Federal Regulations, 2012 CFR

...Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray...active service. (a) Active disease. X-ray evidence alone...direct service connection for pulmonary tuberculosis....

2012-07-01

25

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

Code of Federal Regulations, 2010 CFR

...Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray...active service. (a) Active disease. X-ray evidence alone...direct service connection for pulmonary tuberculosis....

2010-07-01

26

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

Code of Federal Regulations, 2010 CFR

...2010-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378...Rating Considerations Relative to Specific Diseases § 3.378 Changes from activity in pulmonary tuberculosis pension...

2010-07-01

27

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

Code of Federal Regulations, 2013 CFR

...2013-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378...Rating Considerations Relative to Specific Diseases § 3.378 Changes from activity in pulmonary tuberculosis pension...

2013-07-01

28

Pathogen-derived biomarkers for active tuberculosis diagnosis  

PubMed Central

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

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

2014-01-01

29

Native New Zealand plants with inhibitory activity towards Mycobacterium tuberculosis  

PubMed Central

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

2010-01-01

30

Oral tuberculosis.  

PubMed

Tuberculous lesions of the oral cavity have become so infrequent that it is virtually a forgotten disease entity and may pose a diagnostic problem. Fifteen patients with conditions that were histologically diagnosed as oral tuberculosis were reviewed. All were men ranging in age from 29 to 78 years. The most common clinical presentation was odynophagia with a duration from less than 1 week to several years. The most frequently affected sites were the tongue base and gingiva. The oral lesions took the form of an irregular ulceration or a discrete granular mass. Mandibular bone destruction was evident in two patients. Two patients had a fever, and four had cervical lymphadenopathy. Eight cases were clinically suspicious for malignancy before biopsy. Only four patients had a history of tuberculosis, but 14 of the 15 patients were later found to have active pulmonary tuberculosis. Acid-fast bacilli were demonstrated in all patients. Tuberculosis should be considered in patients with an inflamed ulcer lesion. A biopsy specimen for histologic study, acid-fast stains, and cultures should be obtained for confirmation and differential diagnosis with other conditions. If a tuberculous lesion is suspected, a chest radiograph is indicated to investigate the possibility of pulmonary involvement. PMID:8705586

Eng, H L; Lu, S Y; Yang, C H; Chen, W J

1996-04-01

31

Alteration of serum inflammatory cytokines in active pulmonary tuberculosis following anti-tuberculosis drug therapy.  

PubMed

Active pulmonary tuberculosis (APTB) is associated with a failure of the host immune system to control the invading Mycobacterium tuberculosis (Mtb). The objective of this study was to quantify and assess the role of serum inflammatory cytokines in active pulmonary tuberculosis patients following anti-tuberculosis drug (ATD) therapy. Blood samples were collected from APTB patients and normal healthy subjects (NHS) (total n=204) at baseline and 2, 4 and 6 months post-therapy and the abundance of serum inflammatory cytokines were measured by cytokine specific ELISA. Compared to NHS, APTB patients at baseline had higher levels of serum pro-inflammatory cytokines IL-12p40 (P<0.001), IFN-? (P<0.001), TNF-? (P<0.01), IL-1? (P<0.001) and IL-6 (P<0.001) and anti-inflammatory cytokines IL-10 (P<0.001) and TGF-?1 (P<0.001) while there was no change in the level of IL-4. In APTB patients, the serum levels of IFN-?, TNF-?, IL-6 and TGF-?1 directly relate to the bacterial load while the TNF-?, IL-1?, IL-6 and TGF-?1 relate to radiological severity. At baseline, the IL-6 level in NHS and APTB patients differed most and following ATD therapy, this level rapidly decreased and stabilized by 4-month in APTB patients. It is concluded that a subtle reduction in the serum level of IL-6 of the APTB patients following ATD therapy might play a vital role in immune-protection of the host against Mtb infection and hence the serum IL-6 level can be a useful marker to diagnose the effectiveness of therapy in the patients. PMID:25019566

Chowdhury, Imran Hussain; Ahmed, Albin Mostaque; Choudhuri, Subhadip; Sen, Aditi; Hazra, Avijit; Pal, Nishith Kumar; Bhattacharya, Basudev; Bahar, Bojlul

2014-11-01

32

Anti-Mycobacterium tuberculosis activity of fungus Phomopsis stipata  

PubMed Central

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

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

2012-01-01

33

In Vitro and In Vivo Activities of Gatifloxacin against Mycobacterium tuberculosis  

PubMed Central

Gatifloxacin (GAT) and moxifloxacin (MXF) were evaluated in vitro to determine their activities against Mycobacterium tuberculosis. GAT was subsequently compared in a dose range study to isoniazid (INH) in a murine tuberculosis model. GAT was somewhat less active than INH. GAT and MXF were evaluated in mice infected with M. tuberculosis and were found to have similar activities. GAT was studied alone and in combination with ethambutol, ethionamide (ETA), and pyrazinamide (PZA) and compared to INH and rifampin (RIF). GAT appears to have sufficient activity alone and in combination with ETA with or without PZA to merit evaluation for treatment of tuberculosis. PMID:11897584

Alvirez-Freites, Enrique J.; Carter, Janna L.; Cynamon, Michael H.

2002-01-01

34

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

PubMed Central

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 low antiglycolipid antibody concentrations in the infected individuals. The sera from the tuberculosis patient group had significantly higher concentrations of antiglycolipid antibody than the sera from uninfected control subjects, with 94% sensitivity and 98.3% specificity. Glycolipids of Mycobacterium tuberculosis H37Rv antigens were isolated, purified, and characterized. After interchelation with liposome particles, these purified antigens specifically bound to the antiglycolipid antibodies present in the sera of patients with tuberculosis, resulting in the formation of a blue agglutination. This protocol clearly differentiates healthy controls and M. bovis BCG-vaccinated subjects from those with active tuberculosis. The resultant diagnostic tool, the TB Screen Test, is more economical and rapid (4 min) than other currently available products and can be used for the mass screening of a heavily afflicted population. PMID:15753260

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

2005-01-01

35

Systemic Immune Activation and Microbial Translocation in Dual HIV/Tuberculosis-Infected Subjects  

PubMed Central

Background.?Systemic immune activation is a strong predictor of progression of human immunodeficiency virus type 1 (HIV-1) disease and a prominent feature of infection with Mycobacterium tuberculosis. Objective.?To understand the role of systemic immune activation and microbial translocation in HIV/tuberculosis dually infected patients over the full spectrum of HIV-1 immunodeficiency, we studied circulating sCD14 and lipopolysaccharide (LPS) and their relationship to HIV-1 activity. Methods.?Two cohorts of HIV/tuberculosis subjects defined by CD4 T-cell count at time of diagnosis of tuberculosis were studied: those with low (<350/?L) and those with high (?350/?L) CD4 T-cell count. Circulating soluble CD14 (sCD14) and LPS were assessed. Results.?Levels of sCD14 were higher in HIV/tuberculosis with high (?350/?L) as compared to low CD4 T-cell count (P < .001). Whereas sCD14 levels remained elevated in HIV/tuberculosis subjects with lower CD4 T-cell counts despite treatment of tuberculosis, in HIV/tuberculosis patients with higher CD4 T-cell count (?350/?L), levels declined regardless of whether highly active antiretroviral therapy (HAART) was included with the anti-tuberculosis regimen. Circulating LPS levels in HIV/tuberculosis patients with CD4 T-cell count ?350/?L were unaffected by treatment of tuberculosis with or without HAART. Conclusion.?During HIV/tuberculosis, systemic immune activation is dissociated from microbial translocation. Changes in circulating sCD14 and LPS are dependent on CD4 T-cell count. PMID:23479321

Toossi, Zahra; Funderburg, Nicholas T.; Sirdeshmuk, Sohani; Whalen, Christopher C.; Nanteza, Maria W.; Johnson, Denise F.; Mayanja-Kizza, Harriet; Hirsch, Christina S.

2013-01-01

36

The Risk and Timing of Tuberculosis Diagnosed in Smear-Negative TB Suspects: A 12 Month Cohort Study in Harare, Zimbabwe  

PubMed Central

Background Cases of smear-negative TB have increased dramatically in high prevalence HIV settings and pose considerable diagnostic and management challenges. Methods and Findings Between February 2006 and July 2007, a cohort study nested within a cluster-randomised trial of community-based case finding strategies for TB in Harare, Zimbabwe was undertaken. Participants who had negative sputum smears and remained symptomatic of TB were follow-up for one year with standardised investigations including HIV testing, repeat sputum smears, TB culture and chest radiography. Defaulters were actively traced to the community. The objectives were to investigate the incidence and risk factors for TB. TB was diagnosed in 218 (18.2%) participants, of which 39.4% was bacteriologically confirmed. Most cases (84.2%) were diagnosed within 3 months, but TB incidence remained high thereafter (111.3 per 1000 person-years, 95% CI: 86.6 to 146.3). HIV prevalence was 63.3%, and HIV-infected individuals had a 3.5-fold higher risk of tuberculosis than HIV-negative individuals. Conclusion We found that diagnosis of TB was insensitive and slow, even with early radiography and culture. Until more sensitive and rapid diagnostic tests become widely available, a much more proactive and integrated approach towards prompt initiation of ART, ideally from within TB clinics and without waiting for TB to be excluded, is needed to minimise the risk and consequences of diagnostic delay. PMID:20676374

Dimairo, Munyaradzi; MacPherson, Peter; Bandason, Tsitsi; Zezai, Abbas; Munyati, Shungu S.; Butterworth, Anthony E.; Mungofa, Stanley; Rusikaniko, Simba; Fielding, Katherine; Mason, Peter R.; Corbett, Elizabeth L.

2010-01-01

37

Nutrient-Starved Incubation Conditions Enhance Pyrazinamide Activity against Mycobacterium tuberculosis  

Microsoft Academic Search

Pyrazinamide (PZA) is an unconventional frontline tuberculosis drug characterized by high in vivo sterilizing activity, but poor in vitroactivity. The study on the mechanism of action of PZA has attracted significant attention because of the peculiarity of PZA and its ability to shorten the tuberculosis chemotherapy. In this study, we examined the effect of nutrient-starved conditions on PZA activity in

Qiang Huang; Zhi-Fei Chen; Yuan-Yuan Li; Ying Zhang; Yi Ren; Zhijun Fu; Shun-Qing Xu

2007-01-01

38

In vitro activities of 2,2?-bipyridyl analogues against Mycobacterium avium and M. tuberculosis  

Microsoft Academic Search

Setting: Because of widespread emergence of resistant Mycobacterium tuberculosis and the high incidence of opportunistic infection caused by M. avium complex (MAC) in AIDS patients, there is an urgent need for new drugs against these organisms.Objective: To evaluate the activity of newly synthesized 2?2-bipyridyl analogues against MAC and M. tuberculosis.Design: Susceptibility of MAC and M. tuberculosis to VUF-8514 and VUF-8842

A. M. Dhople; A. A. Dhople; M. A. Ibanez

1995-01-01

39

Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis.  

PubMed

Ethionamide (ETA) is an important component of second-line therapy for the treatment of multidrug-resistant tuberculosis. Synthesis of radiolabeled ETA and an examination of drug metabolites formed by whole cells of Mycobacterium tuberculosis (MTb) have allowed us to demonstrate that ETA is activated by S-oxidation before interacting with its cellular target. ETA is metabolized by MTb to a 4-pyridylmethanol product remarkably similar in structure to that formed by the activation of isoniazid by the catalase-peroxidase KatG. We have demonstrated that overproduction of Rv3855 (EtaR), a putative regulatory protein from MTb, confers ETA resistance whereas overproduction of an adjacent, clustered monooxygenase (Rv3854c, EtaA) confers ETA hypersensitivity. Production of EtaA appears to be negatively regulated by EtaR and correlates directly with [(14)C]ETA metabolism, suggesting that EtaA is the activating enzyme responsible for thioamide oxidation and subsequent toxicity. Coding sequence mutations in EtaA were found in 11 of 11 multidrug-resistant MTb patient isolates from Cape Town, South Africa. These isolates showed broad cross-resistance to thiocarbonyl containing drugs including ETA, thiacetazone, and thiocarlide. PMID:10944230

DeBarber, A E; Mdluli, K; Bosman, M; Bekker, L G; Barry, C E

2000-08-15

40

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

PubMed Central

Background New diagnosis tests are urgently needed to address the global tuberculosis (TB) burden and to improve control programs especially in resource-limited settings. An effective in vitro diagnostic of TB based on serological methods would be regarded as an attractive progress because immunoassays are simple, rapid, inexpensive, and may offer the possibility to detect cases missed by standard sputum smear microscopy. However, currently available serology tests for TB are highly variable in sensitivity and specificity. Lipolytic enzymes have recently emerged as key factors in lipid metabolization during dormancy and/or exit of the non-replicating growth phase, a prerequisite step of TB reactivation. The focus of this study was to analyze and compare the potential of four Mycobacterium tuberculosis lipolytic enzymes (LipY, Rv0183, Rv1984c and Rv3452) as new markers in the serodiagnosis of active TB. Methods Recombinant proteins were produced and used in optimized ELISA aimed to detect IgG and IgM serum antibodies against the four lipolytic enzymes. The capacity of the assays to identify infection was evaluated in patients with either active TB or latent TB and compared with two distinct control groups consisting of BCG-vaccinated blood donors and hospitalized non-TB individuals. Results A robust humoral response was detected in patients with active TB whereas antibodies against lipolytic enzymes were infrequently detected in either uninfected groups or in subjects with latent infection. High specifity levels, ranging from 93.9% to 97.5%, were obtained for all four antigens with sensitivity values ranging from 73.4% to 90.5%, with Rv3452 displaying the highest performances. Patients with active TB usually exhibited strong IgG responses but poor IgM responses. Conclusion These results clearly indicate that the lipolytic enzymes tested are strongly immunogenic allowing to distinguish active from latent TB infections. They appear as potent biomarkers providing high sensitivity and specificity levels for the immunodiagnosis of active TB. PMID:21966416

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

2011-01-01

41

Interleukin 17-Producing ?? T Cells Increased in Patients with Active Pulmonary Tuberculosis  

Microsoft Academic Search

Although it has been known that ?? T cells may play an important role in the immune response to infection of Mycobacterium tuberculosis (M. tb), the mechanisms by which the ?? T cells participate in the innate and\\/or acquired immunity to tuberculosis (TB) have not been full elucidated. In the present study, 27 patients with active pulmonary TB and 16

Meiyu Peng; Zhaohua Wang; Chunyan Yao; Lina Jiang; Qili Jin; Jing Wang; Baiqing Li

2008-01-01

42

Serial counts of Mycobacterium tuberculosis in sputum as surrogate markers of the sterilising activity of rifampicin and pyrazinamide in treating pulmonary tuberculosis  

Microsoft Academic Search

BACKGROUND: Since the sterilising activity of new antituberculosis drugs is difficult to assess by conventional phase III studies, surrogate methods related to eventual relapse rates are required. METHODS: A suitable method is suggested by a retrospective analysis of viable counts of Mycobacterium tuberculosis in 12-hr sputum collections from 122 newly diagnosed patients with pulmonary tuberculosis in Nairobi, done pretreatment and

Richard Brindle; Joseph Odhiambo; Denis Mitchison

2001-01-01

43

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...

44

Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication by transcriptional activation at the long terminal repeat.  

PubMed Central

Tuberculosis has emerged as an epidemic fueled by the large number of individuals infected with the human immunodeficiency virus, especially those who are injecting drug users. We found a striking increase from 4- to 208-fold in p24 levels in bronchoalveolar lavage fluid from involved sites of Mycobacterium tuberculosis infection vs uninvolved sites in three HIV+ patients. We used an in vitro cell culture model to determine if tuberculosis could activate replication of HIV-1. Mononuclear phagocyte cell lines U937 and THP-1 infected with HIV-1JR-CSF, in vitro and stimulated with live M. tuberculosis H37Ra, had a threefold increase in p24 in culture supernatants. Using the HIV-1 long terminal repeat with a chloramphenicol acetyltransferase (CAT) reporter construct, live M. tuberculosis increased transcription 20-fold in THP-1 cells, and cell wall components stimulated CAT expression to a lesser extent. The nuclear factor-kappa B enhancer element was responsible for the majority of the increased CAT activity although two upstream nuclear factor-IL6 sites may also contribute to enhanced transcription. Antibodies to TNF-alpha and IL-1 inhibited the increase in CAT activity of the HIV-1 long terminal repeat by M. tuberculosis from 21-fold to 8-fold. Stimulation of HIV-1 replication by M. tuberculosis may exacerbate dysfunction of the host immune response in dually infected individuals. Images PMID:7738195

Zhang, Y; Nakata, K; Weiden, M; Rom, W N

1995-01-01

45

Retrospective observational study of diagnostic accuracy of the Xpert(R) MTB/RIF assay on fiberoptic bronchoscopy sampling for early diagnosis of smear-negative or sputum-scarce patients with suspected tuberculosis  

PubMed Central

Background Fiberoptic bronchoscopy (FOB) is a useful diagnosis tool in low-burden countries for patients with suspected pulmonary tuberculosis (TB) who are smear-negative or sputum-scarce. This study sought to determine the accuracy of the Xpert® MTB/RIF (XP) assay using FOB samples. Methods We retrospectively reviewed clinical, radiological, and microbiological characteristics of 175 TB-suspected patients requiring diagnostic FOB (bronchial aspirate or bronchoalveolar lavage) with XP assay. Polymerase chain reaction (PCR) and smear microscopy (SM) performances were first compared to culture, then to the final diagnosis, established based on clinical or radiological evolution when cultures were negative. Results Of the total 162 included patients, 30 (18.5%) had a final diagnosis of pulmonary TB, with positive cultures reported in 23. As compared to culture, sensitivity and specificity values were 80.0% and 98.6% for the XP assay, and 25.0% and 95.8% for SM, respectively. As compared to final diagnosis, the corresponding performance values were 60.0% and 100.0% for the XP assay, and 16.7% and 95.5% for SM, respectively. The sensitivity of the XP assay was significantly higher than that of SM in both cases (p?=?0.003 and p?=?0.001). Concerning the final diagnosis, both XP assay and culture sensitivities were similar (60% vs. 66.7%). PCR assay enabled pulmonary TB to be diagnosed earlier in 13 more cases, compared to SM. Conclusion Our study has confirmed the clinical benefits provided by XP assay compared to SM for the early diagnosis of suspected pulmonary TB cases requiring FOB, on per procedure samples, especially in a low TB-burden country. PMID:25115239

2014-01-01

46

Activity of SQ641, a Capuramycin Analog, in a Murine Model of Tuberculosis ?  

PubMed Central

New delivery vehicles and routes of delivery were developed for the capuramycin analogue SQ641. While this compound has remarkable in vitro potency against Mycobacterium tuberculosis, it has low solubility in water and poor intracellular activity. We demonstrate here that SQ641 dissolved in the water-soluble vitamin E analogue ?-tocopheryl polyethylene glycol 1000 succinate (TPGS) or incorporated into TPGS-micelles has significant activity in a mouse model of tuberculosis. PMID:19414567

Nikonenko, Boris V.; Reddy, Venkata M.; Protopopova, Marina; Bogatcheva, Elena; Einck, Leo; Nacy, Carol A.

2009-01-01

47

In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis  

PubMed Central

Existing macrolides have never shown definitive clinical efficacy in tuberculosis. Recent reports suggest that ribosome methylation is involved in macrolide resistance in Mycobacterium tuberculosis, a mechanism that newer macrolides have been designed to overcome in gram-positive bacteria. Therefore, selected macrolides and ketolides (descladinose) with substitutions at positions 9, 11,12, and 6 were assessed for activity against M. tuberculosis, and those with MICs of ?4 ?M were evaluated for cytotoxicity to Vero cells and J774A.1 macrophages. Several compounds with 9-oxime substitutions or aryl substitutions at position 6 or on 11,12 carbamates or carbazates demonstrated submicromolar MICs. For the three macrolide-ketolide pairs, macrolides demonstrated superior activity. Four compounds with low MICs and low cytotoxicity also effected significant reductions in CFU in infected macrophages. Active compounds were assessed for tolerance and the ability to reduce CFU in the lungs of BALB/c mice in an aerosol infection model. A substituted 11,12 carbazate macrolide demonstrated significant dose-dependent inhibition of M. tuberculosis growth in mice, with a 10- to 20-fold reduction of CFU in lung tissue. Structure-activity relationships, some of which are unique to M. tuberculosis, suggest several synthetic directions for further improvement of antituberculosis activity. This class appears promising for yielding a clinically useful agent for tuberculosis. PMID:15793125

Falzari, Kanakeshwari; Zhu, Zhaohai; Pan, Dahua; Liu, Huiwen; Hongmanee, Poonpilas; Franzblau, Scott G.

2005-01-01

48

Phosphorylation of mitogen-activated protein kinases contributes to interferon ? production in response to Mycobacterium tuberculosis.  

PubMed

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

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

2013-01-15

49

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

PubMed Central

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

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

50

Mycobacterium tuberculosis inhibits IFN-gamma transcriptional responses without inhibiting activation of STAT1.  

PubMed

IFN-gamma activates macrophages to kill diverse intracellular pathogens, but does not activate human macrophages to kill virulent Mycobacterium tuberculosis. We tested the hypothesis that this is due to inhibition of IFN-gamma signaling by M. tuberculosis and found that M. tuberculosis infection of human macrophages blocks several responses to IFN-gamma, including killing of Toxoplasma gondii and induction of FcgammaRI. The inhibitory effect of M. tuberculosis is directed at transcription of IFN-gamma-responsive genes, but does not affect proximal steps in the Janus kinase-STAT pathway, as STAT1alpha tyrosine and serine phosphorylation, dimerization, nuclear translocation, and DNA binding are intact in M. tuberculosis-infected cells. In contrast, there is a marked decrease in IFN-gamma-induced association of STAT1 with the transcriptional coactivators CREB binding protein and p300 in M. tuberculosis-infected macrophages, indicating that M. tuberculosis directly or indirectly disrupts this protein-protein interaction that is essential for transcriptional responses to IFN-gamma. Gamma-irradiated M. tuberculosis and isolated cell walls reproduce the effects of live bacteria, indicating that the bacterial component(s) that initiates inhibition of IFN-gamma responses is constitutively expressed. Although lipoarabinomannan has been found to exert effects on macrophages, it does not account for the inhibitory effects of cell walls. These results indicate that one mechanism for M. tuberculosis to evade the human immune response is to inhibit the IFN-gamma signaling pathway, and that the mechanism of inhibition is distinct from that reported for Leishmania donovani or CMV, in that it targets the interaction of STAT1 with the basal transcriptional apparatus. PMID:10490990

Ting, L M; Kim, A C; Cattamanchi, A; Ernst, J D

1999-10-01

51

Cytokine-secreting activity of blood eosinophils in pulmonary tuberculosis.  

PubMed

Modern immunological studies showed that eosinophilic granulocytes producing the key mediators of cellular and humoral immune response contribute to the common cytokine imbalance developing in tuberculous infection. A significant increase in BCG-induced secretion of IL-2, IL-5, and TNF-? by eosinophils in patients with pulmonary tuberculosis indicated high reserve reactivity of eosinophilic cells realizing their functional potential in regulation of the specific resistance reactions of the microorganism under conditions of M. tuberculosis infection. PMID:22866301

Kolobovnikova, U V; Urazova, O I; Novitsky, V V; Voronkova, O V; Naslednikova, I O; Mikheeva, K O; Ignatov, M V

2012-07-01

52

Pulmonary Immune-Compartment-Specific Interferon Gamma Responses in HIV-Infected Individuals with Active Tuberculosis (TB) in an Area of High TB Prevalence  

PubMed Central

There is a paucity of data on the pulmonary immune-compartment interferon gamma (IFN?) response to M. tuberculosis, particularly in settings of high tuberculosis (TB) prevalence and in HIV-coinfected individuals. This data is necessary to understand the diagnostic potential of commercially available interferon gamma release assays (IGRAs) in both the pulmonary immune-compartment and peripheral blood. We used intracellular cytokine staining by flow cytometry to assess the IFN? response to purified protein derivative (PPD) and early secretory antigen 6 (ESAT6) in induced sputa (ISp) and blood samples from HIV-infected, smear-negative, TB suspects. We found that individuals with active TB disease produced significantly less IFN? in response to PPD in their induced sputa samples than individuals with non-active TB (control group). This difference was not reflected in the peripheral blood, even within the CD27? CD4+ memory T lymphocyte population. These findings suggest that progression to active TB disease may be associated with the loss of IFN? secretion at the site of primary infection. Our findings highlight the importance of studying pulmonary immune-compartment M. tuberculosis specific responses to elucidate IFN? secretion across the spectrum of TB disease. PMID:22778764

Buldeo, S.; Murdoch, D. M.; Suchard, M. S.

2012-01-01

53

Altered microRNA Signatures in Sputum of Patients with Active Pulmonary Tuberculosis  

PubMed Central

Role of microRNA (miRNA) has been highlighted in pathogen-host interactions recently. At present, their role in active pulmonary tuberculosis is unknown. The aim of the study was to delineate miRNA expression in sputum supernatant of patients with active pulmonary tuberculosis. Expression of miRNAs was evaluated by microarray analysis and differentially expressed miRNAs were validated by RT-qPCR. Secreted cytokines TNF-? and IL-6 were measured by ELISA. We found that 95 miRNAs were differentially expressed between tuberculosis group and controls. More miRNAs (52 out of 95 miRNAs) were underexpressed than overexpressed during tuberculosis infection. Overexpression of miR-3179, miR-147 and underexpression of miR-19b-2* in TB group compared with controls were confirmed in the validation cohort. TNF-? and IL-6 levels were not significantly altered between TB group and controls. For the first time, differential expression of miRNAs in sputum was found in active pulmonary tuberculosis. The study provides rationale for identifying the role of miRNAs in the pathogenesis of pulmonary tuberculosis and indicates potential for miRNA-based therapeutic strategies. PMID:22900099

Ji, Rui; Li, Ruifang; Guan, Zhiyu

2012-01-01

54

Mycobacterium tuberculosis Alters the Metalloprotease Activity of the COP9 Signalosome  

PubMed Central

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

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

2014-01-01

55

Substituted aminopyrimidine protein kinase B (PknB) inhibitors show activity against Mycobacterium tuberculosis  

PubMed Central

A high-throughput screen against PknB, an essential serine–threonine protein kinase present in Mycobacterium tuberculosis (M. tuberculosis), allowed the identification of an aminoquinazoline inhibitor which was used as a starting point for SAR investigations. Although a significant improvement in enzyme affinity was achieved, the aminoquinazolines showed little or no cellular activity against M. tuberculosis. However, switching to an aminopyrimidine core scaffold and the introduction of a basic amine side chain afforded compounds with nanomolar enzyme binding affinity and micromolar minimum inhibitory concentrations against M. tuberculosis. Replacement of the pyrazole head group with pyridine then allowed equipotent compounds with improved selectivity against a human kinase panel to be obtained. PMID:22469702

Chapman, Timothy M.; Bouloc, Nathalie; Buxton, Roger S.; Chugh, Jasveen; Lougheed, Kathryn E.A.; Osborne, Simon A.; Saxty, Barbara; Smerdon, Stephen J.; Taylor, Debra L.; Whalley, David

2012-01-01

56

Gamma/delta T cell subsets in patients with active Mycobacterium tuberculosis infection and tuberculin anergy.  

PubMed

Earlier data suggest that gamma/delta T cells may play an important role in the immune response to Mycobacterium tuberculosis. The aim of this study was to determine the percentage of different gamma/delta subsets in peripheral blood of active tuberculosis patients with a positive or negative tuberculin reaction. Thirty-eight patients infected with M. tuberculosis and 22 healthy controls were included in the study. Venous blood was taken before starting antimycobacterial treatment. Lymphocytes were reacted with monoclonal antibodies specific for different gamma/delta V chains (Vdelta1, Vdelta2, Vgamma9 and Vgamma4). The results were analysed in the context of tuberculin reactivity and X-ray findings. Our results revealed a selective loss of Vgamma9/Vdelta2 T cells in the peripheral blood of tuberculin-negative patients with active tuberculosis compared to healthy controls, while the ratio of Vgamma9/Vdelta2 T cells in the peripheral blood of patients with a positive skin test did not differ from that of healthy controls. These findings demonstrate a relationship between the loss of the major M. tuberculosis-reactive subset of gammadelta T cells and the absence of tuberculin reactivity. The data are consistent with the hypothesis that gammadelta T cells play a role in the protective immune response to M. tuberculosis infection. PMID:12562390

Szereday, L; Baliko, Z; Szekeres-Bartho, J

2003-02-01

57

?/? T cell subsets in patients with active Mycobacterium tuberculosis infection and tuberculin anergy  

PubMed Central

Earlier data suggest that ?/? T cells may play an important role in the immune response to Mycobacterium tuberculosis. The aim of this study was to determine the percentage of different ?/? subsets in peripheral blood of active tuberculosis patients with a positive or negative tuberculin reaction. Thirty-eight patients infected with M. tuberculosis and 22 healthy controls were included in the study. Venous blood was taken before starting antimycobacterial treatment. Lymphocytes were reacted with monoclonal antibodies specific for different ?/? V chains (V?1, V?2, V?9 and V?4). The results were analysed in the context of tuberculin reactivity and X-ray findings. Our results revealed a selective loss of V?9/V?2 T cells in the peripheral blood of tuberculin-negative patients with active tuberculosis compared to healthy controls, while the ratio of V?9/V?2 T cells in the peripheral blood of patients with a positive skin test did not differ from that of healthy controls. These findings demonstrate a relationship between the loss of the major M. tuberculosis-reactive subset of ?? T cells and the absence of tuberculin reactivity. The data are consistent with the hypothesis that ?? T cells play a role in the protective immune response to M. tuberculosis infection. PMID:12562390

SZEREDAY, L; BALIKO, Z; SZEKERES-BARTHO, J

2003-01-01

58

Glutamine synthetase of Mycobacterium tuberculosis: extracellular release and characterization of its enzymatic activity.  

PubMed Central

We have investigated the activity and extracellular release of glutamine synthetase [L-glutamate:ammonia ligase (ADP-forming), EC 6.3.1.2] of Mycobacterium tuberculosis. The purified, homogeneous M. tuberculosis glutamine synthetase appears to consist of 12 most likely identical subunits of M(r) 58,000, arranged in two superimpose hexagons. In the catalysis of L-glutamine, the enzyme has an apparent Km for L-glutamate of approximately 3 mM at the pH optimum of 7.5. M. tuberculosis releases a large proportion (approximately 30%) of its total measurable enzyme activity into the culture medium, a feature that is highly specific for pathogenic mycobacteria. Immunogold electron microscopy revealed that M. tuberculosis also releases the enzyme into its phagosome in infected human monocytes. Two potentially important roles for glutamine synthase in the pathogenesis of M. tuberculosis infection are (i) the synthesis of L-glutamine, a major component of the cell wall of pathogenic but not nonpathogenic mycobacteria, and (ii) the modulation of the ammonia level in the M. tuberculosis phagosome, which may in turn influence phagosomal pH and phagosomelysosome fusion. Images PMID:7937767

Harth, G; Clemens, D L; Horwitz, M A

1994-01-01

59

In vitro activity of moxifloxacin, levofloxacin, gatifloxacin and linezolid against Mycobacterium tuberculosis  

Microsoft Academic Search

The in vitro activity of moxifloxacin, gatifloxacin, levofloxacin and linezolid was evaluated against 234 strains of Mycobacterium tuberculosis isolated in the Southeast of Spain. All drugs tested showed good activity, with an MIC90 of less than 1 mg\\/l, and were active against isociacide and rifampicin resistant strains. Three strains were resistant to isoniazid and to the fluoroquinolones, which suggested the

J. C Rodr??guez; M Ruiz; M López; G Royo

2002-01-01

60

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

PubMed Central

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

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

2013-01-01

61

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

PubMed Central

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.

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

62

Total antioxidant levels are low during active TB and rise with anti-tuberculosis therapy.  

PubMed

In tuberculosis, oxidative stress is a result of tissue inflammation, poor dietary intake of micronutrients due to illness, free radical burst from activated macrophages, and anti-tuberculosis drugs. These free radicals may in turn contribute towards pulmonary inflammation if not neutralized by antioxidants. The total antioxidant status (TAS) of individuals is a function of dietary, enzymatic, and other systemic antioxidants and is therefore an indicator of the free radical load. Our aim was to evaluate the TAS of healthy and M. tuberculosis-infected persons from a high TB incidence community, as well as tuberculosis patients at various stages of antituberculosis drug treatment and to correlate results with plasma micronutrient levels. Blood plasma samples from TB infected patients and following antituberculosis drug treatment were assayed for TAS, vitamins A, E and Zinc. Statistical analysis of results was by one-way ANOVA and the Tukey multiple comparison post test. Active TB patients showed a significantly lower TAS (P < 0.001) compared to the community controls. We also show that TAS values increase during therapy. Results correlated with micronutrients vitamin A and zinc but vitamin E remained unaffected. We suggest that total antioxidant status of TB patients should be considered for more effective disease control and that diets low in antioxidants may render individuals susceptible to tuberculosis. PMID:15085934

Wiid, I; Seaman, T; Hoal, E G; Benade, A J S; Van Helden, Paul D

2004-02-01

63

Circulating B-Lymphocytes as Potential Biomarkers of Tuberculosis Infection Activity  

PubMed Central

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

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

2014-01-01

64

Hematopoietic stem cell transplantation for treatment of patients with leukemia concomitant with active tuberculosis infection.  

PubMed

Background Currently, hematopoietic stem cell transplantation is still an essential treatment approach for leukemia. However, patients with leukemia often have weakened immune function, especially more seriously compromised cellular immune response, and appear to be at greater risk for tuberculosis infection during the transplantation process. We aimed to investigate the efficacy and safety of hematopoietic stem cell transplantation for the treatment of patients with leukemia accompanying active tuberculosis infection. Material and Methods We retrospectively analyzed records of 7 consecutive patients who were diagnosed with leukemia concomitant with active tuberculosis infection and who underwent hematopoietic stem cell transplantation in our hospital from January 2006 to December 2012. Results Among these 7 patients (4 males and 3 females; median age: 38 years; range: 30-46 years), the mean duration of anti-TB treatment before transplantation was 3 months (range: 2-4.5 months). All patients acquired engraftment, with an implantation rate of 100%. After transplantation, the mean duration of anti-TB treatment was 12 months. All patients had response after receiving anti-TB treatment. One patient died of leukemia relapse 6 months after the transplantation, but no tuberculosis infection-related death was reported. Conclusions Patients with leukemia concomitant with active tuberculosis infection can be treated with hematopoietic stem cell transplantation if they receive an effective anti-TB treatment regimen. The anti-TB treatment regimen had no effect against hematopoietic stem cell transplantation and was well-tolerated. All post-transplanted patients experienced no relapse of tuberculosis during the immune-suppression period. The findings in the present investigation deserve further in-depth study. PMID:25433702

Liu, Mingjuan; Yang, Caie; Liu, Lihui; Shi, Bing; Hu, Wenqing; Ye, Liping; Zhang, Yongqing

2014-01-01

65

Effects of chemoprophylaxis on minimal pulmonary tuberculosis lesions of doubtful activity.  

PubMed

In mass radiographic surveys, minimal pulmonary lesions of tuberculous appearance but doubtful activity are often found in persons without symptoms of tuberculosis. Whether to treat such persons or merely keep them under observation is a problem, as many of them manifest tuberculosis subsequently. The New Delhi Tuberculosis Centre carried out a controlled study from 1958 to 1968 to study this question in the conditions prevailing in India. A randomly selected group of persons with this type of lesion was given isoniazid prophylaxis for 1 year, a control group of almost equal size receiving placebo during the same period. Both were regularly re-examined, radiologically and bacteriologically, over a period of 6 years, and persons who developed clinical tuberculosis were immediately referred to the appropriate treatment services.THE RESULTS SHOW THAT THE TREATED PATIENTS FARED MUCH BETTER THAN THOSE IN THE CONTROL GROUP: fewer of them developed tuberculosis and more of them showed radiological improvement. This superiority was maintained for at least 4 years beyond the treatment year. However, this advantage must be weighed against the comparative inacceptability of treatment by such persons and the consequent high cost of organizing the treatment. It is concluded that, except when special circumstances justify it, prophylaxis of this kind cannot be recommended as a routine procedure. PMID:4947493

Pamra, S P; Mathur, G P

1971-01-01

66

In vitro and in vivo activities of three oxazolidinones against nonreplicating Mycobacterium tuberculosis.  

PubMed

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

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

2014-06-01

67

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

PubMed Central

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

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

2014-01-01

68

In Vitro Activity of a New Isothiazoloquinolone, ACH-702, against Mycobacterium tuberculosis and Other Mycobacteria?  

PubMed Central

In this work, we describe the activity of ACH-702 against clinical isolates of Mycobacterium tuberculosis and six different nontuberculous mycobacteria. The MIC50 and MIC90 of both susceptible and drug-resistant M. tuberculosis strains tested were 0.0625 and 0.125 ?g/ml, respectively. The MIC50 and MIC90 values for Mycobacterium fortuitum isolates were 0.0625 ?g/ml in both cases; Mycobacterium avium complex isolates showed MIC50 and MIC90 values of 0.25 and 4 ?g/ml, respectively. PMID:20231398

Molina-Torres, Carmen A.; Ocampo-Candiani, Jorge; Rendon, Adrian; Pucci, Michael J.; Vera-Cabrera, Lucio

2010-01-01

69

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

PubMed Central

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

2014-01-01

70

Rapid detection and identification of Mycobacterium tuberculosis by Real Time PCR and Bactec 960 MIGT  

Microsoft Academic Search

We have developed a Real-Time PCR assay to detect M. tuberculosis using the iCycler iQ detection system by TaqMan assay directly on the clinical specimen. A total of 513 clinical samples were taken from patients with suspected tuberculosis and other patients that had an active mycobacterial infection, as well as patients with diagnosed tuber- culosis who were receiving antitubercular therapy.

Silvia Ortu; Paola Molicotti; Leonardo Antonio Sechi; Pierp Pirina; Franca Saba; Cono Vertuccio; Antonella Deriu; Ivana Maida; Maria Stella Mura; Stefania Zanetti

2006-01-01

71

Expression of functional interleukin 2 receptors by peripheral blood monocytes from patients with active pulmonary tuberculosis.  

PubMed Central

Peripheral blood monocytes from patients with active tuberculosis are "activated" by a number of criteria, including selective depression of T-lymphocyte responses to the mycobacterial antigen, tuberculin-purified protein derivative (PPD). We studied monocytes from patients with tuberculosis and healthy skin test reactive controls for expression and function of IL 2 receptors (IL 2R). Depletion of adherent monocytes increased the IL 2 activity of supernatants of PPD-stimulated T cell cultures from patients by 30-fold. When cultured with purified IL 2, adherent cells from the patients depleted IL 2 activity by 66%. Monocytes from patients displayed IL 2R on their surface as evidenced by anti-Tac reactivity, and released soluble IL 2R into the medium during culture. The release of soluble IL 2R was augmented when monocytes were cultured with PPD. Finally, freshly isolated adherent monocytes from patients but not healthy individuals expressed the gene encoding Tac protein. Thus, blood monocytes from patients with tuberculosis express functional IL 2R constitutively. This property may be important in the immunoregulatory and effector function of mononuclear phagocytes during tuberculosis. Images PMID:2347912

Toossi, Z; Sedor, J R; Lapurga, J P; Ondash, R J; Ellner, J J

1990-01-01

72

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

PubMed

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

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

2010-05-01

73

Antibacterial activity of ergosterol peroxide against Mycobacterium tuberculosis: dependence upon system and medium employed.  

PubMed

Ergosterol peroxide, cycloart-23-en-3beta,25-diol, vanillin and 4-hydroxybenzaldehyde have been isolated and characterized from a crude methanol extract of Euphorbia lagascae. Previous studies have shown contradictory results about the antibacterial activity of ergosterol peroxide against Mycobacterium tuberculosis. In order to clarify this question, the activity of this compound was tested against Mycobacterium tuberculosis H37Rv ATCC 27294 strain using two different systems: BACTEC 460TB (Bactec 460) and BACTEC MGIT 960 system (Bactec 960). The results obtained show that significant activity was demonstrable only with the Bactec 460 system. The lack of activity noted with the Bactec 960 system appears to be due to the much faster growth rate of the organism in the medium of this system as opposed to that of the Bactec 460 system. Ergosterol peroxide is also shown by the current study to be devoid of any activity against an antibiotic sensitive ATCC strain of Staphylococcus aureus. PMID:17357175

Duarte, Noélia; Ferreira, Maria-José U; Martins, Marta; Viveiros, Miguel; Amaral, Leonard

2007-07-01

74

BALToma masquerading as pulmonary tuberculosis.  

PubMed

A 53-year-old man with a significant smoking history presented with chronic cough, exertional breathlessness, intermittent fever, weight loss and anorexia. A review of his past medical records revealed he was diagnosed to have sputum smear-positive pulmonary tuberculosis 5?years earlier, for which he had received multiple courses of incomplete antitubercular therapy. This time, though he was primarily suspected to have active pulmonary tuberculosis, lack of microbiological evidence and further investigations including histopathological evaluation of lung lesions confirmed a diagnosis of Marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALToma/BALToma). The patient was managed with radical radiation therapy to which he responded well. PMID:25398919

Magazine, Rahul; Shahul, Hameed Aboobackar; Monappa, Vidya; Chogtu, Bharti

2014-01-01

75

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

PubMed Central

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

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

2014-01-01

76

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

PubMed Central

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

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

2012-01-01

77

[Crohn's disease or intestinal tuberculosis: A diagnostic challenge].  

PubMed

Distinguishing intestinal tuberculosis from Crohn disease is difficult and can result in misdiagnosis, especially when active pulmonary infection is absent. A 13-year-old girl was admitted to our hospital with a 2-month history of watery diarrhea, abdominal pain, and 12-kg weight loss. Based on clinical, radiological, endoscopic, and histological findings, she was initially misdiagnosed as having Crohn disease and treated with glucocorticosteroids, with a poor response after 4 weeks. Intestinal tuberculosis was then suspected. Improvement was observed during the 1st week of antituberculous treatment. The differentiation of intestinal tuberculosis from Crohn disease may be very difficult in some patients. A positive response to antituberculous treatment associated with clinical, endoscopic, and histological features argue in favor of the diagnosis of intestinal tuberculosis. PMID:25169807

Gargouri, L; Boudabous, M; Safi, F; Maalej, B; Mnif, H; Chtourou, L; Mejdoub, I; Mnif, L; Amouri, A; Boudawara, T; Tahri, N; Mahfoudh, A

2014-10-01

78

Comparative in vitro activities of ciprofloxacin and other 4-quinolones against Mycobacterium tuberculosis and Mycobacterium intracellulare.  

PubMed Central

The in vitro activity of ciprofloxacin, ofloxacin, amifloxacin, and norfloxacin against 22 clinical isolates of Mycobacterium tuberculosis was evaluated by agar dilution. The MICs for 90% of the isolates of ciprofloxacin and ofloxacin were 0.5 and 1 microgram/ml, respectively. Amifloxacin and norfloxacin were less active. The MICs for 90% of the isolates of ciprofloxacin and ofloxacin against 20 clinical isolates of Mycobacterium intracellulare were determined by agar dilution to be 2 and 8 micrograms/ml, respectively. PMID:2940969

Fenlon, C H; Cynamon, M H

1986-01-01

79

Activity of IQG-607, a new orally active compound, in a murine model of Mycobacterium tuberculosis infection.  

PubMed

We have previously demonstrated a potent in vitro inhibitory activity for two pentacyano(isoniazid)ferrate(II) compounds, namely IQG-607 and IQG-639, against the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase enzyme. In this study, the activity of these compounds was evaluated using an in vivo murine model of tuberculosis. Swiss mice were infected with M. tuberculosis H37Rv strain and then IQG-607 or IQG-639 (250 mg/kg) was administered for 28 days or 56 days. In addition, a dose-response study was performed with IQG-607 at 5, 10, 25, 50, 100, 200 and 250 mg/kg. The activity of test compounds was compared with that of the positive control drug isoniazid (INH) (25 mg/kg). After 28 days or 56 days of treatment, both IQG-607 and INH significantly reduced M. tuberculosis-induced splenomegaly as well as significantly diminishing the colony-forming units in the spleen and lungs. IQG-607 and INH ameliorated the lung macroscopic aspect, reducing lung lesions to a similar extent. However, IQG-639 did not significantly modify any evaluated parameter. Experiments using early and late controls of infection revealed a bactericidal activity for IQG-607. IQG-607 might well represent a good candidate for clinical development as a new antimycobacterial agent. PMID:22748570

Rodrigues-Junior, Valnês S; Dos Santos Junior, André; Dos Santos, Anderson Jader; Schneider, Cristopher Zandoná; Calixto, João B; Sousa, Eduardo Henrique Silva; de França Lopes, Luiz Gonzaga; Souto, André Arigony; Basso, Luiz Augusto; Santos, Diógenes Santiago; Campos, Maria M

2012-08-01

80

Human immunodeficiency virus type-1 group M quasispecies evolution: diversity and divergence in patients co-infected with active tuberculosis  

Microsoft Academic Search

The evolution of intra-host human immunodeficiency virus type 1 (HIV-1) quasispecies prior and after treating active tuberculosis\\u000a (TB) with chemotherapy in HIV-1\\/TB patients was assessed. Two time points HIV-1 quasispecies were evaluated by comparing HIV-1-infected\\u000a patients with active tuberculosis (HIV-1\\/TB) and HIV-1-infected patients without tuberculosis (HIV-1\\/non-TB). Plasma samples\\u000a were obtained from the Frankfurt HIV cohort, and HIV-1 RNA was isolated.

T. Biru; T. Lennemann; M. Stürmer; C. Stephan; G. Nisius; J. Cinatl; S. Staszewski; L. G. Gürtler

2010-01-01

81

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

PubMed

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

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

2014-05-01

82

Identification of novel Mt-Guab2 inhibitor series active against M. tuberculosis.  

PubMed

Tuberculosis (TB) remains a leading cause of mortality worldwide. With the emergence of multidrug resistant TB, extensively drug resistant TB and HIV-associated TB it is imperative that new drug targets be identified. The potential of Mycobacterium tuberculosis inosine monophosphate dehydrogenase (IMPDH) as a novel drug target was explored in the present study. IMPDH exclusively catalyzes the conversion of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) in the presence of the cofactor nicotinamide adenine dinucleotide (NAD(+)). Although the enzyme is a dehydrogenase, the enzyme does not catalyze the reverse reaction i.e. the conversion of XMP to IMP. Unlike other bacteria, M. tuberculosis harbors three IMPDH-like genes, designated as Mt-guaB1, Mt-guaB2 and Mt-guaB3 respectively. Of the three putative IMPDH's, we previously confirmed that Mt-GuaB2 was the only functional ortholog by characterizing the enzyme kinetically. Using an in silico approach based on designed scaffolds, a series of novel classes of inhibitors was identified. The inhibitors possess good activity against M. tuberculosis with MIC values in the range of 0.4 to 11.4 µg mL(-1). Among the identified ligands, two inhibitors have nanomolar K(i)s against the Mt-GuaB2 enzyme. PMID:22479467

Usha, Veeraraghavan; Hobrath, Judith V; Gurcha, Sudagar S; Reynolds, Robert C; Besra, Gurdyal S

2012-01-01

83

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

PubMed

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

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

2003-09-01

84

Activity of linezolid-containing regimens against multidrug-resistant tuberculosis in mice.  

PubMed

The objective of the present study was to compare the activities of regimens containing linezolid (LZD) with those not containing LZD against Mycobacterium tuberculosis infection in mice. The three regimens excluding LZD selected in this study are often used in practice against multidrug-resistant tuberculosis (MDR-TB). When LZD was added to these MDR-TB regimens, the combinations were significantly more active after 2 months of therapy with regard to lung CFU reductions. The activity of LZD-containing regimens was greater than the World Health Organization's standard first-line regimen of rifampicin+isoniazid+pyrazinamide. In particular, when LZD was included in the combination levofloxacin+amikacin+para-aminosalicylic acid+pyrazinamide+clofazimine, culture negativity of the lungs was reached after 2 months of treatment in every case. In addition, the serum levels of interleukin-10 and interferon-? of mice were determined and were found not to be surrogate markers of bacterial clearance. PMID:24290060

Zhao, Weijie; Guo, Zhenyong; Zheng, Meiqin; Zhang, Jinfu; Wang, Bin; Li, Peng; Fu, Lei; Liu, Shuo

2014-02-01

85

Whole-Genome Sequencing of Streptomycin-Resistant Mycobacterium tuberculosis Isolate VRFCWCF MRTB 180 Reveals Novel and Potential Mutations for Resistance  

PubMed Central

We announce the draft genome sequence of a streptomycin monoresistant Mycobacterium tuberculosis strain (VRFCWCF MRTB 180) isolated from sputum of a clinically suspected tuberculosis patient. PMID:25212629

Ramasubban, Gayathri; Lakshmipathy, Dhanurekha; Vetrivel, Umashankar; Madhavan, Hajib Narahari; Sridhar, R.; Meenakshi, N.

2014-01-01

86

Community involvement in tuberculosis control: lessons from other health care programmes.  

PubMed

Decentralising tuberculosis control measures beyond health facilities by harnessing the contribution of the community could increase access to effective tuberculosis care. This review of community-based health care initiatives in developing countries gives examples of the lessons for community contribution to tuberculosis control learned from health care programmes. Sources of information were Medline and Popline databases and discussions with community health experts. Barriers to success in tuberculosis control stem from biomedical, social and political factors. Lessons are relevant to the issues of limited awareness of tuberculosis and the benefits of treatment, stigma, restricted access to drugs, case-finding and motivation to continue treatment. The experience of other programmes suggests potential for an expansion of both formal and informal community involvement in tuberculosis control. Informal community involvement includes delivery of messages to encourage tuberculosis suspects to come forward for treatment and established tuberculosis patients to continue treatment. A wide range of community members provide psychological and logistic support to patients to complete their treatment. Lessons from formal community involvement indicate that programmes should focus on ensuring that treatment is accessible. This activity could be combined with a variety of complementary activities: disseminating messages to increase awareness and promote adherence, tracing patients who interrupt treatment, recognising adverse effects, and case detection. Programmes should generally take heed of existing political and cultural structures in planning community-based tuberculosis control programmes. Political support, the support of health professionals and the community are vital, and planning must involve or stem from the patients themselves. PMID:10815732

Hadley, M; Maher, D

2000-05-01

87

Tuberculosis Exposure Control 1.0 BACKGROUND  

E-print Network

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

de Lijser, Peter

88

Co-existence of HIV, active tuberculosis and aspergilloma in a single individual--a case report.  

PubMed

Tuberculosis (TB) is a disease as old as mankind, whereas in India the first case of Human Immunodeficiency Virus (HIV) was reported in 1986. HIV and TB are so closely connected that their relationship is often described as a co-epidemic. Aspergilloma (Fungal Ball, Mycetoma) represents a saprophytic growth of aspergillus that colonizes in the preformed cavities commonly due to pulmonary tuberculosis (PTB). We report a case of HIV, active pulmonary tuberculosis and aspergilloma occurring in the same patient. Despite our best efforts, we could not lay our hands on any similar case in the medical literature. PMID:23540090

Singh, Urvinder Pal; Aneja, Pooja; Aditi; Patel, Kalpesh

2013-01-01

89

Mechanistic and functional insights into fatty acid activation in Mycobacterium tuberculosis  

Microsoft Academic Search

The recent discovery of fatty acyl-AMP ligases (FAALs) in Mycobacterium tuberculosis (Mtb) provided a new perspective of fatty acid activation. These proteins convert fatty acids to the corresponding adenylates, which are intermediates of acyl-CoA–synthesizing fatty acyl-CoA ligases (FACLs). Presently, it is not evident how obligate pathogens such as Mtb have evolved such new themes of functional versatility and whether the

Pooja Arora; Aneesh Goyal; Vivek T Natarajan; Eerappa Rajakumara; Priyanka Verma; Radhika Gupta; Malikmohamed Yousuf; Omita A Trivedi; Debasisa Mohanty; Anil Tyagi; Rajan Sankaranarayanan; Rajesh S Gokhale

2009-01-01

90

Neonatal exposure to active pulmonary tuberculosis in a health care professional  

PubMed Central

NOSOCOMIAL TRANSMISSION OF TUBERCULOSIS (TB) is a recognized risk. Although many outbreaks of TB in health care settings have been reported, there are few cases of nosocomial transmission to neonates. We report our experience in investigating and managing the exposure over 16 days of 124 neonates, 301 visitors and 219 health care workers to a health care worker with active TB in a neonatal intensive care unit. PMID:15911860

Sen, Mithu; Gregson, Daniel; Lewis, James

2005-01-01

91

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

Microsoft Academic Search

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

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

92

Sterilizing Activities of Fluoroquinolones against Rifampin-Tolerant Populations of Mycobacterium tuberculosis  

Microsoft Academic Search

The bactericidal activities of ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, and gatifloxacin were tested in three models of rifampin-tolerant Mycobacterium tuberculosis persisters. Model 1 was a 100-day-old, un- shaken, anaerobically adapted culture in which serial dilutions of the quinolones were incubated for 5 days and CFU counts were then done In models 2 and 3, 100 mg of rifampin\\/liter was added to

Yanmin Hu; Anthony R. M. Coates; Denis A. Mitchison

2003-01-01

93

Urease Activity Represents an Alternative Pathway for Mycobacterium tuberculosis Nitrogen Metabolism  

PubMed Central

Urease represents a critical virulence factor for some bacterial species through its alkalizing effect, which helps neutralize the acidic microenvironment of the pathogen. In addition, urease serves as a nitrogen source provider for bacterial growth. Pathogenic mycobacteria express a functional urease, but its role during infection has yet to be characterized. In this study, we constructed a urease-deficient Mycobacterium tuberculosis strain and confirmed the alkalizing effect of the urease activity within the mycobacterium-containing vacuole in resting macrophages but not in the more acidic phagolysosomal compartment of activated macrophages. However, the urease-mediated alkalizing effect did not confer any growth advantage on M. tuberculosis in macrophages, as evidenced by comparable growth profiles for the mutant, wild-type (WT), and complemented strains. In contrast, the urease-deficient mutant exhibited impaired in vitro growth compared to the WT and complemented strains when urea was the sole source of nitrogen. Substantial amounts of ammonia were produced by the WT and complemented strains, but not with the urease-deficient mutant, which represents the actual nitrogen source for mycobacterial growth. However, the urease-deficient mutant displayed parental colonization profiles in the lungs, spleen, and liver in mice. Together, our data demonstrate a role for the urease activity in M. tuberculosis nitrogen metabolism that could be crucial for the pathogen's survival in nutrient-limited microenvironments where urea is the sole nitrogen source. Our work supports the notion that M. tuberculosis virulence correlates with its unique metabolic versatility and ability to utilize virtually any carbon and nitrogen sources available in its environment. PMID:22645285

Lin, Wenwei; Mathys, Vanessa; Ang, Emily Lei Yin; Koh, Vanessa Hui Qi; Martinez Gomez, Julia Maria; Ang, Michelle Lay Teng; Zainul Rahim, Siti Zarina; Tan, Mai Ping; Pethe, Kevin

2012-01-01

94

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

PubMed

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

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

2014-10-01

95

Determination of the activity of standard anti-tuberculosis drugs against intramacrophage Mycobacterium tuberculosis, in vitro: MGIT 960 as a viable alternative for BACTEC 460.  

PubMed

BACTEC 460 has now been phased out, so the search for an alternative is imperative. We have determined the activity of standard anti-tuberculosis drugs against intramacrophage Mycobacterium tuberculosis, in vitro, by using BACTEC 460 and MGIT 960 methods. The minimum inhibitory concentrations of isoniazid, rifampicin, ethambutol and streptomycin against intracellular M. tuberculosis H37Rv were found to be 0.2, 0.8, 8.0, and 5.0 ?g/mL, respectively, by both methods. These results show a significant (p<0.001) concordance between minimum inhibitory concentrations obtained by these two different methods. MGIT 960 system uses a robust florescence quenching-based oxygen sensor, requires no radioisotope, is safe, and relatively easy to operate. Apparently, this is the first report wherein MGIT 960 has been validated for anti-tubercular susceptibility testing against intracellular M. tuberculosis H37Rv. Our preliminary data thus clearly demonstrate that the MGIT 960 method can be considered as a promising alternative to BACTEC 460 method. PMID:24709416

Jhamb, Sarbjit Singh; Goyal, Amit; Singh, Prati Pal

2014-01-01

96

Intra- and Extracellular Activities of Trimethoprim-Sulfamethoxazole against Susceptible and Multidrug-Resistant Mycobacterium tuberculosis.  

PubMed

We investigated the activity of trimethoprim-sulfamethoxazole (SXT) against Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB). The MIC distribution of SXT was 0.125/2.4 to 2/38 mg/liter for the 100 isolates tested, including multi- and extensively drug-resistant isolates (MDR/XDR-TB), whereas the intracellular MIC90 of sulfamethoxazole (SMX) for the pansusceptible strain H37Rv was 76 mg/liter. In an exploratory analysis using a ratio of the unbound area under the concentration-time curve from 0 to 24 h over MIC (fAUC0-24/MIC) using ?25 as a potential target, the cumulative fraction response was ?90% at doses of ?2,400 mg of SMX. SXT is a potential treatment option for MDR/XDR-TB. PMID:25246405

Davies Forsman, L; Schön, T; Simonsson, U S H; Bruchfeld, J; Larsson, M; Juréen, P; Sturegård, E; Giske, C G; Angeby, K

2014-12-01

97

In vitro activity of AZD5847 against geographically diverse clinical isolates of Mycobacterium tuberculosis.  

PubMed

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

Werngren, Jim; Wijkander, Maria; Perskvist, Nasrin; Balasubramanian, V; Sambandamurthy, Vasan K; Rodrigues, Camilla; Hoffner, Sven

2014-07-01

98

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

PubMed

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

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

2013-03-01

99

Role of Metal Ions on the Activity of Mycobacterium tuberculosis Pyrazinamidase  

PubMed Central

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

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

100

Challenges of Loss to Follow-up in Tuberculosis Research  

Microsoft Academic Search

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

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

2012-01-01

101

Bisubstrate specificity in histidine/tryptophan biosynthesis isomerase from Mycobacterium tuberculosis by active site metamorphosis.  

PubMed

In histidine and tryptophan biosynthesis, two related isomerization reactions are generally catalyzed by two specific single-substrate enzymes (HisA and TrpF), sharing a similar (?/?)(8)-barrel scaffold. However, in some actinobacteria, one of the two encoding genes (trpF) is missing and the two reactions are instead catalyzed by one bisubstrate enzyme (PriA). To unravel the unknown mechanism of bisubstrate specificity, we used the Mycobacterium tuberculosis PriA enzyme as a model. Comparative structural analysis of the active site of the enzyme showed that PriA undergoes a reaction-specific and substrate-induced metamorphosis of the active site architecture, demonstrating its unique ability to essentially form two different substrate-specific actives sites. Furthermore, we found that one of the two catalytic residues in PriA, which are identical in both isomerization reactions, is recruited by a substrate-dependent mechanism into the active site to allow its involvement in catalysis. Comparison of the structural data from PriA with one of the two single-substrate enzymes (TrpF) revealed substantial differences in the active site architecture, suggesting independent evolution. To support these observations, we identified six small molecule compounds that inhibited both PriA-catalyzed isomerization reactions but had no effect on TrpF activity. Our data demonstrate an opportunity for organism-specific inhibition of enzymatic catalysis by taking advantage of the distinct ability for bisubstrate catalysis in the M. tuberculosis enzyme. PMID:21321225

Due, Anne V; Kuper, Jochen; Geerlof, Arie; von Kries, Jens Peter; Wilmanns, Matthias

2011-03-01

102

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

PubMed

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

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

2008-06-01

103

Synthesis and anti-tuberculosis activity of N-aryl-C-nitroazoles.  

PubMed

Twelve N-aryl derivatives of 4-nitroimidazole, 2-methyl-4-nitroimidazole, 4-nitropyrazole or 3-nitro-1,2,4-triazole have been synthesized either by a degenerated ring transformation reaction of 1,4-dinitroimidazoles with 4-substituted anilines or by a condensation of fluoronitrobenzenes with salts prepared from C-nitro-1H-azoles and 1,8-diazabicyclo[5.4.0]-7-undecene. The Tuberculosis Antimicrobial Acquisition and Coordinating Facility has provided anti-mycobacterial data concerning inhibition activity of 12 compounds. PMID:15464618

Walczak, Krzysztof; Gondela, Andrzej; Suwi?ski, Jerzy

2004-10-01

104

Sterilizing activity of thioridazine in combination with the first-line regimen against acute murine tuberculosis.  

PubMed

We recently reported that in lung tissue, thioridazine accumulates at high concentrations relative to serum levels, displaying modest synergy with isoniazid and reducing the emergence of isoniazid-resistant mutants in mouse lungs. In this study, we sought to investigate the sterilizing activity of human-equivalent doses of thioridazine when given in combination with the "Denver regimen" against acute murine tuberculosis. We found a trend toward a positive impact of thioridazine on the bacterial clearance and lowering relapse rates of the combined standard TB chemotherapy. PMID:24936590

Dutta, Noton K; Pinn, Michael L; Karakousis, Petros C

2014-09-01

105

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

PubMed Central

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

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

1984-01-01

106

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

PubMed Central

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

Canche Chay, Cristina I.; Gomez Cansino, Rocio; Espitia Pinzon, Clara I.; Torres-Ochoa, Ruben O.; Martinez, Roberto

2014-01-01

107

Potent activity against multidrug-resistant Mycobacterium tuberculosis of ?-mangostin analogs.  

PubMed

A new series of mangostin analogs of natural ?-mangostin from mangosteen was prepared and their antimycobacterial activity was evaluated in vitro against Mycobacterium tuberculosis H(37)Ra. The results showed that the monoalkyl tetrahydro ?-mangostin analogs displayed increased antimycobacterial activity as compared with the lead natural xanthone, ?-mangostin. Among the tested compounds, 6-methoxytetrahydro ?-mangostin (16) exhibited the most potent antimycobacterial activity with minimum inhibitory concentration (MIC) of 0.78 µg/mL. The activity of the monoalkylated and monoacylated tetrahydro ?-mangostins decreases as the length of carbon chain increases. The methyl ether analog was also active against the multidrug-resistant (MDR) strains with pronounced MICs of 0.78-1.56 µg/mL. PMID:23150066

Sudta, Pichit; Jiarawapi, Payung; Suksamrarn, Apichart; Hongmanee, Poonpilas; Suksamrarn, Sunit

2013-01-01

108

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

PubMed Central

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

Encinales, Liliana; Zuniga, Joaquin; Yunis, Maria; Granados-Montiel, Julio; Granados, Julio; Almeciga, Ingrid; Clavijo, Olga; Awad, Carlos; Collazos, Vilma; Vargas-Rojas, Maria Ines; Banales-Mendez, Jose Luis; Vazquez-Castaneda, Lilia; Stern, Joel N.; Romero, Viviana; Frindkis-Hareli, Masha; Terreros, Daniel; Fernandez-Vina, Marcelo; Yunis, Edmond J.

2009-01-01

109

Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis.  

PubMed

A high-throughput screening (HTS) hit compound displayed moderate inhibition of Mycobacterium tuberculosis and Escherichia coli riboflavin synthases. The structure of the hit compound provided by the commercial vendor was reassigned as [3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](o-tolyl)methanone (18). The hit compound had a k(is) of 8.7 microM vs. M. tuberculosis riboflavin synthase and moderate antibiotic activity against both M. tuberculosis replicating phenotype and nonreplicating persistent phenotype. Molecular modeling studies suggest that two inhibitor molecules bind in the active site of the enzyme, and that the binding is stabilized by stacking between the benzene rings of two adjacent ligands. The most potent antibiotic in the series proved to be [5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](m-tolyl)methanone (16), which displayed a minimum inhibitory concentration (MIC) of 36.6 microM vs. M. tuberculosis replicating phenotype and 48.9 microM vs. M. tuberculosis nonreplicating phenotype. The HTS hit compound and its analogues provide the first examples of riboflavin synthase inhibitors with antibiotic activity. PMID:19545132

Zhao, Yujie; Bacher, Adelbert; Illarionov, Boris; Fischer, Markus; Georg, Gunda; Ye, Qi-Zhuang; Fanwick, Phillip E; Franzblau, Scott G; Wan, Baojie; Cushman, Mark

2009-08-01

110

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

PubMed Central

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

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

2014-01-01

111

Assessment of Clofazimine Activity in a Second-Line Regimen for Tuberculosis in Mice  

PubMed Central

Rationale: Although observational studies suggest that clofazimine-containing regimens are highly active against drug-resistant tuberculosis, the contribution of clofazimine for the treatment of this disease has never been systematically evaluated. Objectives: Our goal was to directly compare the activity of a standard second-line drug regimen with or without the addition of clofazimine in a mouse model of multidrug-resistant tuberculosis. Our comparative outcomes included time to culture conversion in the mouse lungs and the percentage of relapses after treatment cessation. Methods: Mice were aerosol-infected with an isoniazid-resistant (as a surrogate of multidrug-resistant) strain of Mycobacterium tuberculosis. Treatment, which was administered for 5 to 9 months, was initiated 2 weeks after infection and comprised the following second-line regimen: daily (5 d/wk) moxifloxacin, ethambutol, and pyrazinamide, supplemented with amikacin during the first 2 months. One-half of the mice also received daily clofazimine. The decline in lung bacterial load was assessed monthly using charcoal-containing agar to reduce clofazimine carryover. Relapse was assessed 6 months after treatment cessation. Measurements and Main Results: After 2 months, the bacillary load in lungs was reduced from 9.74 log10 at baseline to 3.61 and 4.68 in mice treated with or without clofazimine, respectively (P < 0.001). Mice treated with clofazimine were culture-negative after 5 months, whereas all mice treated without clofazimine remained heavily culture-positive for the entire 9 months of the study. The relapse rate was 7% among mice treated with clofazimine for 8 to 9 months. Conclusions: The clofazimine contribution was substantial in these experimental conditions. PMID:23822735

Tyagi, Sandeep; Almeida, Deepak V.; Converse, Paul J.; Li, Si-Yang; Ammerman, Nicole C.; Bishai, William R.; Enarson, Donald; Trébucq, Arnaud

2013-01-01

112

Active screening for pulmonary tuberculosis by chest x-ray among immigrants at the Swiss border  

Microsoft Academic Search

Aim: To assess the number of immigrants with pulmonary tuberculosis detected by chest x-ray screening at the Swiss border. Method: All adult immigrants entering Switzerland in 2004 were screened by chest x-ray (CXR). The number of radiological abnormalities suggestive of pulmonary tuberculosis, and the proportion requiring treatment for tuberculosis, were assessed retrospectively. The frequency of symptoms among immigrants with documented

Christian Mathez; Yolande Bangala; Pierre Bady; Jean-Pierre Zellweger

113

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

114

Early Bactericidal Activity of Moxifloxacin in Treatment of Pulmonary Tuberculosis: a Prospective, Randomized Study  

Microsoft Academic Search

Tuberculosis remains one of the deadliest diseases in the world. The World Health Organization (WHO) estimates that more than 8 million new cases of tuberculosis occur each year, and approximately 3 million people die from the disease. The emerging resistance of Mycobacterium tuberculosis to standard antituberculous drugs raises the need for the devel- opment of new agents. Fluoroquinolones are of

Mathias W. R. Pletz; Andres De Roux; Andreas Roth; Karl-Heinz Neumann; Harald Mauch; Hartmut Lode

2004-01-01

115

Comparison of Three Methods for the Identification of Mycobacterium tuberculosis  

Microsoft Academic Search

The present study was conducted to compare three methods, culture and morphology of colonies, biochemical tests and polymerase chain reaction for the identification of Mycobacterium tuberculosis by using well characterized clinical specimens from patients who were assessed according to standard parameters for Mycobacterium tuberculosis. Seventy seven isolated Mycobacterium species from patient's samples suspected to have tuberculosis from March 2003 till

TAVAKKOL AFSHARI; KHODADOOST MA

116

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

SciTech Connect

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.

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

2006-01-01

117

Characterization of activity and expression of isocitrate lyase in Mycobacterium avium and Mycobacterium tuberculosis.  

PubMed

Analysis by two-dimensional gel electrophoresis revealed that Mycobacterium avium expresses several proteins unique to an intracellular infection. One abundant protein with an apparent molecular mass of 50 kDa was isolated, and the N-terminal sequence was determined. It matches a sequence in the M. tuberculosis database (Sanger) with similarity to the enzyme isocitrate lyase of both Corynebacterium glutamicum and Rhodococcus fascians. Only marginal similarity was observed between this open reading frame (ORF) (termed icl) and a second distinct ORF (named aceA) which exhibits a low similarity to other isocitrate lyases. Both ORFs can be found as distinct genes in the various mycobacterial databases recently published. Isocitrate lyase is a key enzyme in the glyoxylate cycle and is essential as an anapleurotic enzyme for growth on acetate and certain fatty acids as carbon source. In this study we express and purify Icl, as well as AceA proteins, and show that both exhibit isocitrate lyase activity. Various known inhibitors for isocitrate lyase were effective. Furthermore, we present evidence that in both M. avium and M. tuberculosis the production and activity of the isocitrate lyase is enhanced under minimal growth conditions when supplemented with acetate or palmitate. PMID:10572116

Höner Zu Bentrup, K; Miczak, A; Swenson, D L; Russell, D G

1999-12-01

118

Pulmonary Tuberculoma and Miliary Tuberculosis in Silicosis  

PubMed Central

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

Verma, Sanjeev Kumar; Karmakar, Saurabh

2013-01-01

119

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

PubMed Central

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

2014-01-01

120

Mycobacterium tuberculosis catalase and peroxidase activities and resistance to oxidative killing in human monocytes in vitro.  

PubMed

Mycobacterium tuberculosis has a relatively high resistance to killing by hydrogen peroxide and organic peroxides. Resistance may be mediated by mycobacterial catalase-peroxidase (KatG) and possibly by alkyl hydroperoxide reductase (AhpC). To determine the interrelationship between sensitivity to H2O2, catalase and peroxidase activities, and bacillary growth rates measured both intracellularly in human monocytes and in culture medium, we examined one laboratory strain, two clinical isolates, and three recombinant strains of M. tuberculosis with differing levels of KatG and AhpC. Five of the mycobacterial strains had intracellular doubling times of 27 to 32 h, while one KatG-deficient clinical isolate (ATCC 35825) doubled in approximately 76 h. Killing of mycobacteria by exogenously added H2O2 was more pronounced for intracellular bacilli than for those bacilli derived from disrupted monocytes. Strains with no detectable KatG expression or catalase activity were relatively sensitive to killing (43 to 67% killing) by exogenous H2O2. However, once even minimal catalase activity was present, mycobacterial catalase activity over a 10-fold range (0.56 to 6.2 U/mg) was associated with survival of 85% of the bacilli. Peroxidase activity levels correlated significantly with resistance of the mycobacterial strains to H2O2-mediated killing. An endogenous oxidative burst induction by 4beta-phorbol 12beta-myristate 13alpha-acetate treatment of infected monocytes reduced the viability of the KatG null strain (H37Rv Inhr) but not the KatG-overexpressing strain [H37Rv(pMH59)]. These results suggest that mycobacterial resistance to oxidative metabolites (including H2O2 and other peroxides) may be an important mechanism of bacillary survival within the host phagocyte. PMID:9864198

Manca, C; Paul, S; Barry, C E; Freedman, V H; Kaplan, G

1999-01-01

121

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

PubMed Central

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

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

2014-01-01

122

Etanercept exacerbates inflammation and pathology in a rabbit model of active pulmonary tuberculosis.  

PubMed

Treatment of chronic inflammatory diseases with tumor necrosis factor alpha (TNF-?) antagonists has been associated with increased risk of tuberculosis (TB). We examined the usefulness of the rabbit model of active pulmonary TB for studying the impact of the human immune modulatory reagent etanercept on the host immune response. Control of Mycobacterium tuberculosis (Mtb) infection, disease pathology, and the global transcriptional response in Mtb-infected lungs of rabbits were studied. Etanercept treatment exacerbated disease pathology and reduced bacillary control in the lungs, compared with infected untreated animals. Reduced collagen and fibrin deposition in the granulomas was associated with significant downregulation of the collagen metabolism and fibrosis network genes and upregulation of genes in the inflammatory response and cell recruitment networks in the lungs of etanercept treated, compared with untreated rabbits. Our results suggest that targeting the TNF-? signaling pathway disrupts the tissue remodeling process, which is required for the formation and maintenance of well-differentiated granulomas and for control of Mtb growth in the lungs. These results validate the use of the rabbit model for investigating the impact of selected human immune modulatory drugs, such as a TNF-? antagonist, on the host immune response and pathogenesis in TB. PMID:24831609

Tsenova, Liana; O'Brien, Paul; Holloway, Jennifer; Peixoto, Blas; Soteropoulos, Patricia; Fallows, Dorothy; Kaplan, Gilla; Subbian, Selvakumar

2014-09-01

123

Chlorinated coumarins from the polypore mushroom Fomitopsis officinalis and their activity against Mycobacterium tuberculosis.  

PubMed

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 by ab initio spectroscopic methods and confirmed by chemical synthesis. In addition, an analogue of each was synthesized as 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

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

2013-10-25

124

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

PubMed Central

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

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

2013-01-01

125

Novel metal based anti-tuberculosis agent: synthesis, characterization, catalytic and pharmacological activities of copper complexes.  

PubMed

Copper complexes of molecular formulae, [CuL(1)(OAc)], [CuL(2)(H(2)O)], [CuL(3)(H(2)O)], [CuL(4)(H(2)O)], [CuL(5)(H(2)O)] where L(1)-L(5) represents Schiff base ligands [by the condensation of 3-hydroxyflavone with 4-aminoantipyrine (L(1))/o-aminophenol (L(2))/o-aminobenzoic acid (L(3))/o-aminothiazole (L(4))/thiosemicarbazide (L(5))], have been prepared. They were characterized using analytical and spectral techniques. The DNA binding properties of copper complexes were studied using electronic absorption spectra and viscosity measurements. Superoxide dismutase and antioxidant activities of the copper complexes have also been studied. Furthermore, the copper complexes have been found to promote pUC18 DNA cleavage in the presence of oxidant. Anti-tuberculosis activity was also performed. PMID:22321994

Joseph, J; Nagashri, K; Janaki, G Boomadevi

2012-03-01

126

Rapid diagnosis of active tuberculosis by detecting antibodies from lymphocyte secretions.  

PubMed

In the present study, we investigated the tuberculosis (TB) diagnostic performance of an assay on the basis of detection of TB-specific antibodies from peripheral blood mononuclear cells (PBMCs), to determine whether antibodies in lymphocyte secretions obtained from PBMCs would better reflect active disease than antibodies in serum. PBMCs from patients with and without TB cultured in various concentrations for different times were assessed. Immunoglobulin G (IgG) specific for antigen (bacille Calmette-Guérin [BCG] vaccine and purified protein derivative [PPD]) was measured in lymphocyte secretions. Patients with active TB had higher BCG- or PPD-specific IgG antibody responses than patients without TB or healthy subjects (P=.001). This method can be used as a quick diagnostic aid to facilitate rapid detection of TB cases. PMID:12870117

Raqib, Rubhana; Rahman, Jubayer; Kamaluddin, A K M; Kamal, S M Mostafa; Banu, Fauzia A; Ahmed, Shakeel; Rahim, Zeaur; Bardhan, Pradip K; Andersson, Jan; Sack, David A

2003-08-01

127

Antimycobacterial activity of ferutinin alone and in combination with antitubercular drugs against a rapidly growing surrogate of Mycobacterium tuberculosis  

Microsoft Academic Search

The aim of this study was to investigate the antimycobacterial activity of the major daucane constituent, ferutinin (jaeschkeandiol p-hydroxybenzoate, 1), four of its natural analogues, its hydrolysis products, as well as methyl p-hydroxybenzoate (methylparaben) against Mycobacterium smegmatis, a rapidly growing surrogate of Mycobacterium tuberculosis. The agar dilution assay was utilised for an antimycobacterial evaluation of single compounds. A modified agar

Ehab A. Abourashed; Ahmed M. Galal; Atef M. Shibl

2011-01-01

128

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

Microsoft Academic Search

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

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

2000-01-01

129

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

PubMed Central

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

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

2014-01-01

130

The prodrug activator EtaA from Mycobacterium tuberculosis is a Baeyer-Villiger monooxygenase.  

PubMed

EtaA is a newly identified FAD-containing monooxygenase that is responsible for activation of several thioamide prodrugs in Mycobacterium tuberculosis. It was found that purified EtaA displays a remarkably low activity with the antitubercular prodrug ethionamide. Hinted by the presence of a Baeyer-Villiger monooxygenase sequence motif in the EtaA sequence, we have been able to identify a large number of novel EtaA substrates. It was discovered that the enzyme converts a wide range of ketones to the corresponding esters or lactones via a Baeyer-Villiger reaction, indicating that EtaA represents a Baeyer-Villiger monooxygenase. With the exception of aromatic ketones (phenylacetone and benzylacetone), long-chain ketones (e.g. 2-hexanone and 2-dodecanone) also are converted. EtaA is also able to catalyze enantioselective sulfoxidation of methyl-p-tolylsulfide. Conversion of all of the identified substrates is relatively slow with typical k(cat) values of around 0.02 s(-1). The best substrate identified so far is phenylacetone (K(m) = 61 microM, k(cat) = 0.017 s(-1)). Redox monitoring of the flavin cofactor during turnover of phenylacetone indicates that a step in the reductive half-reaction is limiting the rate of catalysis. Intriguingly, EtaA activity could be increased by one order of magnitude by adding bovine serum albumin. This reactivity and substrate acceptance-profiling study provides valuable information concerning this newly identified prodrug activator from M. tuberculosis. PMID:14610090

Fraaije, Marco W; Kamerbeek, Nanne M; Heidekamp, Annelies J; Fortin, Riccardo; Janssen, Dick B

2004-01-30

131

Mycobacterium tuberculosis multidrug resistant strain M induces an altered activation of cytotoxic CD8+ T cells.  

PubMed

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

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

2014-01-01

132

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

PubMed

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

Wheelwright, Matthew; Kim, Elliot W; Inkeles, Megan S; De Leon, Avelino; Pellegrini, Matteo; Krutzik, Stephan R; Liu, Philip T

2014-03-01

133

Mycobactericidal Activity of Sutezolid (PNU-100480) in Sputum (EBA) and Blood (WBA) of Patients with Pulmonary Tuberculosis  

PubMed Central

Rationale Sutezolid (PNU-100480) is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models. Like linezolid, it is unaffected by mutations conferring resistance to standard TB drugs. This study of sutezolid is its first in tuberculosis patients. Methods Sputum smear positive tuberculosis patients were randomly assigned to sutezolid 600 mg BID (N?=?25) or 1200 mg QD (N?=?25), or standard 4-drug therapy (N?=?9) for the first 14 days of treatment. Effects on mycobacterial burden in sputum (early bactericidal activity or EBA) were monitored as colony counts on agar and time to positivity in automated liquid culture. Bactericidal activity was also measured in ex vivo whole blood cultures (whole blood bactericidal activity or WBA) inoculated with M. tuberculosis H37Rv. Results All patients completed assigned treatments and began subsequent standard TB treatment according to protocol. The 90% confidence intervals (CI) for bactericidal activity in sputum over the 14 day interval excluded zero for all treatments and both monitoring methods, as did those for cumulative WBA. There were no treatment-related serious adverse events, premature discontinuations, or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. Seven sutezolid-treated patients (14%) had transient, asymptomatic ALT elevations to 173±34 U/L on day 14 that subsequently normalized promptly; none met Hy's criteria for serious liver injury. Conclusions The mycobactericidal activity of sutezolid 600 mg BID or 1200 mg QD was readily detected in sputum and blood. Both schedules were generally safe and well tolerated. Further studies of sutezolid in tuberculosis treatment are warranted. Trial Registration ClinicalTrials.gov NCT01225640 PMID:24732289

Wallis, Robert S.; Dawson, Rodney; Friedrich, Sven O.; Venter, Amour; Paige, Darcy; Zhu, Tong; Silvia, Annette; Gobey, Jason; Ellery, Craig; Zhang, Yao; Eisenach, Kathleen; Miller, Paul; Diacon, Andreas H.

2014-01-01

134

Comparison of Culture and PCR Methods for Diagnosis of Mycobacterium tuberculosis in Different Clinical Specimens  

PubMed Central

Background: Tuberculosis remains a global epidemic, especially in developing countries, including Iran. Rapid diagnosis of active Mycobacterium tuberculosis infection plays a critical role in controlling the spread of tuberculosis. Conventional methods may take up to several weeks or longer to produce results. In addition to multiplicity of steps involved in conventional detection, including isolation, identification and drug susceptibility testing, the slow growth rate of M. tuberculosis is also responsible for this lengthy time. Objectives: The aim of this study was to compare the polymerase chain reaction (PCR) and culture methods for the detection of M. tuberculosis in different clinical specimens. Materials and Methods: This study was performed on different samples (urine, gastric aspirate, bronchoalveolar lavage, pleural fluid, cerebrospinal fluid, ascetic fluid and joint fluid specimens) of tuberculosis suspected patients. M. tuberculosis DNA was extracted directly from different samples using two different protocols. Next, PCR was performed using three sets of specific primers to detect members of Mycobacterium genus, M. tuberculosis complex and non-tuberculosis Mycobacteria. The results were then compared with that of the culture method, which is considered as the gold standard method. Results: The concordance rate between the three sets of primers was calculated and IS6110/buffer PCR method showed good agreement with the LJ culture method (? = 0.627, P < 0.0001). The sensitivity of IS6110/buffer PCR was 58.33%, with specificity of 77.78%; the positive and negative predictive values were 100% and 78.26%, respectively. Buffer method for DNA extraction was proved to give a higher accuracy to PCR in comparison with the boiling method. Conclusions: PCR method is a valuable, cost-effective and alternative tool for quick diagnosis of active tuberculosis in different clinical specimens. PMID:25147673

Gholoobi, Aida; Masoudi-Kazemabad, Ali; Meshkat, Mojtaba; Meshkat, Zahra

2014-01-01

135

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

PubMed Central

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

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

2002-01-01

136

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

PubMed Central

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

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

2014-01-01

137

Plasma drug activity in patients on treatment for multidrug-resistant tuberculosis.  

PubMed

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

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

2014-01-01

138

Tuberculosis among Children in Alaska.  

ERIC Educational Resources Information Center

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…

Gessner, Bradford D.

1997-01-01

139

Thyroid Tuberculosis in a Child: A Rare Entity  

PubMed Central

Thyroid tuberculosis is a rare disease even in countries where tuberculosis is endemic. Clinically tuberculosis is not often suspected in cases of thyroid nodule or swelling. We report a case of 11 years female child who presented with a thyroid swelling. Fine-needle aspiration cytology revealed caseating epithelioid granulomas and acid fast bacilli. Patient improved with antitubercular drugs. Tuberculosis may be considered as differential diagnosis of thyroid swelling. PMID:24696559

Bodh, Anita; Sharma, Neelam; Negi, Lalita; Chandel, Suman S

2014-01-01

140

Th2 biased immune response in cases with active Mycobacterium tuberculosis infection and tuberculin anergy.  

PubMed

This study was aimed at investigating the immunologic relationship between cytokine production pattern and tuberculin negativity in patients with active Mycobacterium tuberculosis infection. After classifying patients by the extent of pulmonary involvement and the size of the tuberculin reaction, we evaluated the rate of cytokine positivity in peripheral blood to determine whether there is a characteristic cellular immune reaction pattern which could partly explain the tuberculin negativity in some of these cases. The significance of tuberculin anergy occurring in some cases with M. tuberculosis infection is still not clear. We investigated the ratio of IL- 4, IL-10, IL-12, CD-4, CD-8 expressing lymphocytes in the peripheral blood of patients with active M. tuberculosis infection and correlated the percentage of the reactive cells with the positivity or negativity of tuberculin skin reactions. Twenty-eight patients were included in the study, with 11 healthy volunteers serving as controls. 10 ml of venous blood was drawn before starting anti-mycobacterial treatment. A tuberculin skin test was performed, introducing intracutaneously 5 TU PPD on the forearm with results evaluated after 72 h. Consistent with the reactivity or non-reactivity of the tuberculin skin test, we found a significantly higher ratio of IL-4 and IL-10 positive lymphocytes and a significantly lower ratio of IL-12 in the peripheral blood of patients with tuberculin anergy than in that of tuberculin positive patients or healthy donors. There was no difference in the ratio of the CD-4 CD-8 positive lymphocytes among the three groups. To evaluate whether the differences could be explained by the degree of pulmonary tubercular involvement, we classified the patients into three groups according to the extent and type of X-ray findings. Seven out of eight tuberculin negative patients were classified as grade III, whereas in the tuberculin positive group only seven out of 20 fell in this category. There was no significant correlation between the radiological grade of the patients and the examined in vitro parameters unless the tuberculin reactivity of each patients was also considered. Tuberculin anergy may reflect an inappropriate immune response to the intracellular pathogen. The high percentage of IL-4 and IL-10 positive lymphocytes together with a low percentage of IL-12 positive lymphocytes in the peripheral blood of anergic patients suggests a Th2 biased immune response during the early course of the disease. PMID:9848680

Balikó, Z; Szereday, L; Szekeres-Bartho, J

1998-11-01

141

[Pulmonary sarcoidosis diagnosed in 2 cases suspected to be neoplasms].  

PubMed

Two young patients suspected of neoplasms were admitted to Thoracic Surgery Department of Institute of Tuberculosis in first case (35-years old woman) chest x-ray showed atelectasis of upper right lobe, enlarged lymph nodes of mediastinum and right hillium-lymphoproliferative process was suspected. Repeated bronchoscopies revealed narrowing of upper right bronchus and in biopsy--granulomas with small focus of necrosis were found. Tuberculosis was not excluded. During short antituberculous treatment progression of lung lesions and enlarged supraclavicular lymph node were observed. Following biopsy confirmed sarcoidosis. Treatment with prednisone was successful. In second case the chest x-ray showed large masses in both lungs suspected of seminoma metastases. Lung biopsy made during thoracotomy revealed sarcoidosis. PMID:11320568

Bernard, J; Wiatr, E; Langfort, R; Burakowska, B

2000-01-01

142

Suspected rotavirus encephalitis.  

PubMed Central

A 9 month old boy with suspected rotavirus encephalitis developed infantile spasms and delayed psychomotor development. Anti-rotavirus antibodies in cerebrospinal fluid, blood, and faeces were studied. PMID:3017236

Ushijima, H; Bosu, K; Abe, T; Shinozaki, T

1986-01-01

143

Active pulmonary tuberculosis manifesting with idiopathic thrombocytopenic purpura: a rare presentation.  

PubMed

A 17-year-old girl presented with a 3-day history of epistaxis, vaginal bleeding and petechiae over the lower extremities. The patient had been feeling unwell with productive cough, fever, chills, poor appetite and weight loss for 2 months. Laboratory findings revealed anemia and thrombocytopenia, whereas bone marrow examination was unremarkable. She was diagnosed as having idiopathic thrombocytopenic purpura (ITP) in association with active tuberculosis (TB). The patient was treated with intravenous immunoglobulin (IVIg) and corticosteroid along with anti-TB drugs. During the follow-up period there was no recurrence of thrombocytopenia or TB. It is important to consider TB in the differential diagnosis of ITP, particularly in high TB-burden areas. PMID:21340308

Tabarsi, Payam; Merza, Muayad Aghali; Marjani, Majid

2010-01-01

144

Mycobacterium tuberculosis ribose-5-phosphate isomerase has a known fold, but a novel active site.  

PubMed

Ribose-5-phosphate isomerases (EC 5.3.1.6) inter-convert ribose-5-phosphate and ribulose-5-phosphate. This reaction allows the synthesis of ribose from other sugars, as well a means for salvage of carbohydrates after nucleotide breakdown. Two unrelated types of enzyme are known to catalyze the isomerization. The most common one, RpiA, is present in almost all organisms. The second type, RpiB, is found in many bacterial species.Here, we demonstrate that the RpiB from Mycobacterium tuberculosis (Rv2465c) has catalytic properties very similar to those previously reported for the Escherichia coli RpiB enzyme. Further, we report the structure of the mycobacterial enzyme, solved by molecular replacement and refined to 1.88A resolution. Comparison with the E.coli structure shows that there are important differences in the two active sites, including a change in the position and nature of the catalytic base. Sequence comparisons reveal that the M.tuberculosis and E.coli RpiB enzymes are in fact representative of two distinct sub-families. The mycobacterial enzyme represents a type found only in actinobacteria, while the enzyme from E.coli is typical of that seen in many other bacterial proteomes. Both RpiBs are very different from RpiA in structure as well as in the construction of the active site. Docking studies allow additional insights into the reactions of all three enzymes, and show that many features of the mechanism are preserved despite the different catalytic components. PMID:14687575

Roos, Annette K; Andersson, C Evalena; Bergfors, Terese; Jacobsson, Micael; Karlén, Anders; Unge, Torsten; Jones, T Alwyn; Mowbray, Sherry L

2004-01-16

145

Essential residues for the enzyme activity of ATP-dependent MurE ligase from Mycobacterium tuberculosis.  

PubMed

The emergence of total drug-resistant tuberculosis (TDRTB) has made the discovery of new therapies for tuberculosis urgent. The cytoplasmic enzymes of peptidoglycan biosynthesis have generated renewed interest as attractive targets for the development of new anti-mycobacterials. One of the cytoplasmic enzymes, uridine diphosphate (UDP)-MurNAc-tripeptide ligase (MurE), catalyses the addition of meso-diaminopimelic acid (m-DAP) into peptidoglycan in Mycobacterium tuberculosis coupled to the hydrolysis of ATP. Mutants of M. tuberculosis MurE were generated by replacing K157, E220, D392, R451 with alanine and N449 with aspartate, and truncating the first 24 amino acid residues at the N-terminus of the enzyme. Analysis of the specific activity of these proteins suggested that apart from the 24 N-terminal residues, the other mutated residues are essential for catalysis. Variations in K(m) values for one or more substrates were observed for all mutants, except the N-terminal truncation mutant, indicating that these residues are involved in binding substrates and form part of the active site structure. These mutant proteins were also tested for their specificity for a wide range of substrates. Interestingly, the mutations K157A, E220A and D392A showed hydrolysis of ATP uncoupled from catalysis. The ATP hydrolysis rate was enhanced by at least partial occupation of the uridine nucleotide dipeptide binding site. This study provides an insight into the residues essential for the catalytic activity and substrate binding of the ATP-dependent MurE ligase. Since ATP-dependent MurE ligase is a novel drug target, the understanding of its function may lead to development of novel inhibitors against resistant forms of M. tuberculosis. PMID:21153518

Basavannacharya, Chandrakala; Moody, Paul R; Munshi, Tulika; Cronin, Nora; Keep, Nicholas H; Bhakta, Sanjib

2010-11-01

146

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

Microsoft Academic Search

Moxifloxacin (BAY12-8039) is a new 8-methoxyquinolone shown to be active against Mycobacterium tubercu- losis in vitro. We tested moxifloxacin for activity in mice against M. tuberculosis CSU93, a highly virulent, re- cently isolated clinical strain. The MIC of moxifloxacin for the CSU93 strain was 0.25 mg\\/ml. The serum moxi- floxacin concentration after oral administration in mice peaked within 0.25 h,

EISHI MIYAZAKI; MIKI MIYAZAKI; JONG MIN CHEN; RICHARD E. CHAISSON; WILLIAM R. BISHAI

1999-01-01

147

Synergistic Activities of Clarithromycin and Pyrazinamide against Mycobacterium tuberculosis in Human Macrophages  

Microsoft Academic Search

One of the major components of the strategic plan to elim- inate tuberculosis (6) is the use of antimycobacterial drugs to destroy Mycobacterium tuberculosis residing in the body in a clinically quiescent condition. Isoniazid (INH) has been the drug of choice for over 30 years in treating a quiescent condi- tion and in prophylaxis therapy (1, 10). However, long-term therapy

NATAN MOR; ADELEH ESFANDIARI

1997-01-01

148

An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity  

PubMed Central

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

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

2014-01-01

149

Bactericidal Activity of an Imidazo[1, 2-a]pyridine Using a Mouse M. tuberculosis Infection Model  

PubMed Central

Tuberculosis remains a global threat due in part to the long treatment regimen and the increased prevalence of drug resistant M. tuberculosis strains. Therefore, new drug regimens are urgently required to combat this deadly disease. We previously synthesized and evaluated a series of new anti-tuberculosis compounds which belong to the family of imidazo[1,2-a]pyridines. This family of compounds showed low nM MIC (minimal inhibitory concentration) values against M. tuberculosis in vitro. In this study, a derivative of imidazo[1,2-a]pyridines, (N-(4-(4-chlorophenoxy)benzyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide) (ND-09759), was selected as a promising lead compound to determine its protective efficacy using a mouse infection model. Pharmacokinetic analysis of ND-09759 determined that at a dosage of 30 mg/kg mouse body weight (PO) gave a maximum serum drug concentration (Cmax) of 2.9 µg/ml and a half-life of 20.1 h. M. tuberculosis burden in the lungs and spleens was significantly decreased in mice treated once daily 6 days per week for 4-weeks with ND-09759 compared to untreated mice and this antibiotic activity was equivalent to isoniazid (INH) and rifampicin (RMP), two first-line anti-TB drugs. We observed slightly higher efficacy when using a combination of ND-09759 with either INH or RMP. Finally, the histopathological analysis revealed that infected mice treated with ND-09759 had significantly reduced inflammation relative to untreated mice. In conclusion, our findings indicate ND-09759 might be a potent candidate for the treatment of active TB in combination with current standard anti-TB drugs. PMID:24498115

Cheng, Yong; Moraski, Garrett C.; Cramer, Jeffrey; Miller, Marvin J.; Schorey, Jeffrey S.

2014-01-01

150

Detection and confirmation of alkaloids in leaves of Justicia adhatoda and bioinformatics approach to elicit its anti-tuberculosis activity.  

PubMed

The extraction and determination of alkaloids was performed and confirmed by phytochemical analysis. Six different quinazoline alkaloids (vasicoline, vasicolinone, vasicinone, vasicine, adhatodine and anisotine) were found in the leaf of Justicia adhatoda (J. adhatoda). The presence of the peaks obtained through HPLC indicated the diverse nature of alkaloid present in the leaf. The enzyme ?-ketoacyl-acyl-carrier protein synthase III that catalyses the initial step of fatty acid biosynthesis (FabH) via a type II fatty acid synthase has unique structural features and universal occurrence in Mycobacterium tuberculosis (M. tuberculosis). Thus, it was considered as a target for designing of anti-tuberculosis compounds. Docking simulations were conducted on the above alkaloids derived from J. adhatoda. The combination of docking/scoring provided interesting insights into the binding of different inhibitors and their activity. These results will be useful for designing inhibitors for M. tuberculosis and also will be a good starting point for natural plant-based pharmaceutical chemistry. PMID:22899014

Jha, Deepak Kumar; Panda, Likun; Lavanya, P; Ramaiah, Sudha; Anbarasu, Anand

2012-11-01

151

Cutinase-like proteins of Mycobacterium tuberculosis: characterization of their variable enzymatic functions and active site identification  

PubMed Central

Discovery and characterization of novel secreted enzymes of Mycobacterium tuberculosis are important for understanding the pathogenesis of one of the most important human bacterial pathogens. The proteome of M. tuberculosis contains over 400 potentially secreted proteins, the majority of which are uncharacterized. A family of seven cutinase-like proteins (CULPs) was identified by bioinformatic analysis, expressed and purified from Escherichia coli, and characterized in terms of their enzymatic activities. These studies revealed a functional diversity of enzyme classes based on differential preferences for substrate chain length. One member, Culp1, exhibited strong esterase activity, 40-fold higher than that of Culp6, which had strong activity as a lipase. Another, Culp4, performed moderately as an esterase and weakly as a lipase. Culp6 lipase activity was optimal above pH 7.0, and fully maintained to pH 8.5. None of the CULP members exhibited cutinase activity. Site-directed mutagenesis of each residue of the putative catalytic triad in Culp6 confirmed that each was essential for activity toward all fatty acid chain lengths of nitrophenyl esters and lipolytic function. Culp1 and Culp2 were present only in culture supernatants of M. tuberculosis, while Culp6, which is putatively essential for mycobacterial growth, was retained in the cell wall, suggesting the proteins play distinct roles in mycobacterial biology.—West, N. P., Chow, F. M. E., Randall, E. J., Wu, J., Chen, J., Ribeiro, J. M. C., Britton, W. J. Cutinase-like proteins of Mycobacterium tuberculosis: characterization of their variable enzymatic functions and active site identification. PMID:19225166

West, Nicholas P.; Chow, Frances M. E.; Randall, Elizabeth J.; Wu, Jing; Chen, Jian; Ribeiro, Jose M. C.; Britton, Warwick J.

2009-01-01

152

Adjuvant and immunostimulating activities of water-soluble substances extracted from Mycobacterium tuberculosis (var. hominis).  

PubMed

Water-soluble substances have been extracted from two strains of Mycobacterium tuberculosis var. hominis: the native hydrosoluble part (polysaccharide and peptidoglycan), a substance in which the polysaccharide moiety is less abundant than in the latter, the acetylated peptidoglycan and, finally a tetrasaccharide-heptapeptide. All four types of substances, when they were injected together with Freund's incomplete adjuvant, exerted an adjuvant effect on the production of delayed-type hypersensitivity to ovalbumin in the guinea pig and on the production of anti-influenza virus antibodies in the rabbit. Injected intravenously in the mouse, they increased the number of antibody-producing cells in the spleen and enhanced the graft versus host reaction; no effect was seen on the phagocytic activity of the reticulo-endothelial system. By contrast with wax D, the water-soluble substances were devoid of arthritis-inducing activity in the rat. Altogether, these water-soluble substances seem to be endowed with at least some of the adjuvant activities of Freund's complete adjuvant and some of the immunostimulant activities of a live Mycobacterium like BCG. PMID:4166

Werner, G H; Maral, R; Floch, F; Migliore-Samour, D; Jollès, P

1975-09-01

153

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

PubMed

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

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

2014-01-01

154

IgG, IgM and IgA antibodies against the novel polyprotein in active tuberculosis  

PubMed Central

Background The present study was aimed to evaluate whether IgG, IgM and IgA antibodies levels detected against a novel Mycobacterium tuberculosis polyprotein 38 F-64 F (with 38 F being the abbreviation for 38kD-ESAT6-CFP10 and 64 F for Mtb8.4-MPT64-TB16.3-Mtb8) are suitable for diagnosing active tuberculosis, and for monitoring the efficacy of chemotherapy on TB patients. Methods In this study, a total of 371 active TB patients without treatment were selected and categorized into S+/C+?group (n?=?143), S-/C+?group (n?=?106) or S-/C- group (n?=?122). A series of serum samples were collected from 82 active TB patients who had undergone anti-TB chemotherapy for 0–6 months at one month interval. Humoral responses (IgG, IgM and IgA) were determined for the novel Mycobacterium tuberculosis polyprotein using indirect ELISA methods in all of serum samples. Results For S+/C+, S-/C+?and S-/C- active tuberculosis patients before anti-TB chemotherapy, the sensitivities of tests based on IgG were 65.7%, 46.2% and 52.5% respectively; the sensitivities based on IgM were 21.7%, 24.5% and 18.9%; and the sensitivities based on IgA were 25.2%, 17.9% and 23.8%. By combination of three isotypes, for all active tuberculosis patients, the test sensitivity increased to 70.4% with the specificity being 91.5%. After anti-TB chemotherapy, there were no significant differences between groups with different courses of anti-TB chemotherapy. Conclusions The novel Mycobacterium tuberculosis polyprotein 38 F-64 F represents potential antigen suitable for measuring IgG, IgM and IgA antibodies. However, the serodiagnostic test based on the 38 F-64 F polyprotein appears unsuitable for monitoring the efficacy of chemotherapy. PMID:24939009

2014-01-01

155

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

PubMed Central

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

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

2013-01-01

156

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

PubMed Central

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

Kim, Hyun; Shibayama, Keigo; Rimbara, Emiko; Mori, Shigetarou

2014-01-01

157

The intensity of QuantiFERON TB-gold response does not differentiate active from latent tuberculosis.  

PubMed

We analyzed positive QuantiFERON (QFT) assays, performed between July 2009 and April 2011 in the Mercy University Hospital, Cork, Ireland, which included, 94 patients with latent tuberculosis (LTBI) and 35 patients with active tuberculosis. There was no difference in the intensity of response between patients with LTBI and active tuberculosis (p = 0.1589). In patients with LTBI, there were no correlations between age (p = 0.353), sex (p = 0.476), smoking (p = 0.323), contact (p = 0.612), Mantoux response (p = 0.055), Irish nationality (p=0.768), previous BCG vaccination (p = 0.504), WCC (p = 0.187), lymphocyte count (p = 0.786), neutrophil count (p = 0.157) and the intensity of QFT response. Similarly in patients with active TB, there were no correlations between these variables and QFT response. The intensity of QFT response does not help to differentiate active from LTBI. The intensity of QFT response is not influenced by age, sex, smoking, remoteness of contact history, Mantoux response, nationality, CXR abnormalities, BCG vaccination and peripheral lymphocyte count. PMID:24579411

Khan, F; Cotter, O; Kennedy, B; Clair, J; O'Connor, B; Collins, J; Curran, D; O'Connor, T

2013-01-01

158

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

PubMed Central

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

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

2013-01-01

159

Cutaneous Tuberculosis  

PubMed Central

Cutaneous tuberculosis occurs rarely, despite a high and increasing prevalence of tuberculosis worldwide. Mycobacterium tuberculosis, Mycobacterrium bovis, and the Bacille Calmette-Guérin vaccine can cause tuberculosis involving the skin. Cutaneous tuberculosis can be acquired exogenously or endogenously and present as a multitude of differing clinical morphologies. Diagnosis of these lesions can be difficult, as they resemble many other dermatological conditions that are often primarily considered. Further, microbiological confirmation is poor, despite scientific advances, such as the more frequent use of polymerase chain reaction. The authors report a case that illustrates the challenges faced by dermatologists when considering a diagnosis of cutaneous tuberculosis. PMID:20725570

Frankel, Amylynne; Penrose, Carolin

2009-01-01

160

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

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

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

161

Rheumatoid Arthritis Increases the Risk of Nontuberculosis Mycobacterial Disease and Active Pulmonary Tuberculosis  

PubMed Central

Background Few studies have examined the association of rheumatoid arthritis (RA) with nontuberculosis mycobacterium (NTM) disease and pulmonary tuberculosis (PTB). Methods We identified 29 131 patients with RA from the catastrophic illness registry who were diagnosed from 1998–2008; 116 524 patients without RA from inpatient data files were randomly frequency matched according to sex, age, and index year and used as a comparison group. Both groups were followed-up until the end of 2010 to measure the incidence of NTM disease and active PTB. We analyzed the risk of NTM disease and active PTB using the Cox proportional hazards regression models, controlling for sex, age, and Charlson comorbidity index (CCI). Results The incidence of NTM disease was 4.22 times greater in the RA group than in the non-RA group (1.91 vs 0.45 per 10,000 person-years). The incidence of PTB was 2.99 times greater in the RA group than in the non-RA group (25.3 vs 8.46 per 10,000 person-years). After adjusting for age, sex, and CCI, the adjusted hazard ratios (HRs) of NTM disease and active PTB for the RA group were 4.17 (95% CI?=?2.61–6.65) and 2.87 (95% CI?=?2.55–3.23), respectively, compared with the non-RA group. In the first 2 years of follow-up, the RA group yielded corresponding adjusted HRs of 4.98 and 3.39 compared with the non-RA group. The follow-up time-specific RA group to the non-RA group HR of both the NTM disease and active PTB varied. Conclusion This study can serve as a reference for clinical physicians to increase awareness regarding the detection of NTM disease and active PTB in RA patients among the any stage of the clinical course even without CCI. PMID:25337995

Yeh, Jun-Jun; Wang, Yu-Chiao; Sung, Fung-Chang; Kao, Chia-Hung

2014-01-01

162

An evolutionarily conserved alternate metal ligand is important for activity in ?-isopropylmalate synthase from Mycobacterium tuberculosis.  

PubMed

Members of the DRE-TIM metallolyase superfamily rely on an active-site divalent cation to catalyze various reactions involving the making and breaking of carbon-carbon bonds. While the identity of the metal varies, the binding site is well-conserved at the superfamily level with an aspartic acid and two histidine residues acting as ligands to the metal. Previous structural and bioinformatics results indicate that the metal can adopt an alternate architecture through the addition of an asparagine residue as a fourth ligand. This asparagine residue is strictly conserved in all members of the DRE-TIM metallolyase superfamily except fungal homocitrate synthase (HCS-lys) where it is replaced with isoleucine. The role of this additional metal ligand in ?-isopropylmalate synthase from Mycobacterium tuberculosis (MtIPMS) has been investigated using site-directed mutagenesis. Substitution of the asparagine ligand with alanine or isoleucine results in inactive enzymes with respect to ?-isopropylmalate formation. Control experiments suggest that the substitutions have not drastically affected the enzyme's structure indicating that the asparagine residue is essential for catalysis. Interestingly, all enzyme variants retained acetyl CoA hydrolysis activity in the absence of ?-ketoisovalerate, similar to the wild-type enzyme. In contrast to the requirement of magnesium for ?-isopropylmalate formation, hydrolytic activity could be inhibited by the addition of magnesium chloride in wild-type, D81E, and N321A MtIPMS, but not in the other variants studied. Attempts to rescue loss of activity in N321I MtIPMS by mimicking the fungal HCS active site through the D81E/N321I double variant were unsuccessful. This suggests epistatic constraints in evolution of function in IPMS and HCS-lys enzymes. PMID:25064783

Frantom, Patrick A; Birman, Yuliya; Hays, Brittani N; Casey, Ashley K

2014-10-01

163

[The activity of immunocompetent cells and macrophages in pulmonary sarcoidosis (in comparison to tuberculosis)].  

PubMed

Composition of immunocompetent cells and production of cytokins (IL-1, IL-2, IL-6 and PNO) by stimulated and nonstimulated cells of blood and bronchoalveolar lavage (BAL) were evaluated in 35 and 25 sarcoidosis and tuberculosis patients, respectively. Comparable differences were recorded in concentration of T-cells and T-helpers versus BAL in sarcoidosis and tuberculosis as well as in intensity of cytokin production by mononuclears obtained from various sources. PMID:8907484

Gergert, V Ia; Abramova, Z P; Kosmiadi, G A

1996-01-01

164

Limited activity of clofazimine as a single drug in a mouse model of tuberculosis exhibiting caseous necrotic granulomas.  

PubMed

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

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

2014-07-01

165

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

PubMed Central

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

2013-01-01

166

Structure-activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis  

PubMed Central

A series of 2-aminothiazoles was synthesized based on a HTS scaffold from a whole-cell screen against Mycobacterium tuberculosis (Mtb). The SAR shows the central thiazole moiety and the 2-pyridyl moiety at C-4 of the thiazole are intolerant to modification. However, the N-2 position of the aminothiazole exhibits high flexibility and we successfully improved the antitubercular activity of the initial hit by more than 128-fold through introduction of substituted benzoyl groups at this position. N-(3-Chlorobenzoyl)-4-(2-pyridinyl)-1,3-thiazol-2-amine (55) emerged as one of the most promising analogues with a MIC of 0.024 ?M or 0.008 ?g/mL in 7H9 media and therapeutic index of nearly ~300. However, 55 is rapidly metabolized by human liver microsomes (t1/2 = 28 min) with metabolism occurring at the invariant aminothiazole moiety and Mtb develops spontaneous resistance with a high frequency of ~10?5. PMID:24075144

Meissner, Anja; Boshoff, Helena I.; Vasan, Mahalakshmi; Duckworth, Benjamin P.; Barry, Clifton E.; Aldrich, Courtney C.

2013-01-01

167

Comprehensive insights into Mycobacterium tuberculosis DevR (DosR) regulon activation switch.  

PubMed

DevR regulon function is believed to be crucial for the survival of Mycobacterium tuberculosis during dormancy. In this study, we undertook a comprehensive analysis of the DevR regulon. All the regulon promoters were assigned to four classes based on the number of DevR binding sites (Dev boxes). A minimum of two boxes are essential for complete interaction and their tandem arrangement is an architectural hallmark at all promoters. Initial interaction of DevR with the conserved box is essential for its cooperative binding to adjacent sites bearing low to very poor sequence conservation and is the universal mechanism underlying DevR-mediated transcriptional induction. The functional importance of tandem arrangement was established by analyzing promoter variants harboring Dev boxes with altered spacing. Conserved sequence logos were generated from 47 binding sequences which included 24 newly discovered Dev boxes. In each half site of an 18-bp binding motif, G(5) and C(7) are essential for DevR binding. Finally, we show that DevR regulon induction occurs in a temporal manner and genes that are induced early are also usually powerfully induced. The information theory-based approach along with binding and temporal expression studies provide us with comprehensive insights into the complex pattern of DevR regulon activation. PMID:21653552

Chauhan, Santosh; Sharma, Deepak; Singh, Alka; Surolia, Avadhesha; Tyagi, Jaya Sivaswami

2011-09-01

168

Unique transcriptome signature of Mycobacterium tuberculosis in pulmonary tuberculosis.  

PubMed

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

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

2006-02-01

169

IL-17 and IFN-? expression in lymphocytes from patients with active tuberculosis correlates with the severity of the disease  

PubMed Central

Th1 lymphocytes are crucial in the immune response against Mycobacterium tuberculosis. Nevertheless, IFN-? alone is not sufficient in the complete eradication of the bacteria, suggesting that other cytokines might be required for pathogen removal. Th17 cells have been associated with M. tuberculosis infection, but the role of IL-17-producing cells in human TB remains to be understood. Therefore, we investigated the induction and regulation of IFN-? and IL-17 during the active disease. TB patients were classified as High and Low Responder individuals according to their T cell responses against the antigen, and cytokine expression upon M. tuberculosis stimulation was investigated in peripheral blood and pleural fluid. Afterwards, the potential correlation among the proportions of cytokine-producing cells and clinical parameters was analyzed. In TB patients, M. tuberculosis induced IFN-? and IL-17, but in comparison with BCG-vaccinated healthy donors, IFN-? results were reduced significantly, and IL-17 was markedly augmented. Moreover, the main source of IL-17 was represented by CD4+IFN-?+IL-17+ lymphocytes, a Th1/Th17 subset regulated by IFN-?. Interestingly, the ratio of antigen-expanded CD4+IFN-?+IL-17+ lymphocytes, in peripheral blood and pleural fluid from TB patients, was correlated directly with clinical parameters associated with disease severity. Indeed, the highest proportion of CD4+IFN-?+IL-17+ cells was detected in Low Responder TB patients, individuals displaying severe pulmonary lesions, and longest length of disease evolution. Taken together, the present findings suggest that analysis of the expansion of CD4+IFN-?+IL-17+ T lymphocytes in peripheral blood of TB patients might be used as an indicator of the clinical outcome in active TB. PMID:22416258

Jurado, Javier O.; Pasquinelli, Virginia; Alvarez, Ivana B.; Pena, Delfina; Rovetta, Ana I.; Tateosian, Nancy L.; Romeo, Horacio E.; Musella, Rosa M.; Palmero, Domingo; Chuluyan, H. Eduardo; Garcia, Veronica E.

2012-01-01

170

T-cell responses to the Mycobacterium tuberculosis-specific antigens in active tuberculosis patients at the beginning, during, and after antituberculosis treatment.  

PubMed

The objectives of the study were to assess the performance of the QuantiFERON-TB Gold In-Tube (QFN-G-IT) and the T-SPOT.TB tests in the immunodiagnosis of active tuberculosis (TB) in adult patients, and to study the T-cell interferon gamma (IFN-gamma) responses during treatment and in patients who have recovered after curative treatment and self-healed TB patients. When only analyzing patients included at the beginning of treatment, the sensitivity was 83.3% for T-SPOT.TB and 69.4% for QFN-G-IT. In contrast, when evaluating patients during treatment, the sensitivity of the T-SPOT.TB and QFN-G-IT decreased to 69.8% and 48.8%, respectively. The response to the specific antigens increased after finishing the treatment compared with the values during the treatment. The T-SPOT.TB was more sensitive in diagnosing active TB than the QFN-G-IT. The IFN-gamma tests could be used as a complementary method in the diagnosis of active TB. PMID:19026511

Domínguez, Jose; De Souza-Galvão, Malú; Ruiz-Manzano, Juan; Latorre, Irene; Prat, Cristina; Lacoma, Alicia; Milà, Celia; Jiménez, Maria Angeles; Blanco, Silvia; Maldonado, José; Altet, Neus; Ausina, Vicente

2009-01-01

171

Lingual tuberculosis.  

PubMed

Oral tuberculosis is very rare and when present they are usually secondary to pulmonary tuberculosis. Tuberculous lesions of the tongue have become so infrequent that they are virtually a forgotten disease entity and may pose a diagnostic problem. The case reported in this paper emphasizes the importance of including tuberculosis in the differential diagnosis of any chronic oral ulcer. The low number of oral infections by M. tuberculosis could be due to underreporting. PMID:22670511

Mohanapriya, T; Singh, K Balaji; Arulappan, T; Dhanasekar, T

2012-01-01

172

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

PubMed Central

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

Garrido, Joseba M.; Aranaz, Alicia; Sevilla, Iker; Villar, Margarita; Boadella, Mariana; Galindo, Ruth C.; Perez de la Lastra, Jose M.; Moreno-Cid, Juan A.; Fernandez de Mera, Isabel G.; Alberdi, Pilar; Santos, Gracia; Ballesteros, Cristina; Lyashchenko, Konstantin P.; Minguijon, Esmeralda; Romero, Beatriz; de Juan, Lucia; Dominguez, Lucas; Juste, Ramon; Gortazar, Christian

2014-01-01

173

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

PubMed

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

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

2014-04-01

174

Detection of gasoline on arson suspects' hands.  

PubMed

An arson suspect's contact with an ignitable liquid container can leave small traces of the substance on his hands, but detecting these traces is difficult. This research paper presents a method to obtain clear gasoline detection even 3h after hands have been moistened with 50 ?L of gasoline using activated charcoal strips to adsorb the ignitable liquid traces directly from the suspect's hands. Light heating of the hands to 45 °C significantly increases the ability to detect gasoline traces. This methodology is part of a system to sample a suspect's hands at the scene of crime or in a police station. Samples are taken by investigators then analyzed in a laboratory. The suggested method provides an important improvement in detection sensitivity for ignitable liquids on suspect's hands. PMID:20729020

Muller, Dan; Levy, Aharon; Shelef, Ran

2011-03-20

175

Impact of fluoroquinolone resistance on bactericidal and sterilizing activity of a moxifloxacin-containing regimen in murine tuberculosis.  

PubMed

It has been shown previously that fluoroquinolone resistance (defined by resistance to at least 2 mg/liter ofloxacin) has a different impact on moxifloxacin monotherapy depending on the mutation in the sole fluoroquinolone target in Mycobacterium tuberculosis, i.e., DNA gyrase. Since tuberculosis treatment relies on multidrug therapy, we wished to determine the impact of fluoroquinolone resistance on the bactericidal and sterilizing activity of a second-line antituberculous regimen containing moxifloxacin. A total of 280 mice were inoculated with the wild-type Mycobacterium tuberculosis H37Rv strain or one of 3 isogenic fluoroquinolone-resistant mutant strains with increasing moxifloxacin resistance (the GyrB D500N, GyrA A90V, and GyrA D94G strains) and then treated for 6 months with a second-line regimen containing moxifloxacin, pyrazinamide, and ethionamide supplemented with amikacin during the first 2 months. Mice were sacrificed during treatment for measurement of bactericidal activity and 3 months after treatment completion for measurement of relapse rates (sterilizing activity). The CFU counts decreased faster in mice inoculated with the wild type than in mice inoculated with the mutant strains. The relapse rate after treatment completion was different among mice inoculated with mutant strains in relation to the drug resistance level: wild type, 0%; GyrB D500N strain, 33%; GyrA A90V strain, 50%; and GyrA D94G strain, 86%. The relapse rate observed with the GyrB D500N strain was the only one not statistically different from that observed with the wild-type strain. We demonstrated that the impact on sterilizing activity of the most active second-line drug regimen containing moxifloxacin depends on the MIC of moxifloxacin. We suggest that the precise level of moxifloxacin resistance be determined for all strains resistant to 2 mg/liter ofloxacin. PMID:23836169

Fillion, Aurélie; Aubry, Alexandra; Brossier, Florence; Chauffour, Aurélie; Jarlier, Vincent; Veziris, Nicolas

2013-09-01

176

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

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

Plachno, Bartosz Jan; Adamec, Lubomir; Huet, Herve

2009-01-01

177

Pediatric glaucoma suspects  

PubMed Central

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

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

2014-01-01

178

[A rare cause of urinary obstruction: urogenital tuberculosis].  

PubMed

The authors reported a rare cause of urogenital tuberculosis complicated by an obstructive acute renal failure in 44 years old man with solitary anatomic kidney. The authors insisted of using the upper urinary tract opacification by percutaneous nephrostomy for diagnosis, the urogenital tuberculosis with this exploration, we can suspected the tuberculosis by abnormalities of the radiologic imagine, and confirmed the koch bacilli urinary into urinary tract. The upper chance of positives of finding koch bacilli in higher than urinary bladder. PMID:12741196

Fekak, H; Rabii, R; Moufid, K; Joual, A; Debbagh, A; Bennani, A; el Mrini, M; Benjelloun, S

2003-04-01

179

6-Mercaptopurine complexes with silver and gold ions: anti-tuberculosis and anti-cancer activities.  

PubMed

Synthesis, characterization and biological studies of silver and gold complexes with 6-mercaptopurine (H2MP) are described. The Ag(I) and Au(I) complexes with HMP-, AgHMP and AuIHMP, were obtained by mixing an acidified H2MP aqueous solution with an equimolar aqueous solution of AgNO3 or Au(CN)2. The Au(III) complex with HMP-, AuIIIHMP, was obtained by adding an aqueous solution of K(AuCl4) to an acidified H2MP aqueous solution (1:1 molar ratio) and the final solution was acidified with HCl to pH=1.0. The Au(III)MP complex, KAu(MP)2, was obtained by adding an aqueous solution of K(AuCl4) to a basic H2MP solution (M:L - 1:2 molar ratio). Formulas for the complexes are: (Ag[C5H3N4S])*½H2O for AgHMP, (Au[C5H3N4S]) for AuIHMP, (Au[C5H3N4S][Cl]2)*2H2O for AuIIIHMP and K(Au[C5H2N4S]2)·2H2O for KAu(MP)2. The AuIHMP and KAu(MP)2 complexes decreased cell viability of HeLa cancer cells in vitro. The IC50 values for AuIHMP and KAu(MP)2 are 3.0 and 30.0 ?M, respectively. Anti-M.tuberculosis assays showed a MIC value of 2.24 ?M for AuIHMP and 5.12 ?M for free MP while AgHMP is active at the concentration 93.2 ?M. PMID:21775091

Cuin, Alexandre; Massabni, Antonio Carlos; Pereira, Guilherme Alves; Leite, Clarice Queico Fujimura; Pavan, Fernando Rogério; Sesti-Costa, Renata; Heinrich, Tassiele Andréa; Costa-Neto, Claudio M

2011-08-01

180

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

PubMed

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

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

2011-07-01

181

Plasminogen activator inhibitor type I may contribute to transient, non-specific changes in immunity in the subacute phase of murine tuberculosis.  

PubMed

Tuberculosis, caused by Mycobacterium (M.) tuberculosis, is a devastating infectious disease causing many deaths worldwide. Non-specific host defense mechanisms such as the coagulation and fibrinolytic system may give insight in possible new therapeutic targets. Plasminogen activator inhibitor type-1 (PAI-1), an important regulator of inflammation and fibrinolysis, might be of interest as tuberculosis patients have elevated plasma levels of PAI-1. In this study we set out to investigate the role of PAI-1 during tuberculosis in vivo. Wildtype (WT) and PAI-1 deficient (PAI-1?/?) mice were intranasally infected with M. tuberculosis H37rv and sacrificed after 2, 5 and 29 weeks. Five weeks post-infection, bacterial loads in lungs of PAI-1?/? mice were significantly higher compared to WT mice, while no differences were seen 2 and 29 weeks post-infection. At two weeks post-infection increased influx of macrophages and lymphocytes was observed. PAI-1 deficiency was associated with a reduced cytokine response in the lungs; however, upon stimulation with tuberculin purified protein derivative (PPD), PAI-1?/? splenocytes released increased levels of IFN-? compared to WT. No clear differences were found between PAI-1?/? and WT mice at 29 weeks after infection. In conclusion, these data suggest that PAI-1 contributes to transient, non-specific changes in immunity during the early phase of murine tuberculosis. PMID:22484384

Kager, Liesbeth M; van der Windt, Gerritje J W; Wieland, Catharina W; Florquin, Sandrine; van 't Veer, Cornelis; van der Poll, Tom

2012-08-01

182

Whole Genome Sequence of Polyresistant Mycobacterium tuberculosis CWCFVRF PRTB 19 Sputum Isolate from Chennai, India, Closely Clustering with East African Indian 5 Genogroup  

PubMed Central

We announce the draft genome sequence of a polyresistant Mycobacterium tuberculosis strain (CWCFVRF PRTB 19) isolated from the sputum of a clinically suspected tuberculosis patient, and it closely clusters to the East African Indian 5 (EAI5) lineage. PMID:25035331

Lakshmipathy, Dhanurekha; Vetrivel, Umashankar; Ramasubban, Gayathri; Madhavan, Hajib Narahari; Sridhar, R.; Meenakshi, N.

2014-01-01

183

[Ultrasound in suspected intussusception].  

PubMed

Intussusception is one of the main abdominal emergencies in children. Accuracy of clinical diagnosis is poor and in only 30-40% of cases is the clinical diagnosis of intussusception confirmed. Many unnecessary barium enemas are performed due to clinical misdiagnosis. Sonography can demonstrate intussusception, is widely available, easily performed, does not produce radiation and can be used to screen suspected cases. From 1991-1993, in 6 of 14 consecutive cases of clinically suspected intussusception the ultrasound examination was positive. In 4 of them barium enema revealed intussusception, which was reduced by the barium enema procedure. A child was sent for surgery because ultrasonography showed a duplication cyst which was considered the leading point for the bowel invagination. In the last case surgery for bowel obstruction revealed impacted stool misdiagnosed by ultrasound as an intussusception mass. In all the 8 cases in which ultrasound was negative, follow-up confirmed the absence of intussusception. The sensitivity of the ultrasound examination was 100% and the negative predictive value 100%. These results are not in accord with those of other authors. We find ultrasound a reliable imaging modality for the diagnosis of intussusception. It can identify leading points as well as other causes for the clinical presentation, including ovarian torsion or appendicitis. PMID:7959392

Barzilai, M

1994-07-01

184

Bactericidal activity of 2-nitroimidazole against the active replicating stage of Mycobacterium bovis BCG and Mycobacterium tuberculosis with intracellular efficacy in THP-1 macrophages.  

PubMed

This study evaluated the antituberculous potential of 2-nitroimidazole under in vitro conditions. Minimal bactericidal concentrations of the compound against actively replicating Mycobacterium bovis BCG and Mycobacterium tuberculosis H37Ra were found to be 0.226 microg/mL and 0.556 microg/mL in enriched and minimal medium, respectively. Minimal inhibitory concentrations were >100 times lower than reported antituberculous nitroimidazoles such as nitrofurantoin and furaltadone, indicating the greater potential of 2-nitroimidazole. No discernible effect of 2-nitroimidazole was seen on saprophytic Mycobacterium smegmatis and the representative bacterial strain Escherichia coli DH5alpha, indicating the specificity of the molecule against tuberculous mycobacteria. The compound was also found to be effective against M. tuberculosis in the intracellular environment of the human monocytic cell line THP-1, with a reduction in viability of bacilli by 2.5 log after 144 h of incubation at a concentration of 0.113 microg/mL. A five-fold higher concentration (0.565 microg/mL) of 2-nitroimidazole sterilised the macrophages of intracellular pathogens within 192 h, without affecting the host. However, 2-nitroimidazole was unable to affect significantly the viability of dormant non-replicating bacilli of M. bovis BCG and M. tuberculosis in Wayne's in vitro model. Overall, the results indicate that 2-nitroimidazole is a potent antituberculous agent active against the organism's active replicating stage, with promising intracellular efficacy as well. PMID:18538548

Khan, Arshad; Sarkar, Sampa; Sarkar, Dhiman

2008-07-01

185

The Early Bactericidal Activity of Isoniazid Related to Its Dose Size in Pulmonary Tuberculosis  

Microsoft Academic Search

Collections of sputum from 105 patients with newly diagnosed pulmonary tuberculosis were made before and at 1 and 2 d after the start of chemotherapy with isoniazid (INH) alone given to groups of patients in doses of 600 mg, 300 mg, 150 mg, 75 mg, 37.5 mg, 18.75 mg, and 9 mg daily, as well as from an untreated group.

PETER R. DONALD; FREDERICK A. SIRGEL; FREDERICK J. BOTHA; HEINER I. SEIFART; DONALD P. PARKIN; MICHEL L. VANDENPLAS; JOHANNES S. MARITZ; DENIS A. MITCHISON

186

Towards a point-of-care test for active tuberculosis: obstacles and opportunities  

Microsoft Academic Search

Limited access to diagnostic services and the poor performance of current tests result in a failure to detect millions of tuberculosis cases each year. An accurate test that could be used at the point of care to allow faster initiation of treatment would decrease death rates and could reduce disease transmission. Previous attempts to develop such a test have failed,

Peter Daley; Ruth McNerney

2011-01-01

187

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

PubMed

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

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

2013-05-01

188

[Procedure in case of suspected mycobacterial infection of lymph nodes of the neck].  

PubMed

Procedure in Case of Suspected Mycobacterial Infection of Lymph Nodes of the Neck. Cervical lymphadenitis of unknown origin is frequently observed in ENT. Besides metastasis, lymphomas and non specific cervical lymphadenitis, tuberculosis or infection with atypical mycobacteria has to be considered. This article tries to present the state of the art procedure in diagnostics to differentiate tuberculosis and atypical mycobacterial infections from other pathologies of cervical lymph nodes. PMID:16010635

Göpel, B; Götte, K

2005-07-01

189

Population Pharmacokinetic/Pharmacodynamic Analysis of the Bactericidal Activities of Sutezolid (PNU-100480) and Its Major Metabolite against Intracellular Mycobacterium tuberculosis in Ex Vivo Whole-Blood Cultures of Patients with Pulmonary Tuberculosis  

PubMed Central

Sutezolid (PNU-100480 [U-480]) is an oxazolidinone antimicrobial being developed for the treatment of tuberculosis. An active sulfoxide metabolite (PNU-101603 [U-603]), which reaches concentrations in plasma several times those of the parent, has been reported to drive the killing of extracellular Mycobacterium tuberculosis by sutezolid in hollow-fiber culture. However, the relative contributions of the parent and metabolite against intracellular M. tuberculosis in vivo are not fully understood. The relationships between the plasma concentrations of U-480 and U-603 and intracellular whole-blood bactericidal activity (WBA) in ex vivo cultures were examined using a direct competitive population pharmacokinetic (PK)/pharmacodynamic 4-parameter sigmoid model. The data set included 690 PK determinations and 345 WBA determinations from 50 tuberculosis patients enrolled in a phase 2a sutezolid trial. The model parameters were solved iteratively. The median U-603/U-480 concentration ratio was 7.1 (range, 1 to 28). The apparent 50% inhibitory concentration of U-603 for intracellular M. tuberculosis was 17-fold greater than that of U-480 (90% confidence interval [CI], 9.9- to 53-fold). Model parameters were used to simulate in vivo activity after oral dosing with sutezolid at 600 mg twice a day (BID) and 1,200 mg once a day (QD). Divided dosing resulted in greater cumulative activity (?0.269 log10 per day; 90% CI, ?0.237 to ?0.293 log10 per day) than single daily dosing (?0.186 log10 per day; 90% CI, ?0.160 to ?0.208 log10 per day). U-480 accounted for 84% and 78% of the activity for BID and QD dosing, respectively, despite the higher concentrations of U-603. Killing of intracellular M. tuberculosis by orally administered sutezolid is mainly due to the activity of the parent compound. Taken together with the findings of other studies in the hollow-fiber model, these findings suggest that sutezolid and its metabolite act on different mycobacterial subpopulations. PMID:24687496

Zhu, Tong; Friedrich, Sven O.; Diacon, Andreas

2014-01-01

190

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

PubMed

Japan is still "intermediate burden" country as medium-incidence of tuberculosis (TB). But the incidence of TB varies by public health units. The priority for TB control would be lowering in the areas where the incidence of TB is relatively low. In addition, younger age groups get low prevalence of TB infection than elderly persons. As a result, fewer experiences for TB diagnosis and treatment in the hospital and the medical facility would cause the delay in the detection of TB patients which eventually cause outbreaks. Although there are differences in population density and population mobility between urban and rural areas, the socially economic vulnerable patients and foreign patients are the common risks. Any public health units' policies of TB should correspond to the individual situation. At the era of low tuberculosis incidence, the infection risk is to be "From ubiquitous to the uneven distribution". This makes TB detection much more difficult. At this symposium, each speaker presented the case for actually experienced with QFT test and/or VNTR analysis. They mainly focused on the paradigm shift in TB control which is indispensable for resolving the gaps in regional differences and the differences in diagnostic capability. Although the cases in this symposium were not for the low incidence situation, the pioneering approaches presented here would boost the future application of QFT and VNTR analysis nationwide. The discussions also partially covered the technical infrastructure for molecular epidemiology which covers the whole country. By making full use of QFT test and VNTR analysis as a contact screening tool, we can appropriately understand the risk of TB infection in the region from a buildup of bacteria and patient information. Now is the time to prepare for. Active surveillance of TB by this way would clarify the risk of the disease and lead to the advocacy essential for the resolution. 1. Current situation and challenge of contact survey by using QFT test in Tokyo: Hideo MAEDA (Bureau of Social Welfare and Public Health, Tokyo Metropolitan Government). 2. Contact investigation of a tuberculosis outbreak: Kenichi MIYAMOTO (Takaido Community Health Center). We have experienced a TB outbreak in integrated junior and senior high school in Tokyo. Index patient was a student with persistent respiratory symptoms for six months before diagnosis of sputum smear-positive TB. Public health center started contact investigation immediately. QFT-positive rates were high in close contacts, especially in classmates. Additionally, a student outside of contact investigation was diagnosed as TB and considered to be infected from the first patient by VNTR analysis. Therefore, public health center expanded QFT-tests to all students and teachers in this school. Finally, 9 students and 2 teachers in this school were diagnosed as sputum smear-negative TB by contact investigation. 3. Utilization of molecular epidemiological procedure in contact investigation in Kyoto City: Masahiro ITO (Public Health Center of Kyoto City) Molecular epidemiological procedure using VNTR analysis has been used for contact investigation of tuberculosis since January 2011 in Kyoto City. One hundred forty four strains of Mycobacterium tuberculosis from patients with tuberculosis were investigated and 130 strains were fully analyzed. Fourteen clusters were found and the number of strains included in the cluster was ranged from two to 11. Epidemiological relationship between patients in one cluster was found, however, significant relationship in another clusters was not demonstrated. It was suggested that VNTR analysis is useful for molecular epidemiological analysis of tuberculosis. 4. The population based molecular epidemiological studies and QFT test in a contact examination: Riyo FUJIYAMA, Keisuke MATSUBAYASHI, Setsuko MIZUSHIRI, Junko HIGUCHIL Chika SHIRAI, Yuko KATAGAMI, Mieko CHIHARA, Akihiro IJICHI (Kobe City Public Health Center), Kentaro ARIKAWA, Noriko NAKANISHI, Tomotada IWAMOTO (Kobe Institute of Health). The population ba

Maeda, Hideo; Shirai, Chika

2013-03-01

191

Seasonal Variations in Notification of Active Tuberculosis Cases in China, 2005-2012  

PubMed Central

Background Although seasonal variation in tuberculosis (TB) incidence has been described in many countries, it remains unknown in China. Methods A time series decomposition analysis (X-12-ARIMA) was performed to examine the seasonal variation in active TB cases nationwide from 2005 through 2012 in China. Seasonal amplitude was calculated for the evaluation of TB seasonal variation. Results A total of 7.78 million active TB cases were reported over a period of 8 years. A spring peak (April) was observed with seasonal amplitude of 46.3%, compared with the winter trough (February). Most cases in provinces with subtropical and tropical monsoon climate showed lower amplitudes than those in temperate continental, plateau and mountain climate regions. The magnitude of seasonality varied inversely with annual average temperature, r (95% CI)?=?-0.71 (-0.79, -0.61). The seasonal amplitudes were 56.7, 60.5, 40.6, 46.4 and 50.9% for patients aged ?14, 15–24, 25–44, 45–64, and ?65 years, respectively. Students demonstrated greater seasonal amplitude than peasants, migrant workers and workers (115.3% vs. 43.5, 41.6 and 48.1%). Patients with pulmonary TB had lower amplitude compared to patients with pleural and other extra-pulmonary TB (EPTB) (45.9% vs. 52.0 and 56.3%). Relapse cases with sputum smear positive TB (SS+ TB) had significantly higher seasonal amplitude compared to new cases with sputum smear positive TB (52.2% vs. 41.6%). Conclusions TB is a seasonal disease in China. The peak and trough of TB transmission actually are in winter and in autumn respectively after factors of delay are removed. Higher amplitudes of TB seasonality are more likely to happen in temperate continental, plateau and mountain climate regions and regions with lower annual average temperature, and young person, students, patients with EPTB and relapse cases with SS+ TB are more likely to be affected by TB seasonality. PMID:23874512

Li, Xin-Xu; Wang, Li-Xia; Zhang, Hui; Du, Xin; Jiang, Shi-Wen; Shen, Tao; Zhang, Yan-Ping; Zeng, Guang

2013-01-01

192

Modeling of Novel Diagnostic Strategies for Active Tuberculosis - A Systematic Review: Current Practices and Recommendations  

PubMed Central

Introduction The field of diagnostics for active tuberculosis (TB) is rapidly developing. TB diagnostic modeling can help to inform policy makers and support complicated decisions on diagnostic strategy, with important budgetary implications. Demand for TB diagnostic modeling is likely to increase, and an evaluation of current practice is important. We aimed to systematically review all studies employing mathematical modeling to evaluate cost-effectiveness or epidemiological impact of novel diagnostic strategies for active TB. Methods Pubmed, personal libraries and reference lists were searched to identify eligible papers. We extracted data on a wide variety of model structure, parameter choices, sensitivity analyses and study conclusions, which were discussed during a meeting of content experts. Results & Discussion From 5619 records a total of 36 papers were included in the analysis. Sixteen papers included population impact/transmission modeling, 5 were health systems models, and 24 included estimates of cost-effectiveness. Transmission and health systems models included specific structure to explore the importance of the diagnostic pathway (n?=?4), key determinants of diagnostic delay (n?=?5), operational context (n?=?5), and the pre-diagnostic infectious period (n?=?1). The majority of models implemented sensitivity analysis, although only 18 studies described multi-way sensitivity analysis of more than 2 parameters simultaneously. Among the models used to make cost-effectiveness estimates, most frequent diagnostic assays studied included Xpert MTB/RIF (n?=?7), and alternative nucleic acid amplification tests (NAATs) (n?=?4). Most (n?=?16) of the cost-effectiveness models compared new assays to an existing baseline and generated an incremental cost-effectiveness ratio (ICER). Conclusion Although models have addressed a small number of important issues, many decisions regarding implementation of TB diagnostics are being made without the full benefits of insight from mathematical models. Further models are needed that address a wider array of diagnostic and epidemiological settings, that explore the inherent uncertainty of models and that include additional epidemiological data on transmission implications of false-negative diagnosis and the pre-diagnostic period. PMID:25340701

Zwerling, Alice; White, Richard G.; Vassall, Anna; Cohen, Ted; Dowdy, David W.; Houben, Rein M. G. J.

2014-01-01

193

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

PubMed

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

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

2010-11-19

194

Hepatobiliary tuberculosis  

PubMed Central

Hepatobiliary tuberculosis is a rare manifestation of Mycobacterium tuberculosis infection and is usually secondary to tuberculosis of the lungs or gastrointestinal tract. Diagnosis is difficult pre-operatively in local (focal and tubular) forms because of its rarity and presentation in the form of non-specific symptoms and signs and lack of any defined criteria on imaging studies. Histopathological examination is necessary for definite diagnosis but in cases where there is suspicion of hepatobiliary tuberculosis, with PCR assay diagnosis it is possible pre-operatively. Recommended treatment is with conventional antituberculous drugs and surgical intervention in tuberculous abscess or granulomas. The disease is usually associated with good prognosis under complete antituberculous treatment. The author encountered 4 cases of hepatobiliary tuberculosis over 5 years. The aim of this article is to present current knowledge of hepatobiliary tuberculosis and to comprehensively review all the available literature. PMID:24976240

Chaudhary, Poras

2014-01-01

195

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

PubMed Central

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

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

196

38 CFR 3.959 - Tuberculosis.  

Code of Federal Regulations, 2010 CFR

...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...

2010-07-01

197

38 CFR 3.959 - Tuberculosis.  

Code of Federal Regulations, 2011 CFR

...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...

2011-07-01

198

38 CFR 3.959 - Tuberculosis.  

Code of Federal Regulations, 2012 CFR

...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...

2012-07-01

199

38 CFR 3.959 - Tuberculosis.  

Code of Federal Regulations, 2013 CFR

...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...

2013-07-01

200

A predictive signature gene set for discriminating active from latent tuberculosis in Warao Amerindian children  

PubMed Central

Background Tuberculosis (TB) continues to cause a high toll of disease and death among children worldwide. The diagnosis of childhood TB is challenged by the paucibacillary nature of the disease and the difficulties in obtaining specimens. Whereas scientific and clinical research efforts to develop novel diagnostic tools have focused on TB in adults, childhood TB has been relatively neglected. Blood transcriptional profiling has improved our understanding of disease pathogenesis of adult TB and may offer future leads for diagnosis and treatment. No studies applying gene expression profiling of children with TB have been published so far. Results We identified a 116-gene signature set that showed an average prediction error of 11% for TB vs. latent TB infection (LTBI) and for TB vs. LTBI vs. healthy controls (HC) in our dataset. A minimal gene set of only 9 genes showed the same prediction error of 11% for TB vs. LTBI in our dataset. Furthermore, this minimal set showed a significant discriminatory value for TB vs. LTBI for all previously published adult studies using whole blood gene expression, with average prediction errors between 17% and 23%. In order to identify a robust representative gene set that would perform well in populations of different genetic backgrounds, we selected ten genes that were highly discriminative between TB, LTBI and HC in all literature datasets as well as in our dataset. Functional annotation of these genes highlights a possible role for genes involved in calcium signaling and calcium metabolism as biomarkers for active TB. These ten genes were validated by quantitative real-time polymerase chain reaction in an additional cohort of 54 Warao Amerindian children with LTBI, HC and non-TB pneumonia. Decision tree analysis indicated that five of the ten genes were sufficient to classify 78% of the TB cases correctly with no LTBI subjects wrongly classified as TB (100% specificity). Conclusions Our data justify the further exploration of our signature set as biomarkers for potential childhood TB diagnosis. We show that, as the identification of different biomarkers in ethnically distinct cohorts is apparent, it is important to cross-validate newly identified markers in all available cohorts. PMID:23375113

2013-01-01

201

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

PubMed Central

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

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

202

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

Microsoft Academic Search

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

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

2011-01-01

203

[Tuberculosis in compromised hosts].  

PubMed

Recent development of tuberculosis in Japan tends to converge on a specific high risk group. The proportion of tuberculosis developing particularly from the compromised hosts in the high risk group is especially high. At this symposium, therefore, we took up diabetes mellitus, gastrectomy, dialysis, AIDS and the elderly for discussion. Many new findings and useful reports for practical medical treatment are submitted; why these compromised hosts are predisposed to tuberculosis, tuberculosis diagnostic and remedial notes of those compromised hosts etc. It is an important question for the future to study how to prevent tuberculosis from these compromised hosts. 1. Tuberculosis in diabetes mellitus: aggravation and its immunological mechanism: Kazuyoshi KAWAKAMI (Department of Internal Medicine, Division of Infectious Diseases, Graduate School and Faculty of Medicine, University of the Ryukyus). It has been well documented that diabetes mellitus (DM) is a major aggravating factor in tuberculosis. The onset of this disease is more frequent in DM patients than in individuals with any underlying diseases. However, the precise mechanism of this finding remains to be fully understood. Earlier studies reported that the migration, phagocytosis and bactericidal activity of neutrophils are all impaired in DM patients, which is related to their reduced host defense to infection with extracellular bacteria, such as S. aureus and E. colli. Host defense to mycobacterial infection is largely mediated by cellular immunity, and Th1-related cytokines, such as IFN-gamma and IL-12, play a central role in this response. It is reported that serum level of these cytokines and their production by peripheral blood mononuclear cells (PBMC) are reduced in tuberculosis patients with DM, and this is supposed to be involved in the high incidence of tuberculosis in DM. Our study observed similar findings and furthermore indicated that IFN-gamma and IL-12 production by BCG-stimulated PBMC was lower in poorly-controlled DM patients than that in well-controlled DM patients and healthy subjects. Thus, these clinical data suggest that the high incidence of tuberculosis in DM patients is due to the impaired production of Th1-related cytokines. However, direct evidences to prove this possibility remain to be obtained. In 1980, Saiki and co-workers reported that host defense and delayed-type hypersensitivity response to M. tuberculosis was hampered in a mouse DM model established by injecting streptozotocin (Infect Immun. 1980; 28: 127-131). We followed their investigation with the similar observations. Interestingly, levels of IFN-gamma and IL-12 in serum, lung, liver and spleen after infection were significantly reduced in DM mice when compared with those in control mice. Considered collectively, these results strongly suggest that the reduced production of Th1-related cytokines leads to the susceptibility of DM to mycobacterial infection. However, it remains to be understood how DM hampers the synthesis of Th1-related cytokines. In our preliminary study, the production of these cytokines by PBMC from DM patients and healthy subjects was not affected under a high glucose condition. Thus, it is not likely that the increased level of glucose directly suppresses the cell-mediated immune responses. Further investigations are needed to make these points clear. 2. A study of gastrectomy cases in pulmonary tuberculosis patients: Takenori YAGI (Division of Thoracic Disease, National Chiba-Higashi Hospital). Patients who have undergone gastric resection are considered at increased risk of developing pulmonary tuberculosis. I have investigated the role played by gastrectomy in giving rise to pulmonary tuberculosis. Of 654 pulmonary tuberculosis patients admitted to National Chiba-Higashi Hospital from January 1999 to December 2001, 55 patients (31-84 years old, mean 63.5 +/- 12.5 years, 48 males and 7 females) had the history of gastric resection. The incidence of gastrectomy among patients with pulmonary tuberculosis was 8.4 percent. The mean age of gastric resection

2003-11-01

204

Activities of TMC207, Rifampin, and Pyrazinamide against Mycobacterium tuberculosis Infection in Guinea Pigs?  

PubMed Central

The experimental compound TMC207 is showing promise against infections caused by Mycobacterium tuberculosis both in a variety of animal studies and in the field. In this study, we used the guinea pig model, a species that shows several similarities to human tuberculosis, including the hallmark of primary granuloma necrosis, to determine the efficacy of a combination regimen combining TMC207 with rifampin and pyrazinamide. This drug regimen rapidly reduced the bacterial load in the lungs to undetectable levels by 8 weeks of treatment. This reduction was associated with a substantial improvement in lung pathology, but despite this effect areas of residual necrosis still remained. In the draining lymph nodes, however, tissue damage was rapid and not significantly reversed by the drug treatment. Approximately 10 to 11 months after the treatment had ended, the animals began to trigger a Karnovsky scale indicating bacterial regrowth and potential relapse, an event confirmed by the new development of both pulmonary and extrapulmonary granulomatous lesions. Interestingly, a similar rate of relapse was also seen in animals receiving 24 weeks of rifampin, pyrazinamide, and isoniazid standard chemotherapy. These data indicate that TMC207 could be a useful addition to current treatment regimens for tuberculosis. PMID:20937788

Shang, Shaobin; Shanley, Crystal A.; Caraway, Megan L.; Orme, Eileen A.; Henao-Tamayo, Marcela; Hascall-Dove, Laurel; Ackart, David; Lenaerts, Anne J.; Basaraba, Randall J.; Orme, Ian M.; Ordway, Diane J.

2011-01-01

205

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

PubMed Central

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

2014-01-01

206

Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the ?-Ketoacyl-ACP Synthase mtFabH  

PubMed Central

Background Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over one-third of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration. Methodology/Principal Findings Our approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM) to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM's novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H37Rv and, dissociatively, against the ?-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H37Rv with an MIC of 0.06 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)thiazole-4-carboxylate inhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism. Conclusions/Significance These findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents. PMID:19440303

Al-Balas, Qosay; Anthony, Nahoum G.; Al-Jaidi, Bilal; Alnimr, Amani; Abbott, Grainne; Brown, Alistair K.; Taylor, Rebecca C.; Besra, Gurdyal S.; McHugh, Timothy D.; Gillespie, Stephen H.; Johnston, Blair F.; Mackay, Simon P.; Coxon, Geoffrey D.

2009-01-01

207

Enhanced Bactericidal Activity of Rifampin and/or Pyrazinamide When Combined with PA-824 in a Murine Model of Tuberculosis ?  

PubMed Central

PA-824 is in phase II clinical testing to treat tuberculosis. At a dose of 100 mg/kg of body weight, it has demonstrated bactericidal activity during the initial and continuation phases of treatment in a murine model of tuberculosis. In a prior study, substitution of PA-824 for isoniazid in the first-line regimen of rifampin, isoniazid, and pyrazinamide resulted in significantly lower CFU counts at 2 months and shorter time to culture-negative conversion. However, the study design prevented a rigorous assessment of the relapse rate after completion of therapy. The current experiment was designed to assess (i) the extent of the beneficial effect of substituting PA-824 for isoniazid in the first-line regimen, (ii) the influence of the PA-824 dose on the same effect, and (iii) the activity of each one-, two-, and three-drug combination of rifampin, PA-824, and pyrazinamide. Mice were infected by the aerosol route and initiated on treatment 14 days later with more than 7 log10 CFU per lung. Treatment with rifampin and pyrazinamide was more effective than treatment with rifampin, isoniazid, and pyrazinamide at reducing the lung CFU count, consistent with past evidence of isoniazid's antagonism in this model. The addition of PA-824 at 12.5 and 25 mg/kg/day did not increase the activity of rifampin plus pyrazinamide, but the addition of PA-824 at 50 and 100 mg/kg/day did increase the activity in a dose-dependent manner. The combination of rifampin, PA-824 (100 mg/kg), and pyrazinamide rendered all mice culture negative after 2 months of treatment and free of relapse after 4 months of treatment, while some mice receiving rifampin, isoniazid, and pyrazinamide remained culture positive and 15% relapsed after completing 4 months of treatment. The two-drug combination of PA-824 and pyrazinamide displayed synergistic activity that was equivalent to that of the standard first-line regimen. Together, these results support the evaluation of regimens based on the combination of rifampin, PA-824, and pyrazinamide in phase II clinical trials while demonstrating several potential pitfalls in the evaluation of new drug combinations in a murine model of tuberculosis. PMID:18694943

Tasneen, Rokeya; Tyagi, Sandeep; Williams, Kathy; Grosset, Jacques; Nuermberger, Eric

2008-01-01

208

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

PubMed Central

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

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

2013-01-01

209

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

PubMed Central

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

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

2014-01-01

210

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

PubMed

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

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

2011-01-01

211

Clavicular osteomyelitis: a rare presentation of extra pulmonary tuberculosis.  

PubMed

Clavicular tuberculosis is a rare entity, an unusual case of skeletal tuberculosis. We report a case of rare presentation of clavicular tuberculosis as a non-healing ulcer in the medial two-third and lateral one-third of the clavicle. The clinical picture was confusing because of the development of foul-smelling discharge due to secondary infection. The diagnosis is rarely suspected before biopsies because tumours are much more frequent than infections in this bone. With worldwide resurgence of tuberculosis, clinicians should maintain a high index of suspicion as more infection at unusual sites is being reported. PMID:24964439

Dugg, Pankaj; Shivhare, Pankaj; Mittal, Sushil; Singh, Harnam; Tiwari, Punit; Sharma, Ankur

2013-01-01

212

When Tuberculosis Comes Back: Who Develops Recurrent Tuberculosis in California?  

PubMed Central

Background Recurrent tuberculosis suggests potentially modifiable gaps in tuberculosis treatment and control activities. The frequency of late recurrences following treatment completion has not been well-studied. We determined the frequency of, and risk factors associated with, tuberculosis that recurs at least one year after completion of anti-tuberculosis therapy in California. Methods The study population included culture-positive, pulmonary tuberculosis patients reported to the California tuberculosis case registry from 1993 to 2007 who completed anti-tuberculosis therapy. A person with late recurrent tuberculosis was defined as an individual that appeared in the registry more than once, determined by match on name and date-of-birth, with at least one year between treatment completion of the first episode and treatment initiation of the second episode. Results Among 23,517 tuberculosis patients, 148 (0.63%) had a late recurrence. Independent risk factors for recurrence included: infection with a pyrazinamide mono-resistant isolate (adjusted hazard ratio, 2.93; p?=?0.019); initiation of an isoniazid- and rifampin-only treatment regimen (adjusted hazard ratio, 2.55; p?=?0.0412); sputum smear-positive disease (adjusted hazard ratio, 1.96; p?=?0.0003); human immunodeficiency virus infection (adjusted hazard ratio, 1.81; p?=?0.0149); and birth in the United States (adjusted hazard ratio, 1.88; p?=?0.0002). Infection with an isoniazid mono-resistant isolate was protective (adjusted hazard ratio, 0.25; p?=?0.0171). Conclusions The low frequency of late recurrent tuberculosis in California suggests that local TB control programs are largely successful at preventing this adverse outcome. Nonetheless, we identified subpopulations at increased risk of late tuberculosis recurrence that may benefit from additional medical or public health interventions. PMID:22069456

Pascopella, Lisa; DeRiemer, Kathryn; Watt, James P.; Flood, Jennifer M.

2011-01-01

213

Diagnosis and therapy for prostate tuberculosis.  

PubMed

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

Kulchavenya, Ekaterina; Brizhatyuk, Elena; Khomyakov, Victor

2014-08-01

214

Diagnosis and therapy for prostate tuberculosis  

PubMed Central

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

Brizhatyuk, Elena; Khomyakov, Victor

2014-01-01

215

Synthesis of 3-heteryl substituted pyrrolidine-2,5-diones via catalytic Michael reaction and evaluation of their inhibitory activity against InhA and Mycobacterium tuberculosis.  

PubMed

In the present paper, we report the synthesis via catalytic Michael reaction and biological results of a series of 3-heteryl substituted pyrrolidine-2,5-dione derivatives as moderate inhibitors against Mycobacterium tuberculosis H37Rv growth. Some of them present also inhibition activities against InhA. PMID:24269516

Matviiuk, Tetiana; Mori, Giorgia; Lherbet, Christian; Rodriguez, Frédéric; Pasca, Maria Rosalia; Gorichko, Marian; Guidetti, Brigitte; Voitenko, Zoia; Baltas, Michel

2014-01-01

216

The endothelial protein C receptor and activated protein C play a limited role in host defense during experimental tuberculosis.  

PubMed

The protein C (PC) system is an important regulator of both coagulation and inflammation. Activated PC (APC), together with its receptor the endothelial protein C receptor (EPCR), has anticoagulant and anti-inflammatory properties. During tuberculosis (TB), a devastating chronic pulmonary disease caused by Mycobacterium (M.) tuberculosis, both a local inflammatory reaction characterised by the recruitment of mainly mononuclear cells and the formation of pulmonary granulomas as well as activation of coagulation occurs as part of the host immune response. We investigated the role of EPCR and APC in a mouse model of TBusing mice overexpressing EPCR (Tie2-EPCR), mice deficient for EPCR (EPCR-/-), mice treated with APC-inhibiting antibodies and mice overexpressing APC (APChigh) and compared them with wild-type (WT) mice. Blood and organs were harvested to quantify bacterial loads, cellular influxes, cytokines, histopathology and coagulation parameters. Additionally observation studies were performed. Lung EPCR expression was upregulated during experimental TB. No significant differences in bacterial growth were seen between WT and Tie2-EPCR mice. However, Tie2-EPCR mice had decreased pulmonary coagulation activation, displayed an increased influx of macrophages 2 and 6 weeks after infection, but no increase in other proinflammatory markers. On the other hand, in EPCR-/--mice coagulation activation was decreased 6 weeks post-infection, with little impact on other inflammation markers. APC-overexpression or treatment with anti-(A)PC antibodies displayed minimal effects during experimental TB. In conclusion, EPCR and APC play a limited role in the host response during experimental pulmonary TB. PMID:23348224

Kager, Liesbeth M; Roelofs, Joris J T H; de Vos, Alex F; Wieland, Catharina W; Schouten, Marcel; Meijers, Joost C M; Isermann, Berend; Van't Veer, Cornelis; Esmon, Charles T; van der Poll, Tom

2013-04-01

217

Corticosteroid-modulated Immune Activation in the Tuberculosis Immune Reconstitution Inflammatory Syndrome  

PubMed Central

Rationale: HIV–tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an immunopathological reaction to mycobacterial antigens induced by antiretroviral therapy. Prednisone reduces morbidity in TB-IRIS, but the mechanisms are unclear. Objectives: To determine the effect of prednisone on the inflammatory response in TB-IRIS (antigen-specific effector T cells, cytokines, and chemokines). Methods: Blood was taken from participants in a randomized placebo-controlled trial of prednisone for TB-IRIS, at 0, 2, and 4 weeks. Participants received prednisone at a dosage of 1.5 mg/kg/day for 2 weeks followed by 0.75 mg/kg/day for 2 weeks, or placebo at identical dosages. Measurements and Main Results: Analyses included IFN-? enzyme-linked immunospot (ELISPOT), reverse transcription-polymerase chain reaction on peripheral blood mononuclear cells after restimulation with heat-killed Mycobacterium tuberculosis, Luminex multiplex cytokine analysis of corresponding tissue culture supernatants, and Luminex multiplex cytokine analysis of serum. Fifty-eight participants with TB-IRIS (31 receiving prednisone, 27 receiving placebo) were included. In serum, significant decreases in IL-6, IL-10, IL-12 p40, tumor necrosis factor-?, IFN-?, and IFN-?–induced protein-10 concentrations during prednisone, but not placebo, treatment were observed. No differences in ELISPOT responses comparing prednisone and placebo groups were shown in response to ESAT-6 (early secreted antigen target-6), Acr1, Acr2, 38-kD antigen, or heat-killed H37Rv M. tuberculosis. Purified protein derivative ELISPOT responses increased over 4 weeks in the prednisone group and decreased in the placebo group (P = 0.007). Conclusions: The beneficial effects of prednisone in TB-IRIS appear to be mediated via suppression of predominantly proinflammatory cytokine responses of innate immune origin, not via a reduction of the numbers of antigen-specific T cells in peripheral blood. PMID:22700860

Skolimowska, Keira H.; Wilkinson, Katalin A.; Matthews, Kerryn; Tadokera, Rebecca; Conesa-Botella, Anali; Seldon, Ronnett; Rangaka, Molebogeng X.; Rebe, Kevin; Pepper, Dominique J.; Morroni, Chelsea; Colebunders, Robert; Maartens, Gary; Wilkinson, Robert J.

2012-01-01

218

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

PubMed

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

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

2007-10-01

219

Current Concepts in the Management of Tuberculosis  

PubMed Central

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

Sia, Irene G.; Wieland, Mark L.

2011-01-01

220

Suspected Buruli ulcer of the face: a case report from Ethiopia.  

PubMed

We describe the clinical course of a 14-month-old boy with suspected Buruli ulcer of the face treated nonsurgically with rifampin and ciprofloxacin. Our patient presented with comorbid AIDS, presumed tuberculosis (noncutaneous) and severe acute malnutrition. To our knowledge, this is the first report to describe the nonsurgical management of facial Buruli ulcer. PMID:24030348

Gordon, David; Zelalem, Meseret; Schutze, Gordon E; Bilcha, Kasahun

2014-03-01

221

Active site residues in Mycobacterium tuberculosis pantothenate synthetase required in the formation and stabilization of the adenylate intermediate.  

PubMed

Pantothenate synthetase (EC 6.3.2.1) catalyzes the formation of pantothenate from ATP, D-pantoate, and beta-alanine in bacteria, yeast, and plants. The three-dimensional structural determination of pantothenate synthetase from Mycobacterium tuberculosis has indicated specific roles for His44, His47, Asn69, Gln72, Lys160, and Gln164 residues in the binding of substrates and the pantoyl adenylate intermediate. To evaluate the functional roles of these strictly conserved residues, we constructed six Ala mutants and determined their catalytic properties. The substitution of alanine for H44, H47, N69, Q72, and K160 residues in M. tuberculosis pantothenate synthetase caused a greater than 1000-fold reduction in enzyme activity, while the Q164A mutant exhibited 50-fold less activity. The rate of the isolated adenylation reaction in single turnover studies was also reduced 40-1000-fold by the replacement of one of these six amino acids with alanine, suggesting that these residues are essential for the formation of the pantoyl adenylate intermediate. The rate of pantothenate formation from the adenylate and beta-alanine in the second half reaction could not be measured for the H44A, H47A, N69A, Q72A, and K160A mutants and was reduced 40-fold in the Q164A mutants. The activity of the K160C mutant enzyme was markedly enhanced by the alkylation of cysteine with bromoethylamine, further supporting the critical role of the K160 residue in pantoyl adenylate formation. Isothermal titration microcalorimetry analysis demonstrated that the substitution of either H47 or K160 for Ala resulted in a decreased affinity of the enzyme for ATP. These results indicate that the highly conserved His44, His47, Asn69, Gln72, Lys160 and residues are essential for the formation and stabilization of pantoyl adenylate intermediate in the pantothenate synthetase reaction. PMID:15170354

Zheng, Renjian; Dam, Tarum K; Brewer, C Fred; Blanchard, John S

2004-06-01

222

Perinatal tuberculosis.  

PubMed

Perinatal tuberculosis is insufficiently understood. Its early diagnosis is essential but often difficult as the initial manifestations may be delayed. Improved screening of women at risk and sensitivity of the medical community are necessary. A coherent system of cooperation between the hospital and community services and between pediatricians and adult physicians is indispensable to find the index adult case to break the chain of contagion as well as to offer prophylactic therapy to the children at risk. We hereby report a baby with perinatal tuberculosis who was not offered any prophylactic therapy inspite of the mother being diagnosed to have pulmonary tuberculosis. PMID:11370442

Ray, M; Goraya, J S; Basu, S; Parmar, V

2001-04-01

223

Tuberculosis control in India: why are we failing?  

PubMed

In spite of being the pioneer-leader of research into epidemiology and prevention of tuberculosis among low-income countries, India has the highest population-based burden of tuberculosis among all nations. Children with latent tuberculosis are the pool from which adult pulmonary tuberculosis emerges many years later. In the absence of primary prevention of infection by BCG, sociologic/behavioral interventions must be applied to reduce air-borne transmission. In addition to maximizing passive surveillance of adult disease, pediatric tuberculosis must also be brought under surveillance. Those with latent tuberculosis must be detected and treated to remove them from the pool. Epidemiologically, the realistic monitoring method of tuberculosis control trajectory is documenting progressive reduction of the short incubation period pediatric disease through surveillance, and not the reduction of long incubation period adult pulmonary tuberculosis. Application of scientific tools for the detection and management of pediatric tuberculosis infection - latent and active - holds the key to effective tuberculosis control. PMID:25031127

John, T Jacob

2014-07-01

224

Sternal Tuberculosis  

PubMed Central

Extra-pulmonary tuberculosis constitutes 15-20% of total tuberculosis (TB) case load in immuno-competent patients. Affliction of the skeletal system is rare with still rarer presentation of sternal osteomyelitis even in endemic countries. A patient with primary sternal TB presenting with multiple cutaneous sinuses over the anterior chest wall is being reported. A high element of suspicion is needed more so in resource limited setting for early diagnosis and treatment. PMID:24349840

Sachdeva, R; Sachdeva, S; Arora, S

2013-01-01

225

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

ERIC Educational Resources Information Center

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…

Connaghan, Kathryn P.; Moore, Christopher A.

2013-01-01

226

Characterization of suspected illegal skin whitening cosmetics.  

PubMed

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

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

2014-03-01

227

An Unusual Suspect  

ERIC Educational Resources Information Center

In this article, the author discusses the work of Dr. Grace Lee Boggs. It begins with a history of her childhood and education, then provides an account of Boggs's awakening to the cause of Black liberation, the history of her work within the movement, and her current activities. Throughout the article, other scholars discuss their deep…

Lum, Lydia

2007-01-01

228

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

SciTech Connect

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.

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

2009-05-26

229

Design, chemical synthesis of 3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione derivatives and biological activity against enoyl-ACP reductase (InhA) and Mycobacterium tuberculosis.  

PubMed

We report here the discovery, synthesis and screening results of a series of 3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione derivatives as a novel class of potent inhibitors of Mycobacterium tuberculosis H37Rv strain as well as the enoyl acyl carrier protein reductase (ENR) InhA. Among them, several compounds displayed good activities against InhA which is one of the key enzymes involved in the type II fatty acid biosynthesis pathway of the mycobacteria cell wall. Furthermore, some exhibited promising activities against M. tuberculosis and multi-drug resistant M. tuberculosis strains. PMID:24140915

Matviiuk, Tetiana; Rodriguez, Frédéric; Saffon, Nathalie; Mallet-Ladeira, Sonia; Gorichko, Marian; de Jesus Lopes Ribeiro, Ana Luisa; Pasca, Maria Rosalia; Lherbet, Christian; Voitenko, Zoia; Baltas, Michel

2013-01-01

230

Antimycobacterial activity of ferutinin alone and in combination with antitubercular drugs against a rapidly growing surrogate of Mycobacterium tuberculosis.  

PubMed

The aim of this study was to investigate the antimycobacterial activity of the major daucane constituent, ferutinin (jaeschkeandiol p-hydroxybenzoate, 1), four of its natural analogues, its hydrolysis products, as well as methyl p-hydroxybenzoate (methylparaben) against Mycobacterium smegmatis, a rapidly growing surrogate of Mycobacterium tuberculosis. The agar dilution assay was utilised for an antimycobacterial evaluation of single compounds. A modified agar dilution assay, the checkerboard method, was utilised for evaluating the potentiating effect of 1 on different antitubercular drugs, namely isoniazid, ethionamide, rifampin and streptomycin. In the agar dilution assay, 1 exhibited higher potency (minimum inhibitory concentration [MIC] 10?µg?mL?¹) than streptomycin and rifampin (MIC 20?µg?mL?¹ for each). Of the natural analogues, 8,9-epoxyjaeschkeandiol p-hydroxybenzoate and 8,9-epoxyjaeschkeandiol benzoate exhibited marginal activity (MIC???40 and 80?µg?mL?¹, respectively). The checkerboard method showed that the combination of 1 with each antitubercular drug led to mutual enhancement of the antimycobacterial activity with isoniazid and ethionamide, while no such effect was observed with rifampin or streptomycin. Based on this study and earlier studies with Staphylococcus aureus, the major constituent 1 may be responsible for the major part of the antimicrobial activity of the root of Ferula hermonis. PMID:21442547

Abourashed, Ehab A; Galal, Ahmed M; Shibl, Atef M

2011-07-01

231

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

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...

Mire, Joseph Andrew

2013-07-24

232

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

PubMed

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

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

2014-09-01

233

Comparison of interferon-?-, interleukin (IL)-17- and IL-22-expressing CD4 T cells, IL-22-expressing granulocytes and proinflammatory cytokines during latent and active tuberculosis infection  

PubMed Central

In this study, we investigated the role and expression of T helper type 17 (Th17) cells and Th17 cytokines in human tuberculosis. We show that the basal proportion of interferon (IFN)-?-, interleukin (IL)-17- and IL-22-expressing CD4+ T cells and IL-22-expressing granulocytes in peripheral blood were significantly lower in latently infected healthy individuals and active tuberculosis patients compared to healthy controls. In contrast, CD4+ T cells expressing IL-17, IL-22 and IFN-? were increased significantly following mycobacterial antigens stimulation in both latent and actively infected patients. Interestingly, proinflammatory IFN-? and tumour necrosis factor (TNF)-? were increased following antigen stimulation in latent infection. Similarly, IL-1?, IL-4, IL-8, IL-22 and TNF-? were increased in the serum of latently infected individuals, whereas IL-6 and TNF-? were increased significantly in actively infected patients. Overall, we observed differential induction of IL-17-, IL-22- and IFN-?-expressing CD4+ T cells, IL-22-expressing granulocytes and proinflammatory cytokines in circulation and following antigenic stimulation in latent and active tuberculosis. PMID:22236009

Cowan, J; Pandey, S; Filion, L G; Angel, J B; Kumar, A; Cameron, D W

2012-01-01

234

Diagnosis of Childhood Tuberculosis and Host RNA Expression in Africa  

PubMed Central

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

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

235

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

SciTech Connect

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.

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

2009-03-02

236

A quality assessment tool for tuberculosis control activities in resource limited settings  

PubMed Central

Tuberculosis (TB) is a significant problem, infecting nearly 9 million new patients per year and killing about 2 million a year. The primary means with which to affect TB globally are to decrease transmission locally, mainly by effective identification, diagnosis, and treatment of infectious TB patients. Therefore, quality assurance of TB control efforts at the local level is essential. This study describes the creation of a data extraction tool for retrospective chart review based on the International Standards for TB Care, 2009 for the assessment of TB control programs located in resource limited settings. The tool was field tested at a rural mission hospital in central Kenya. Results were used by host site staff to develop a quality improvement plan. The process prompted revision of the tool to clarify questions and answers. This is a tool that can be used in resource limited settings for data collection to assess the quality of TB care and to inform the design, implementation, and further assessment of future quality improvement initiatives. PMID:22088324

Smith, Nathaniel; Shirley, Rhett; Achieng, Loice; Keiser, Philip

2011-01-01

237

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

PubMed

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

2013-03-22

238

IFN-?-inducible protein 10 and pentraxin 3 plasma levels are tools for monitoring inflammation and disease activity in Mycobacterium tuberculosis infection  

Microsoft Academic Search

IFN-?-inducible protein 10 (IP-10\\/CXCL10) is a chemokine involved in delayed-type hypersensitivity and attraction of monocytes and activated T lymphocytes at inflammatory foci, whereas pentraxin 3 (PTX3) is part of the innate immune response. In the Republic of Guinea, 220 newly diagnosed, HIV-negative, pulmonary tuberculosis (TB) patients were studied together with 220 healthy household controls and 220 community controls. CXCL10 and

Annalisa Azzurri; Oumou Y. Sow; Amedeo Amedei; Boubacar Bah; Sadio Diallo; Giuseppe Peri; Marisa Benagiano; Mario M. D’Elios; Alberto Mantovani; Gianfranco Del Prete

2005-01-01

239

Comparative antimicrobial activities of gatifloxacin, sitafloxacin and levofloxacin against Mycobacterium tuberculosis replicating within Mono Mac 6 human macrophage and A-549 type II alveolar cell lines  

Microsoft Academic Search

Mycobacterium tuberculosis (MTB) is capable of invading not only macrophages (M?s) but also type II pneumocytes. In this study, we compared the antimicrobial activities of fluoroquinolones, including gati- floxacin, sitafloxacin and levofloxacin, against the MTB replication in the Mono Mac 6 human M? cell line (MM6-M?s) and the A-549 human type II alveolar epithelial cell line (A-549 cells). When test

K. Sato; H. Tomioka; C. Sano; T. Shimizu; K. Sano; K. Ogasawara; S. Cai; T. Kamei

2003-01-01

240

The DosR Dormancy Regulator of Mycobacterium tuberculosis Stimulates the Na(+)/K (+) and Ca (2+) ATPase Activities in Plasma Membrane Vesicles of Mycobacteria.  

PubMed

The latency global regulator DosR regulon of Mycobacterium tuberculosis, which is stimulated by hypoxia, comprises approximately fifty genes including ctpF (Rv1997), which encodes a putative alkali/alkaline earth ion transporter of the plasma membrane. In this work, the influence of hypoxia and M. tuberculosis DosR on the ATPase activity of mycobacterial plasma membrane was assessed. We performed bioinformatic analyses which indicated that the pma1 gene product is the M. smegmatis ortholog of the M. tuberculosis cation transporter CtpF. In addition, a possible Na(+), K(+) and/or Ca(2+) pumping mediated by Pma1 was also predicted. Enzymatic analyses indicated that the basal ATPase activity of plasma membrane vesicles from M. smegmatis cells cultured under hypoxia and over-expressing DosR, decreased 30 and 40 % respectively in comparison to oxygenated cells. In contrast, the specific Na(+)/K(+) and Ca(2+) ATPase activities of the plasma membrane increased 2.8- and 3.5-fold, respectively, under hypoxia, similar to that observed for cells over-expressing the DosR regulator. In agreement, RT-qPCR experiments demonstrated that the transcription level of the pma1 gene increased under hypoxia at levels similar to that of M. smegmatis cells over-expressing the M. tuberculosis DosR regulator. The entire findings suggest that hypoxia stimulates Na(+)/K(+) and Ca(2+) ATPase activities in the mycobacterial plasma membrane, and this is possibly mediated by the dormancy regulator DosR. PMID:24939385

Pulido, Paola A; Novoa-Aponte, Lorena; Villamil, Nicolás; Soto, Carlos Y

2014-11-01

241

Mycobacterium tuberculosis protein tyrosine phosphatase PtpB structure reveals a diverged fold and a buried active site.  

PubMed

Intracellular pathogenic bacteria manipulate host signal transduction pathways to facilitate infection. Mycobacterium tuberculosis protein tyrosine phosphatases (PTPs) PtpA and PtpB are thought to be secreted into host cells and interfere with unidentified signals. To illuminate the mechanisms of regulation and substrate recognition, we determined the 1.7 A resolution crystal structure of PtpB in complex with the product phosphate. The protein adopts a simplified PTP fold, which combines features of the conventional PTPs and dual-specificity phosphatases. PtpB shows two unusual elaborations--a disordered, acidic loop and a flexible, two-helix lid that covers the active site--that are specific to mycobacterial orthologs. Biochemical studies suggest that substrate mimicry in the lid may protect the phosphatase from oxidative inactivation. The insertion and deletion of large structural elements in PtpB suggest that, outside the active site module, the PTP family is under unusual selective pressure that promotes changes in overall structure. PMID:16271885

Grundner, Christoph; Ng, Ho-Leung; Alber, Tom

2005-11-01

242

Systematic Expression Profiling Analysis Identifies Specific MicroRNA-Gene Interactions that May Differentiate between Active and Latent Tuberculosis Infection  

PubMed Central

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.

Wu, Lawrence Shih-Hsin; Huang, Kai-Yao; Lee, Tzong-Yi; Hsu, Paul Wei-Che

2014-01-01

243

Revisiting the Natural History of Tuberculosis  

Microsoft Academic Search

Once Mycobacterium tuberculosis infects a person it can persist for a long time in a process called latent tuberculosis infection (LTBI). LTBI has traditionally\\u000a been considered to involve the bacilli remaining in a non-replicating state (dormant) in old lesions but still retaining their\\u000a ability to induce reactivation and cause active tuberculosis (TB) once a disruption of the immune response takes

Pere-Joan Cardona

2010-01-01

244

CD4(+) T cell clones producing both interferon-gamma and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients.  

PubMed

The pattern of cytokine production in T cell clones derived from bronchoalveolar lavages (BAL) of active pulmonary tuberculosis (TB) patients was analyzed in clones obtained by limiting dilution procedures which expand with high efficiency either total T lymphocytes, independently of their antigen-recognition specificity, or Mycobacterium tuberculosis-specific T cells. BAL-derived clones, representative of CD4(+) cells from five patients with active TB, produced significantly higher amounts of IFN-gamma than BAL-derived CD4(+) clones from three inactive TB donors or four controls (with unrelated, noninfectious pathology). Average IL-4 and IL-10 production did not differ significantly in the three groups. Although these data suggest a predominant Th1 response to M. tuberculosis infection in the lungs, the majority of BAL-derived CD4(+) clones produced both IFN-gamma and IL-10 and the percentage of clones with this pattern of cytokine production was significantly higher in clones derived from BAL of active TB patients than from controls. Only rare clones derived from peripheral blood (PB)-derived CD45RO(+) CD4(+) T cells of both patients (nine cases) and controls (four cases) produced both IFN-gamma and IL-10; instead, the IL-10-producing clones derived from PB T cells most often also produced IL-4, displaying a typical Th2 phenotype. Higher average amounts of IFN-gamma and IL-10 were produced by BAL-derived CD8(+) clones of four active TB patients than of four controls, although the frequency of CD8(+) clones producing both IFN-gamma and IL-10 was lower than that of CD4(+) clones. The M. tuberculosis-specific BAL-derived T cell clones from three active TB patients were almost exclusively CD4(+) and produced consistently high levels of IFN-gamma often in association with IL-10, but very rarely with IL-4. Unlike the BAL-derived clones, the M. tuberculosis-specific clones derived from PB CD45RO(+) CD4(+) T cells of three different active TB patients and two healthy donors showed large individual variability in cytokine production as well as in the proportion of CD4(+), CD8(+), or TCR gamma/delta(+) clones. These results indicate the predominance of CD4(+) T cells producing both the proinflammatory cytokine IFN-gamma and the anti-inflammatory cytokine IL-10 in BAL of patients with active TB. PMID:10479527

Gerosa, F; Nisii, C; Righetti, S; Micciolo, R; Marchesini, M; Cazzadori, A; Trinchieri, G

1999-09-01

245

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

PubMed Central

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

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

2013-01-01

246

Structural mechanics of the pH-dependent activity of beta-carbonic anhydrase from Mycobacterium tuberculosis.  

PubMed

Carbonic anhydrases catalyze the reversible hydration of carbon dioxide to form bicarbonate, a reaction required for many functions, including carbon assimilation and pH homeostasis. Carbonic anhydrases are divided into at least three classes and are believed to share a zinc-hydroxide mechanism for carbon dioxide hydration. beta-carbonic anhydrases are broadly spread among the domains of life, and existing structures from different organisms show two distinct active site setups, one with three protein coordinations to the zinc (accessible) and the other with four (blocked). The latter is believed to be inconsistent with the zinc-hydroxide mechanism. The Mycobacterium tuberculosis Rv3588c gene, shown to be required for in vivo growth of the pathogen, encodes a beta-carbonic anhydrase with a steep pH dependence of its activity, being active at pH 8.4 but not at pH 7.5. We have recently solved the structure of this protein, which was a dimeric protein with a blocked active site. Here we present the structure of the thiocyanate complexed protein in a different crystal form. The protein now forms distinct tetramers and shows large structural changes, including a carboxylate shift yielding the accessible active site. This structure demonstrated for the first time that a beta-carbonic anhydrase can switch between the two states. A pH-dependent dimer to tetramer equilibrium was also demonstrated by dynamic light scattering measurements. The data presented here, therefore, suggest a carboxylate shift on/off switch for the enzyme, which may, in turn, be controlled by a dimer-to-tetramer equilibrium. PMID:16321983

Covarrubias, Adrian Suarez; Bergfors, Terese; Jones, T Alwyn; Högbom, Martin

2006-02-24

247

The discovery and identification of a candidate proteomic biomarker of active tuberculosis  

PubMed Central

Background Noninvasive and convenient biomarkers for early diagnosis of tuberculosis (TB) remain an urgent need. The aim of this study was to discover and identify potential biomarkers specific for TB. Methods The surface-enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF MS) combined with weak cation exchange (WCX) magnetic beads was used to screen serum samples from 180 cases of TB and 211 control subjects. A classification model was established by Biomarker Pattern Software (BPS). Candidate protein biomarkers were purified by reverse phase-high performance liquid chromatography (RP-HPLC), identified by MALDI-TOF MS, LC-MS/MS and validated using enzyme-linked immunosorbent assay (ELISA). Results A total of 35 discriminating m/z peaks were detected that were related to TB (P?

2013-01-01

248

Population-Level Impact of Active Tuberculosis Case Finding in an Asian Megacity  

PubMed Central

Background The potential population-level impact of private-sector initiatives for tuberculosis (TB) case finding in Southeast Asia remains uncertain. In 2011, the Indus Hospital TB Control Program in Karachi, Pakistan, undertook an aggressive case-finding campaign that doubled notification rates, providing an opportunity to investigate potential population-level effects. Methods We constructed an age-structured compartmental model of TB in the intervention area. We fit the model using field and literature data, assuming that TB incidence equaled the estimated nationwide incidence in Pakistan (primary analysis), or 1.5 times greater (high-incidence scenario). We modeled the intervention as an increase in the rate of formal-sector TB diagnosis and evaluated the potential impact of sustaining this rate for five years. Results In the primary analysis, the five-year intervention averted 24% (95% uncertainty range, UR: 18-30%) of five-year cumulative TB cases and 52% (95% UR: 45-57%) of cumulative TB deaths. Corresponding reductions in the high-incidence scenario were 12% (95% UR: 8-17%) and 27% (95% UR: 21-34%), although the absolute number of lives saved was higher. At the end of five years, TB notification rates in the primary analysis were below their 2010 baseline, incidence had dropped by 45%, and annual mortality had fallen by 72%. About half of the cumulative impact on incidence and mortality could be achieved with a one-year intervention. Conclusions Sustained, multifaceted, and innovative approaches to TB case-finding in Asian megacities can have substantial community-wide epidemiological impact. PMID:24147015

Dowdy, David W.; Lotia, Ismat; Azman, Andrew S.; Creswell, Jacob; Sahu, Suvanand; Khan, Aamir J.

2013-01-01

249

Bowel obstruction caused by intestinal tuberculosis: an update  

PubMed Central

Tuberculosis is one of the most important communicable diseases worldwide, with an increasing incidence within the UK. The abdomen is involved in 11% of patients with extra-pulmonary tuberculosis, and can provide a diagnostic challenge if not suspected. The authors report the case of a 31-year-old Sudanese female who presented with intestinal obstruction due to a mass caused by abdominal tuberculosis. Imaging revealed evidence of multifocal tuberculosis involving the ileo-caecal region with abdominal and mediastinal lymphadenopathy. She went on to have a limited right hemicolectomy and completed antitubercular therapy. It is important to consider abdominal tuberculosis when conditions such as Crohn’s disease or gastrointestinal malignancy are being entertained in those from a high-risk background. Since diagnosis can be difficult, if clinical suspicion is strong, surgery is a safe option. Recommended management combines up to 12 months of antitubercular therapy with conservative surgery. PMID:22673714

Patel, Nimesh; Ondhia, Chandni; Ahmed, Shabbir

2011-01-01

250

Active site loop dynamics of a class IIa fructose 1,6-bisphosphate aldolase from Mycobacterium tuberculosis.  

PubMed

Class II fructose 1,6-bisphosphate aldolases (FBAs, EC 4.1.2.13) comprise one of two families of aldolases. Instead of forming a Schiff base intermediate using an ?-amino group of a lysine side chain, class II FBAs utilize Zn(II) to stabilize a proposed hydroxyenolate intermediate (HEI) in the reversible cleavage of fructose 1,6-bisphosphate, forming glyceraldehyde 3-phosphate and dihydroxyacetone phosphate (DHAP). As class II FBAs have been shown to be essential in pathogenic bacteria, focus has been placed on these enzymes as potential antibacterial targets. Although structural studies of class II FBAs from Mycobacterium tuberculosis (MtFBA), other bacteria, and protozoa have been reported, the structure of the active site loop responsible for catalyzing the protonation-deprotonation steps of the reaction for class II FBAs has not yet been observed. We therefore utilized the potent class II FBA inhibitor phosphoglycolohydroxamate (PGH) as a mimic of the HEI- and DHAP-bound form of the enzyme and determined the X-ray structure of the MtFBA-PGH complex to 1.58 Å. Remarkably, we are able to observe well-defined electron density for the previously elusive active site loop of MtFBA trapped in a catalytically competent orientation. Utilization of this structural information and site-directed mutagenesis and kinetic studies conducted on a series of residues within the active site loop revealed that E169 facilitates a water-mediated deprotonation-protonation step of the MtFBA reaction mechanism. Also, solvent isotope effects on MtFBA and catalytically relevant mutants were used to probe the effect of loop flexibility on catalytic efficiency. Additionally, we also reveal the structure of MtFBA in its holoenzyme form. PMID:23298222

Pegan, Scott D; Rukseree, Kamolchanok; Capodagli, Glenn C; Baker, Erica A; Krasnykh, Olga; Franzblau, Scott G; Mesecar, Andrew D

2013-02-01

251

[Tuberculosis in Iceland. 1976].  

PubMed

Because of signs of tuberculous lesions in old skeletons it can be stated with certainty that tuberculosis has occurred in the country shortly after the settlement. From that time and up to the seventeenth century, little or nothing is known about the occurrence of the disease. A few preserved descriptions of diseases and deaths indicate that tuberculosis has existed in the country before the advent of qualified physicians in 1760. On the basis of papers and reports from the first physicians and the first tuberculosis registers the opinions is set forth that the disease has been rare up to the latter part of the nineteenth century. During the two last decades of that century the disease began to spread more rapidly and increased steadily up to the turn of the century. Although reporting of the disease was started in the last decade of the nineteenth century the reporting was first ordered by law with the passage of the first tuberculosis Act in the year 1903. With this legislation official measures for tuberculosis control work really started in the country. The first sanatorium was built in 1910. In 1921 the tuberculosis Act was revised and since then practically all the expenses for the hospitalization and treatment of tuberculous cases has been defrayed by the state. In the year 1935 organized tuberculosis control work was begun and a special physician appointed to direct it. From then on systematic surveys were made, partly in health centers i.e. tuberculosis clinics, which were established in the main towns, and partly by means of transportable X ray units in outlying rural areas of the country. In 1939 the tuberculosis Act was again revised with special reference to the surveys and the activities of the tuberculosis clinics. This act is still in force. Some items of it are described. The procedure of the surveys and the methods of examination are described. The great majority of subjects were tuberculin tested and all positive reactors X rayed. Furthermore, X ray examination was made in all cases where tuberculin examination had not been made or was incomplete. The negative reactors were not X rayed. The tuberculin tests were percutaneous, cutaneous and intracutaneous. The X ray examination during the first years was performed by means of fluoroscopy and roentgenograms were made in all doubtful cases. In 1945 when the survey of the capital city of Reykjavík was made and comprised a total of 43,595 persons photoroentgenograms were made. After 1948 only this method together with tuberculin testing was used in all the larger towns in the country. During the period 1940-1945 such surveys were carried out in 12 medical districts, or parts thereof and included 58,837 persons or 47 percent of the entire population. The attendance in these surveys ranged from 89.3 percent to 100 percent of those considered able to attend. In the capital city, Reykjavík, the attendance was 99.32 percent. The course and prevalence of tuberculosis in Iceland from 1911 to 1970 are traced on the basis of tuberculosis reporting registers, mortality records which were ordered by law in 1911, tuberculin surveys and post mortem examinations. The deficiencies of these sources are pointed out. Since 1939 the morbidity rates are accurate. The number of reported cases of tuberculosis increases steadily up to the year 1935, when 1.6 percent of the population is reported to have active tuberculosis at the end of that year. Thereafter it begins to decline gradually the first years but abruptly in 1939, then without doubt because of the revision of the tuberculosis legislation and more exact reporting regulations. After that year the fall is almost constant with rather small fluctuations as regards new cases, relapses and total number of reported cases remaining on register at the end of each year. In 1950 the new cases are down to 1.6 per thousand and at the end of the year the rate for those remaining on register is 6.9 per thousand. In the year 1954 there is a noteworthy drop both in new cases and the total number reported, doubtless because of the ne

Sigurdsson, Sigurdur

2005-01-01

252

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

PubMed

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

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

1999-10-01

253

Cigarette smoking as a risk factor for tuberculosis in young adults: A casecontrol study  

Microsoft Academic Search

Setting: The association between smoking and pulmonary tuberculosis has not often been studied.Objective: To assess the influence of cigarette smoking on the development of active pulmonary tuberculosis in young people who were close contacts of new cases of smear-positive pulmonary tuberculosis.Design: A case-control study in which 46 ‘cases’ (patients with active pulmonary tuberculosis: isolation of Mycobacterium tuberculosis or clinical and\\/or

J. Alcaide; M. N. Altet; P. Plans; I. Parrón; Ll. Folguera; E. Saltó; A. Dominguez; H. Pardell; Ll. Salleras

1996-01-01

254

Using Peer Helpers for Tuberculosis Prevention.  

ERIC Educational Resources Information Center

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…

McCue, Maureen; Afifi, Larry Anna

1996-01-01

255

[Situation of tuberculosis in the world and the role expected of Japan in the global fight against tuberculosis].  

PubMed

The whole world is divided into 3 groups by the magnitude of tuberculosis problem: namely, developed countries in which tuberculosis is already a minor health problem and continues to decline; NIES and some oil-producing countries in which tuberculosis started to decline significantly; and most developing countries in which tuberculosis is still highly prevalent and no or only a slow decline. Number of new smear positive pulmonary tuberculosis in the whole world in a year is estimated at about 4.5 million, and adding smear negative pulmonary tuberculosis and extra-pulmonary tuberculosis, total number of new tuberculosis patients amounts to 9 to 10 million, and nearly 3 million persons die every year from tuberculosis, and 97% of these cases occur in developing countries. Failure of tuberculosis control in most developing countries could be explained by slow economic development of financial crisis, which caused poor allocation of budget for health including tuberculosis programme and slow development of primary health care. Activities of tuberculosis supervisory teams are weak. Tuberculosis programmes succeeded in developed countries could not be implemented easily in developing countries. New obstacles to the rapid decline of tuberculosis are the epidemic of AIDS, movement of population and lowering concern on tuberculosis problems, and tuberculosis will remain as one of serious global health problems at least for coming several decades. Maintenance of research and training facilities for tuberculosis is needed, however, they have been disappearing in developed countries. Facilities in developing countries might have difficulties to maintain unless financial and technical support is given from developed countries. Japan is the second biggest economic power in the world, and it is our duty to increase ODA for developing countries. In the field of health, Dr. Nakajima started to work as the director-general of WHO since 1988. We have to intensify our technical cooperation in health. As we succeeded to control tuberculosis in the past 40 years and still maintain research and training facilities for tuberculosis, they should be used for the sake of developing countries. Multi-and bi-lateral cooperation in tuberculosis control should also be intensified. The author would like to urge members of the Japanese Society for Tuberculosis to talk about the importance of tuberculosis problem and role expected to Japan in the global fight against tuberculosis to people outside the society so as to have appropriate understanding on global tuberculosis problems. PMID:2593463

Shimao, T

1989-11-01

256

A rapid method for screening antimicrobial agents for activities against a strain of Mycobacterium tuberculosis expressing firefly luciferase.  

PubMed Central

We developed a rapid method to screen the efficacy of antimicrobial agents against Mycobacterium tuberculosis. A restriction fragment carrying a promoterless firefly luciferase gene was cloned into a 4,488-bp shuttle vector, pMV261, and luciferase was expressed under the control of a mycobacterial heat shock promoter. The resulting plasmid, pLUC10, was introduced by electroporation into the avirulent strain M. tuberculosis H37Ra. Luciferase assays of sonic lysates of Triton X-100-treated cells of M. tuberculosis H37Ra(pLUC10) yielded bioluminescence in excess of 1,000 relative light units/approximately 10(9) tubercle bacilli, compared with 0.0025 for the same number of parental cells. A 48-h microdilution antimicrobial agent-screening assay using this strain was developed. Images PMID:8328785

Cooksey, R C; Crawford, J T; Jacobs, W R; Shinnick, T M

1993-01-01

257

Matrix metalloproteinases in tuberculosis.  

PubMed

Tuberculosis (TB) remains a global health pandemic. Infection is spread by the aerosol route and Mycobacterium tuberculosis must drive lung destruction to be transmitted to new hosts. Such inflammatory tissue damage is responsible for morbidity and mortality in patients. The underlying mechanisms of matrix destruction in TB remain poorly understood but consideration of the lung extracellular matrix predicts that matrix metalloproteinases (MMPs) will play a central role, owing to their unique ability to degrade fibrillar collagens and other matrix components. Since we proposed the concept of a matrix degrading phenotype in TB a decade ago, diverse data implicating MMPs as key mediators in TB pathology have accumulated. We review the lines of investigation that have indicated a critical role for MMPs in TB pathogenesis, consider regulatory pathways driving MMPs and propose that inhibition of MMP activity is a realistic goal as adjunctive therapy to limit immunopathology in TB. PMID:21659415

Elkington, P T; Ugarte-Gil, C A; Friedland, J S

2011-08-01

258

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

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

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

2001-01-01

259

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

PubMed Central

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

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

2012-01-01

260

Treatment of Mycobacterium tuberculosis with antisense oligonucleotides to glutamine synthetase mRNA inhibits glutamine synthetase activity, formation of the poly-l-glutamate/glutamine cell wall structure, and bacterial replication  

PubMed Central

New antibiotics to combat the emerging pandemic of drug-resistant strains of Mycobacterium tuberculosis are urgently needed. We have investigated the effects on M. tuberculosis of phosphorothioate-modified antisense oligodeoxyribonucleotides (PS-ODNs) against the mRNA of glutamine synthetase, an enzyme whose export is associated with pathogenicity and with the formation of a poly-l-glutamate/glutamine cell wall structure. Treatment of virulent M. tuberculosis with 10 ?M antisense PS-ODNs reduced glutamine synthetase activity and expression by 25–50% depending on whether one, two, or three different PS-ODNs were used and the PS-ODNs' specific target sites on the mRNA. Treatment with PS-ODNs of a recombinant strain of Mycobacterium smegmatis expressing M. tuberculosis glutamine synthetase selectively inhibited the recombinant enzyme but not the endogenous enzyme for which the mRNA transcript was mismatched by 2–4 nt. Treatment of M. tuberculosis with the antisense PS-ODNs also reduced the amount of poly-l-glutamate/glutamine in the cell wall by 24%. Finally, treatment with antisense PS-ODNs reduced M. tuberculosis growth by 0.7 logs (1 PS-ODN) to 1.25 logs (3 PS-ODNs) but had no effect on the growth of M. smegmatis, which does not export glutamine synthetase nor possess the poly-l-glutamate/glutamine (P-l-glx) cell wall structure. The experiments indicate that the antisense PS-ODNs enter the cytoplasm of M. tuberculosis and bind to their cognate targets. Although more potent ODN technology is needed, this study demonstrates the feasibility of using antisense ODNs in the antibiotic armamentarium against M. tuberculosis. PMID:10618433

Harth, Gunter; Zamecnik, Paul C.; Tang, Jin-Yan; Tabatadze, David; Horwitz, Marcus A.

2000-01-01

261

Tuberculosis Infection-Control Practices in United States Emergency Departments  

Microsoft Academic Search

Study objective: To determine the frequency with which patients with suspected tuberculosis (TB) or TB risk factors present to US emergency departments and to describe current ED TB infection-control facilities and practices. Design: Mailed survey of a sample of EDs in US acute care facilities. Participants: A random sample (n=446) of subjects who responded to a 1992 survey of all

Gregory J Moran; Mary Anne Fuchs; William R Jarvis; David A Talan

1995-01-01

262

Integration of PET/CT in Current Diagnostic and Response Evaluation Methods in Patients with Tuberculosis.  

PubMed

Tuberculosis is a systemic disease that still affects many people. While pleural involvement is frequently observed in extrapulmonary tuberculosis, multiple skeletal system and articular involvements are quite rare. FDG PET imaging could be a promising diagnostic and treatment monitoring method, especially in complicated cases and if the other methods are inadequate. In this case study, we report a patient who was admitted with suspected malignancy and then diagnosed with tuberculosis pleuritis, lymphadenitis, spondylodiscitis, and sacroiliitis with specific symptoms; the response to anti-tuberculosis therapy was shown using FDG PET/CT. PMID:24900142

Ozmen, Ozlem; Gökçek, Atila; Tatc?, Ebru; Biner, Inci; Akkalyoncu, Behiye

2014-03-01

263

Tuberculous dactylitis (spina ventosa) with concomitant ipsilateral axillary scrofuloderma in an immunocompetent child: A rare presentation of skeletal tuberculosis  

PubMed Central

Tuberculous dactylitis is a distinctly uncommon, yet well recognized form of tuberculosis involving the small bones of the hand or foot. It occurs in young children in endemic areas under 5 years of age. Tuberculosis of the short tubular bones like phalanges, metacarpals or metatarsals is quite uncommon beyond 6 years of age, once the epiphyseal centers are well established. The radiographic features of cystic expansion have led to the name “Spina Ventosa” for tuberculous dactylitis of the short bones. Scrofuloderma is a mycobacterial infection affecting children and young adults, representing direct extension of tuberculosis into the skin from underlying structures e.g. lymph nodes. An 8-year-old malnourished girl had multiple axillary ulcers with lymphadenopathy. Tuberculous dactylitis with ipsilateral axillary scrofuloderma was suspected on clinical and radiological grounds. The suspicion was confirmed by histology and bacteriology. The patient responded to antitubercular drugs with progressive healing of the lesions without surgery. Concomitant presence of these dual lesions suggesting active disseminated tuberculosis in immune-competent child over 6 years is very rare and hardly reported. PMID:23977657

Bhaskar; Khonglah, Tashi; Bareh, Jerryson

2013-01-01

264

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

disease (If yes, please CIRCLE the country/ies below) 4. Have you had frequent or prolonged visits * to one or more of the countries listed below o Yes o No with a high prevalence of TB disease? (If yes who are at increased o Yes o No risk for active TB disease? 6. Have you ever been a member of any

Rhode Island, University of

265

Sarcoidosis following Mycobacterium tuberculosis infection: Coincidence or consequence  

PubMed Central

We describe the case of a 47-year-old Caucasian male patient who developed sarcoidosis 18 months after he was diagnosed with pulmonary tuberculosis for which he was treated according to guidelines. The presentation of sarcoidosis was very similar to his first presentation when he was diagnosed with tuberculosis. Mycobacterium tuberculosis as a possible aetiological agent in sarcoidosis has been point of debate since many years and has been studied thoroughly. Recent advances in immunologic and molecular techniques have strengthened the association between mycobacteria and sarcoidosis.1 Sarcoidosis is a systemic inflammatory disorder of unknown aetiology, characterised by the presence of non-caseating epitheloid cell granulomas. It is generally agreed that this is a tissue reaction to environmental agents in a genetically susceptible individual.2 Tuberculosis is an infectious disease caused by M. tuberculosis and characterised by caseating granulomas. In both clinical and histopathological features sarcoidosis is remarkably similar to tuberculosis and therefore can be difficult to distinguish. First, this case report demonstrates the need of diagnostic testing when reactivation of tuberculosis is suspected. And second the role of M. tuberculosis in the aetiology of sarcoidosis will be discussed.

van Enschot, J.W.T.; van Balkom, R.H.H.

2013-01-01

266

A Novel in vitro Human Macrophage Model to Study the Persistence of Mycobacterium tuberculosis Using Vitamin D3 and Retinoic Acid Activated THP-1 Macrophages  

PubMed Central

Mycobacterium tuberculosis (Mtb) replicates within the human macrophages and we investigated the activating effects of retinoic acid (RA) and vitamin D3 (VD) on macrophages in relation to the viability of intracellular Mtb. A combination of these vitamins (RAVD) enhanced the levels of DC-SIGN and mannose receptors on THP-1 macrophages that increased mycobacterial uptake but inhibited the subsequent intracellular growth of Mtb by inducing reactive oxygen species and autophagy. RAVD also enhanced antigen presenting and chemotactic receptors on THPs suggesting an activated phenotype for RAVD activated THPs. RAVD mediated activation was also associated with a marked phenotypic change in Mtb infected THPs that fused with adjacent THPs to form multinucleated giant cells (MNGCs). Typically, MNGCs occurred over 30?days of in vitro culture and contained non-replicating persisting Mtb for more than 60?days in culture. Latent tuberculosis occurs in over a third of mankind and we propose that RAVD mediated induction of persistent Mtb within human macrophages provides a novel model to develop therapeutic approaches and investigate pathogenesis of latency. PMID:21747789

Estrella, Jaymie L.; Kan-Sutton, Celestine; Gong, Xing; Rajagopalan, Malini; Lewis, Dorothy E.; Hunter, Robert L.; Eissa, N. Tony; Jagannath, Chinnaswamy

2010-01-01

267

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

PubMed

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

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

2014-01-01

268

Prevalence of Latent and Active Tuberculosis among Dairy Farm Workers Exposed to Cattle Infected by Mycobacterium bovis  

PubMed Central

Background Human tuberculosis caused by M. bovis is a zoonosis presently considered sporadic in developed countries, but remains a poorly studied problem in low and middle resource countries. The disease in humans is mainly attributed to unpasteurized dairy products consumption. However, transmission due to exposure of humans to infected animals has been also recognized. The prevalence of tuberculosis infection and associated risk factors have been insufficiently characterized among dairy farm workers (DFW) exposed in settings with poor control of bovine tuberculosis. Methodology/Principal Findings Tuberculin skin test (TST) and Interferon-gamma release assay (IGRA) were administered to 311 dairy farm and abattoir workers and their household contacts linked to a dairy production and livestock facility in Mexico. Sputa of individuals with respiratory symptoms and samples from routine cattle necropsies were cultured for M. bovis and resulting spoligotypes were compared. The overall prevalence of latent tuberculosis infection (LTBI) was 76.2% (95% CI, 71.4–80.9%) by TST and 58.5% (95% CI, 53.0–64.0%) by IGRA. Occupational exposure was associated to TST (OR 2.72; 95% CI, 1.31–5.64) and IGRA (OR 2.38; 95% CI, 1.31–4.30) adjusting for relevant variables. Two subjects were diagnosed with pulmonary tuberculosis, both caused by M. bovis. In one case, the spoligotype was identical to a strain isolated from bovines. Conclusions We documented a high prevalence of latent and pulmonary TB among workers exposed to cattle infected with M. bovis, and increased risk among those occupationally exposed in non-ventilated spaces. Interspecies transmission is frequent and represents an occupational hazard in this setting. PMID:23638198

Torres-Gonzalez, Pedro; Soberanis-Ramos, Orbelin; Martinez-Gamboa, Areli; Chavez-Mazari, Barbara; Barrios-Herrera, Ma Teresa; Torres-Rojas, Martha; Cruz-Hervert, Luis Pablo; Garcia-Garcia, Lourdes; Singh, Mahavir; Gonzalez-Aguirre, Adrian; Ponce de Leon-Garduno, Alfredo; Sifuentes-Osornio, Jose; Bobadilla-del-Valle, Miriam

2013-01-01

269

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

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

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

270

Abdominal tuberculosis.  

PubMed Central

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

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

1994-01-01

271

Brainstem tuberculosis.  

PubMed

We present a case of a 38-year-old-man who presented with 1-week history of developing weakness of peripheral and cranial nerves. His MRI scan of the brain showed a large cavitating lesion at the brainstem and two further lesions of the right cerebral cortex and his CT chest showed features of old tuberculosis (TB). The identification of acid-fast bacilli was confirmed by analysis of bronchoalveolar lavage taken during bronchoscopy. He was started on anti-TB medications and repeat MRI 3 months later confirmed shrinkage of the cavitating lesion. PMID:23868024

Demetriou, George A

2013-01-01

272

System and method for disrupting suspect objects  

DOEpatents

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.

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

2013-07-09

273

Active Tuberculosis Is Associated with Worse Clinical Outcomes in HIV-Infected African Patients on Antiretroviral Therapy  

PubMed Central

Objective This cohort study utilized data from a large HIV treatment program in western Kenya to describe the impact of active tuberculosis (TB) on clinical outcomes among African patients on antiretroviral therapy (ART). Design We included all patients initiating ART between March 2004 and November 2007. Clinical (signs and symptoms), radiological (chest radiographs) and laboratory (mycobacterial smears, culture and tissue histology) criteria were used to record the diagnosis of TB disease in the program’s electronic medical record system. Methods We assessed the impact of TB disease on mortality, loss to follow-up (LTFU) and incident AIDS-defining events (ADEs) through Cox models and CD4 cell and weight response to ART by non-linear mixed models. Results We studied 21,242 patients initiating ART–5,186 (24%) with TB; 62% female; median age 37 years. There were proportionately more men in the active TB (46%) than in the non-TB (35%) group. Adjusting for baseline HIV-disease severity, TB patients were more likely to die (hazard ratio – HR?=?1.32, 95% CI 1.18–1.47) or have incident ADEs (HR?=?1.31, 95% CI: 1.19–1.45). They had lower median CD4 cell counts (77 versus 109), weight (52.5 versus 55.0 kg) and higher ADE risk at baseline (CD4-adjusted odds ratio?=?1.55, 95% CI: 1.31–1.85). ART adherence was similarly good in both groups. Adjusting for gender and baseline CD4 cell count, TB patients experienced virtually identical rise in CD4 counts after ART initiation as those without. However, the overall CD4 count at one year was lower among patients with TB (251 versus 269 cells/µl). Conclusions Clinically detected TB disease is associated with greater mortality and morbidity despite salutary response to ART. Data suggest that identifying HIV patients co-infected with TB earlier in the HIV-disease trajectory may not fully address TB-related morbidity and mortality. PMID:23301015

Siika, Abraham M.; Yiannoutsos, Constantin T.; Wools-Kaloustian, Kara K.; Musick, Beverly S.; Mwangi, Ann W.; Diero, Lameck O.; Kimaiyo, Sylvester N.; Tierney, William M.; Carter, Jane E.

2013-01-01

274

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

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

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

2014-01-01

275

TBNET - Collaborative research on tuberculosis in Europe  

PubMed Central

Networking is a key feature of scientific success. The Tuberculosis Network European Trialsgroup (TBNET) was founded in 2006 as a non-profit, non-governmental peer-initiated scientific organization to collaboratively address research priorities in the area of tuberculosis in Europe. Today, TBNET is the largest tuberculosis research organization in Europe with nearly 500 members from 22 EU countries and 49 countries worldwide (www.tb-net.org). Apart from small multicenter basic research studies, a particular strength of TBNET is the performance of large collaborative projects, pan-European multicenter studies and database projects. In recent years, research from TBNET has substantially contributed to the understanding of the management, risk and prognosis of patients with multidrug (MDR) and extensively drug-resistant (XDR) tuberculosis and led to a better understanding of the clinical value of novel tests for the identification of adults and children with tuberculosis and latent infection with Mycobacterium tuberculosis. In 2009, two branches of TBNET were founded to specifically address tuberculosis in the pediatric population (ptbnet) and non-tuberculous mycobacterial diseases (NTM-NET). In addition to the research activities, TBNET is developing expert consensus documents for clinical management and provides training and capacity building especially for members from Eastern European countries, where tuberculosis is still a prevalent health problem. PMID:24265908

Giehl, C.; Duarte, R.; Bothamley, G.; Gerlach, C.; Cirillo, D.M.; Wagner, D.; Kampmann, B.; Goletti, D.; Juers, T.; Sester, M.

2012-01-01

276

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

SciTech Connect

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.

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

2004-09-15

277

Mycobacterial Dormancy Regulon Protein Rv2623 as a Novel Biomarker for the Diagnosis of Latent and Active Tuberculous Meningitis  

PubMed Central

The present study was designed to investigate Rv2623 antigen, a major dormancy regulon protein of Mycobacterium tuberculosis (MTB) in CSF of suspected latent and active tuberculous meningitis (TBM) patients. A total of 100 CSF samples from TBM (n = 31), suspected latent TBM (n = 22), and suitable noninfectious control subjects (n = 47) were collected and evaluated for Rv2623 antigen level using ELISA protocol. A significantly high (P < 0.05) mean absorbance was observed in samples of suspected latent TBM and active TBM patients as compared to non-TBM control patients. However, no significant difference in Rv2623 level was observed between suspected latent TBM and TBM patients. Our preliminary findings suggest that Rv2623 may be useful as a potential biomarker for the diagnosis of the latent as well as active TBM infection. Futher evaluation of this biomarker in large number of samples is therefore needed to confirm the result. PMID:24167379

Jain, Ruchika K.; Nayak, Amit R.; Husain, Aliabbas A.; Panchbhai, Milind S.; Chandak, Nitin; Purohit, Hemant J.; Taori, Girdhar M.; Daginawala, Hatim F.; Kashyap, Rajpal S.

2013-01-01

278

New drugs to treat tuberculosis  

PubMed Central

Tuberculosis (TB) has been a leading cause of death for more than a century. While effective therapies exist, treatment is long and cumbersome. Tuberculosis control is complicated by the overlapping problems created by global inadequacy of public health infrastructures, the interaction of the TB and human immunodeficiency virus epidemics, and the emergence of drug-resistant TB. After a long period of neglect, there is now significant progress in development of TB diagnostics and therapeutics. Focusing on treatment for active TB, we review the new pathways to TB regimen development, and the new and repurposed anti-TB agents in clinical development. PMID:22719795

2012-01-01

279

Optimal intervention strategies for tuberculosis  

NASA Astrophysics Data System (ADS)

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.

Bowong, Samuel; Aziz Alaoui, A. M.

2013-06-01

280

Tuberculosis diagnostics and biomarkers: needs, challenges, recent advances, and opportunities.  

PubMed

Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostics. PMID:22496353

McNerney, Ruth; Maeurer, Markus; Abubakar, Ibrahim; Marais, Ben; McHugh, Timothy D; Ford, Nathan; Weyer, Karin; Lawn, Steve; Grobusch, Martin P; Memish, Ziad; Squire, S Bertel; Pantaleo, Giuseppe; Chakaya, Jeremiah; Casenghi, Martina; Migliori, Giovanni-Batista; Mwaba, Peter; Zijenah, Lynn; Hoelscher, Michael; Cox, Helen; Swaminathan, Soumya; Kim, Peter S; Schito, Marco; Harari, Alexandre; Bates, Matthew; Schwank, Samana; O'Grady, Justin; Pletschette, Michel; Ditui, Lucica; Atun, Rifat; Zumla, Alimuddin

2012-05-15

281

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

PubMed

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

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

2014-11-01

282

Mycobacterium tuberculosis Serine/Threonine Protein Kinases  

PubMed Central

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.

PRISIC, SLADJANA; HUSSON, ROBERT N.

2014-01-01

283

Antituberculosis agents. VI. Activity of a new ciprofloxacin derivative against Mycobacterium avium and some drug-resistant strains of Mycobacterium tuberculosis.  

PubMed

The in vitro antimycobacterial activity of a new quinolone derivative, 1a containing 2-(2-furyl)-2-oxoethyl group at N-4 position of piperazine ring of Ciprofloxacin was tested for efficacy in vitro in TB-infected macrophage model (EC90 = 3.25 micrograms/ml and EC99 > 12.5 micrograms/ml). The MIC values of 1a were determined against M. tuberculosis strains resistant to Isoniazid (MIC = 1.56 micrograms/ml), Rifampin (MIC = 1.56 micrograms/ml), Ethambutol (MIC = 0.78 microgram/ml), Kanamycin (MIC = 0.78 microgram/ml) and Ciprofloxacin (MIC > 25 micrograms/ml). Furthermore, the MIC and selectivity index (SI) of 1a were evaluated against M. avium. Also, in this study the minimum bactericidal concentration (MBC) of 1a was determined against M. tuberculosis H37Rv (MBC = 6.25 micrograms/ml) and strain resistant to Rifampim (MBC = 25 micrograms/ml) and Isoniazid (MBC = 25 micrograms/ml). PMID:12481384

Foroumadi, A; Soltani, F; Moshafi, M H

2002-01-01

284

Immunological biomarkers of tuberculosis  

Microsoft Academic Search

Currently there are no sufficiently validated biomarkers to aid the evaluation of new tuberculosis vaccine candidates, the improvement of tuberculosis diagnostics or the development of more effective and shorter treatment regimens. To date, the detection of Mycobacterium tuberculosis or its products has not been able to adequately address these needs. Understanding the interplay between the host immune system and M.

Katharina Ronacher; Willem Hanekom; Thomas J. Scriba; Alimuddin Zumla; Gerhard Walzl

2011-01-01

285

Computerized feature systems for identifying suspects  

NASA Astrophysics Data System (ADS)

In suspect identification, witnesses examine photos of known offenders in mugshot albums. The probability of correct identification deteriorates rapidly, however, as the number of mugshots examined increases. Feature approaches, where mugshots are displayed in order of similarity to witness descriptions of suspects, increase identification success by reducing this number. In our computerized feature system, both police raters and witnesses describe facial features of suspects on rating scales such as nose size: small 1 2 3 4 5 large. Feature users consistently identify more target suspects correctly than do album users. Previous experimental tests have failed, however, to examine the effects of feature system performance of the use of live targets as suspects rather than photos, the use of realistic crime scenarios, the number of police raters/mugshot, and differences among raters in their effect on system perfomance. In three experiments, we investigated those four issues. The first experiment used photos as target suspects but with multiple distractors, the second tested live suspects, while the third tested live suspects in a realistic crime scenario. The database contained the official mugshots of 1,000 offenders. Across the three experiments, a second and sometimes a third rater/mugshot significantly reduced the number of photos examined. More raters/mugshot did not affect performance further. Raters differed significantly in their effect on system perfomance. Significantly, our feature system performed well both with target suspects seen live and with live suspects in realistic crime scenarios (performance was comparable to that in previous experiments for photos of target suspects). These results strongly support our contention that feature systems are superior to album systems.

Lee, Eric; Whalen, Thom; McCarthy, Andrew; Sakalauskas, John; Wotton, Cynthia

1995-09-01

286

Acute Myeloid Leukemia Presenting with Pulmonary Tuberculosis  

PubMed Central

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

Thomas, Merlin; AlGherbawe, Mushtak

2014-01-01

287

Tuberculosis revisited: Cytological perspective.  

PubMed

Tuberculosis is a major public health problem, especially in developing countries. The clinical manifestations of tuberculosis are very nonspecific and may mimic many other conditions. An accurate diagnosis is extremely important as the disease is treatable with antituberculous therapy. Cytological examination can provide useful diagnostic material for routine and ancillary techniques for rapid and accurate diagnosis of tuberculosis. Here we review the different morphological patterns of tuberculosis, challenges, and application of ancillary techniques for cytological diagnosis of tuberculosis. Diagn. Cytopathol. 2014;42:993-1001. © 2014 Wiley Periodicals, Inc. PMID:24975566

Chatterjee, Debajyoti; Dey, Pranab

2014-11-01

288

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

PubMed

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

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

2012-04-01

289

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

PubMed Central

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

Carette, Xavier; Blondiaux, Nicolas; Willery, Eve; Hoos, Sylviane; Lecat-Guillet, Nathalie; Lens, Zoe; Wohlkonig, Alexandre; Wintjens, Rene; Soror, Sameh H.; Frenois, Frederic; Dirie, Bertrand; Villeret, Vincent; England, Patrick; Lippens, Guy; Deprez, Benoit; Locht, Camille; Willand, Nicolas; Baulard, Alain R.

2012-01-01

290

The role of interferon-gamma release assay in tuberculosis control.  

PubMed

Tuberculosis is still one of the major global public health threats. Countries with low incidence must focus on exhausting the reservoir of future cases by preventing reactivation. Therefore, it is important to identify and effectively treat those individuals who have latent tuberculosis infection and who may develop active disease. The tuberculin skin test has been the standard for detection of immune response against M. tuberculosis since the beginning of the 20th century. The new millennium has brought advancement in the diagnosis of latent tuberculosis infection. The name of the new blood test is interferon-gamma release assay (IGRA). Croatia is a middle-incidence country with a long decreasing trend and developed tuberculosis control. To reach low incidence and finally eliminate tuberculosis, its tuberculosis programme needs a more aggressive approach that would include intensive contact investigation and treatment of persons with latent tuberculosis infection. This article discusses the current uses of IGRA and its role in tuberculosis control. PMID:22450206

Jur?ev-Savi?evi?, Anamarija; Katalini?-Jankovi?, Vera; Miše, Kornelija; Gudelj, Ivan

2012-03-01

291

Guidelines for identifying suspect/counterfeit material  

SciTech Connect

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.

NONE

1995-09-01

292

The Association between Active and Passive Smoking and Latent Tuberculosis Infection in Adults and Children in the United States: Results from NHANES  

PubMed Central

Background Few studies assessing the relationship between active and passive smoking and tuberculosis have used biomarkers to measure smoke exposure. We sought to determine the association between active and passive smoking and LTBI in a representative sample of US adults and children. Methods We used the 1999–2000 US National Health and Nutrition Examination Survey (NHANES) dataset with tuberculin skin test (TST) data to assess the association between cotinine-confirmed smoke exposure and latent tuberculosis infection (LTBI) among adults ages ?20 years (n?=?3598) and children 3–19 years (n?=?2943) and estimate the prevalence of smoke exposure among those with LTBI. Weighted multivariate logistic regression was used to measure the associations between active and passive smoking and LTBI. Results LTBI prevalence in 1999–2000 among cotinine-confirmed active, passive, and non-smoking adults and children was 6.0%, 5.2%, 3.3% and 0.3%, 1.0%, 1.5%, respectively. This corresponds to approximately 3,556,000 active and 3,379,000 passive smoking adults with LTBI in the US civilian non-institutionalized population in 1999–2000. Controlling for age, gender, socioeconomic status, race, birthplace (US vs. foreign-born), household size, and having ever lived with someone with TB, adult active smokers were significantly more likely to have LTBI than non-smoking adults (AOR?=?2.31 95% CI 1.17–4.55). Adult passive smokers also had a greater odds of LTBI compared with non-smokers, but this association did not achieve statistical significance (AOR?=?2.00 95% CI 0.87–4.60). Neither active or passive smoking was associated with LTBI among children. Among only the foreign-born adults, both active (AOR?=?2.56 (95% CI 1.20–5.45) and passive smoking (AOR?=?2.27 95% CI 1.09–4.72) were significantly associated with LTBI. Conclusions Active adult smokers and both foreign-born active and passive smokers in the United States are at elevated risk for LTBI. Targeted smoking prevention and cessation programs should be included in comprehensive national and international TB control efforts. PMID:24664240

Lindsay, Ryan P.; Shin, Sanghyuk S.; Garfein, Richard S.; Rusch, Melanie L. A.; Novotny, Thomas E.

2014-01-01

293

Diagnosis of sputum-scarce HIV-associated pulmonary tuberculosis in Lima, Peru  

Microsoft Academic Search

Sputum induction, bronchoalveolar lavage, or gastric aspiration are often needed to produce adequate diagnostic respiratory samples from people with HIV in whom tuberculosis is suspected. Since these procedures are rarely appropriate in less-developed countries, we compared the performances of a simple string test and the gold-standard sputum induction. 160 HIV-positive adults under investigation for tuberculosis, and 52 asymptomatic HIV-positive control

Daniel Vargas; Luis García; Robert H Gilman; Carlton Evans; Eduardo Ticona; Marcos Ñavincopa; Robert F Luo; Luz Caviedes; Clemens Hong; Rod Escombe; David A J Moore

2006-01-01

294

PERSPECTIVE Candidate Mycobacterium tuberculosis genes  

E-print Network

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

Wu, Jane Y.

295

Modification of the active site of Mycobacterium tuberculosis KatG after disruption of the Met-Tyr-Trp cross-linked adduct  

PubMed Central

Mycobacterium tuberculosis catalase-peroxidase (Mtb KatG) is a bifunctional enzyme that possesses both catalase and peroxidase activities and is responsible for the activation of the antituberculosis drug isoniazid. Mtb KatG contains an unusual adduct in its distal heme pocket that consists of the covalently linked Trp107, Tyr229, and Met255. The KatG(Y229F) mutant lacks this adduct and has decreased steady-state catalase activity and enhanced peroxidase activity. In order to test a potential structural role of the adduct that supports catalase activity, we have used resonance Raman spectroscopy to probe the local heme environment of KatG(Y229F). In comparison to wild-type KatG, resting KatG(Y229F) contains a significant amount of 6-coordinate, low-spin heme and a more planar heme. Resonance Raman spectroscopy of the ferrous-CO complex of KatG(Y229F) suggest a non-linear Fe-CO binding geometry that is less tilted than in wild-type KatG. These data provide evidence that the Met-Tyr-Trp adduct imparts structural stability to the active site of KatG that seems to be important for sustaining catalase activity. PMID:17188362

Kapetanaki, Sofia M.; Zhao, Xiangbo; Yu, Shengwei; Magliozzo, Richard S.; Schelvis, Johannes P. M.

2007-01-01

296

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

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

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

2014-01-01

297

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

PubMed

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 Å 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. PMID:21543857

Wubben, T; Mesecar, A D

2011-05-01

298

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

SciTech Connect

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.

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

2010-07-20

299

The Impact of HIV Infection on Tuberculosis in Africa  

Microsoft Academic Search

Tuberculosis (TB) notification rates in Africa have doubled since the early 1980s, with the largest rises in countries most\\u000a affected by the HIV epidemic. HIV increases the risk of TB in those latently infected with M tuberculosis and increases the risk of active disease soon after new infection or re-infection with M tuberculosis. Overall, the risk of TB in those

Judith R. Glynn

300

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

PubMed

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

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

2012-12-28

301

Optimization of recombinant Mycobacterium tuberculosis RNA polymerase expression and purification.  

PubMed

Mycobacterium tuberculosis, the human pathogen that causes tuberculosis, warrants enormous attention due to the emergence of multi drug resistant and extremely drug resistant strains. RNA polymerase (RNAP), the key enzyme in gene regulation, is an attractive target for anti-TB drugs. Understanding the structure-function relationship of M. tuberculosis RNAP and the mechanism of gene regulation by RNAP in conjunction with different ? factors and transcriptional regulators would provide significant information for anti-tuberculosis drug development targeting RNAP. Studies with M. tuberculosis RNAP remain tedious because of the extremely slow-growing nature of the bacteria and requirement of special laboratory facility. Here, we have developed and optimized recombinant methods to prepare M. tuberculosis RNAP core and RNAP holo enzymes assembled in vivo in Escherichia coli. These methods yield high amounts of transcriptionally active enzymes, free of E. coli RNAP contamination. The recombinant M. tuberculosis RNAP is used to develop a highly sensitive fluorescence based in vitro transcription assay that could be easily adopted in a high-throughput format to screen RNAP inhibitors. These recombinant methods would be useful to set a platform for M. tuberculosis RNAP targeted anti TB drug development, to analyse the structure/function of M. tuberculosis RNAP and to analyse the interactions among promoter DNA, RNAP, ? factors, and transcription regulators of M. tuberculosis in vitro, avoiding the hazard of handling of pathogenic bacteria. PMID:24832563

Banerjee, Rajdeep; Rudra, Paulami; Prajapati, Ranjit Kumar; Sengupta, Shreya; Mukhopadhyay, Jayanta

2014-07-01

302

Clinical peculiarities of tuberculosis  

PubMed Central

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

2014-01-01

303

[Tuberculosis and traveling].  

PubMed

The traveler faces two types of specific risks for tuberculosis: that of a possible contagion through the unexpected contact with an infected person during a commercial flight (the available studies dealing mostly with cases of transmission during flights, the chapter will deal mainly with this question) and that of a possible contamination during a stay in a country with strong prevalence of TB. The ventilation in airliners is designed to limit movements of air to the front or the back of the aircraft. Moreover, studies have shown that the transmission of M. tuberculosis from passenger to passenger was observed only within the same cabin. Consequently, it is usually admitted that only passengers sitting next to the patient (3 rows ahead and behind, and 3 seats on the right and on the left of the infected passenger, depending on the aircraft's seat set-up) as well as the members of crew working in this same cabin must be warned of the potential risk a posteriori. The recommendations which follow are to be considered all the more carefully that the duration of stay is long, that the country or the geographical area is more at the risk (for example urban environment in a highly endemic zone), that the traveler is more fragile (infants and elderly people, immunodepression, etc.) and that activities during the stay will be more at risk. PMID:15622988

2004-01-01

304

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, ...

305

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 ...

306

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 ...

307

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.

308

Virulence factors of the Mycobacterium tuberculosis complex  

PubMed Central

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

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

2013-01-01

309

[Glutoxim in the complex treatment of tuberculosis].  

PubMed

Results of Glutoxim investigation are presented. Glutoxim is the the drug of the new class--thiopoietins. It is considered to be immunorehabilitator as it modulates intracellular process of thiols metabolism, initiates cytokins system, activates phagocytosis etc. Results of the glutoxim administration at the 42 patients with tuberculosis using traditional treatment regimes are presented. Results of the randomized study at the patients with severe disseminated drug-sensitive and drug-resistant pulmonary tuberculosis demonstrated high efficacy of the glutoxim and its good tolerability. Glutoxim administration allowed to shorten the period of tuberculosis intoxication signs disappearance, to shorten the period of sputum negativation and shortened the period of pulmonary inflammation reverse process. Glutoxim application was specially favorable at the patients with severe tuberculosis complicated by viral or medicamental hepatitis. PMID:12087719

Sokolova, G B; Sinitsyn, M V; Kozhemiakin, L A; Perel'man, M I

2002-01-01

310

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

PubMed

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

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

2014-10-28

311

Endocrine dysfunction among adult patients with tuberculosis: An African experience  

PubMed Central

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

Kibirige, Davis

2014-01-01

312

Analysis of DNA relaxation and cleavage activities of recombinant Mycobacterium tuberculosis DNA topoisomerase I from a new expression and purification protocol  

Microsoft Academic Search

BACKGROUND: Mycobacterium tuberculosis DNA topoisomerase I is an attractive target for discovery of novel TB drugs that act by enhancing the accumulation of the topoisomerase-DNA cleavage product. It shares a common transesterification domain with other type IA DNA topoisomerases. There is, however, no homology between the C-terminal DNA binding domains of Escherichia coli and M. tuberculosis DNA topoisomerase I proteins.

Thirunavukkarasu Annamalai; Neil Dani; Bokun Cheng; Yuk-Ching Tse-Dinh

2009-01-01

313

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

PubMed

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

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

2014-08-01

314

Tuberculosis in indigenous communities of Antioquia, Colombia: epidemiology and beliefs.  

PubMed

Morbidity and mortality caused by tuberculosis are increased in most of the Latin-American indigenous communities. Factors that could explain this situation are poverty and limited health services access due to social conflicts and geographical isolation. We determined the frequency of tuberculosis in Colombian indigenous communities and described their knowledge related to transmission and control. We developed a descriptive study and health survey. Interviews were performed to find ancestral knowledge about tuberculosis. Sputum samples from patients with respiratory symptoms were analyzed. 10 indigenous communities were studied, which tuberculosis incidence was 291/100,000. Communities believe that tuberculosis is a body and spirit disease, which transmission is by direct contact or by witchcraft. Tuberculosis incidence in the studied communities was ninefold higher than that of the general population from Antioquia Department. Knowledge exchange could facilitate the community empowerment and implementation of educational activities which might improve the control of the disease. PMID:22825464

Hernández Sarmiento, José Mauricio; Dávila Osorio, Victoria Lucia; Martínez Sánchez, Lina María; Restrepo Serna, Laura; Grajales Ospina, Diana Carolina; Toro Montoya, Andrés Eduardo; Arango Urrea, Verónica; Vargas Grisales, Natalia; Estrada Gómez, Manuela; Lopera Valle, Johan Sebastián; García Gil, Juan José; Restrepo, Lady; Mejía, Gloria; Zapata, Elsa; Gómez, Verónica; Lopera, Diver; Domicó Domicó, José Leonardo; Robledo, Jaime

2013-02-01

315

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

PubMed Central

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

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

2013-01-01

316

The Social and Legal Construction of Suspects  

Microsoft Academic Search

DNA profiling and searchable databases enhance the ability of policing organizations to search for criminal suspects. In many respects, these technologies are incorporated within traditions of police work, supplementing familiar \\

Simon A. Cole; Michael Lynch

2006-01-01

317

Chemotherapeutic Interventions Against Tuberculosis  

PubMed Central

Tuberculosis is the second leading cause of infectious deaths globally. Many effective conventional antimycobacterial drugs have been available, however, emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has overshadowed the effectiveness of the current first and second line drugs. Further, currently available agents are complicated by serious side effects, drug interactions and long-term administration. This has prompted urgent research efforts in the discovery and development of new anti-tuberculosis agent(s). Several families of compounds are currently being explored for the treatment of tuberculosis. This review article presents an account of the existing chemotherapeutics and highlights the therapeutic potential of emerging molecules that are at different stages of development for the management of tuberculosis disease. PMID:24281707

Shakya, Neeraj; Garg, Gaurav; Agrawal, Babita; Kumar, Rakesh

2012-01-01

318

The 1.9 A crystal structure of alanine racemase from Mycobacterium tuberculosis contains a conserved entryway into the active site.  

PubMed

We report the crystal structure of alanine racemase from Mycobacterium tuberculosis (Alr(Mtb)) at 1.9 A resolution. In our structure, Alr(Mtb) is found to be a dimer formed by two crystallographically different monomers, each comprising 384 residues. The domain makeup of each monomer is similar to that of Bacillus and Pseudomonas alanine racemases and includes both an alpha/beta-barrel at the N-terminus and a C-terminus primarily made of beta-strands. The hinge angle between these two domains is unique for Alr(Mtb), but the active site geometry is conserved. In Alr(Mtb), the PLP cofactor is covalently bound to the protein via an internal aldimine bond with Lys42. No guest substrate is noted in its active site, although some residual electron density is observed in the enzyme's active site pocket. Analysis of the active site pocket, in the context of other known alanine racemases, allows us to propose the inclusion of conserved residues found at the entrance to the binding pocket as additional targets in ongoing structure-aided drug design efforts. Also, as observed in other alanine racemase structures, PLP adopts a conformation that significantly distorts the planarity of the extended conjugated system between the PLP ring and the internal aldimine bond. PMID:15683232

LeMagueres, Pierre; Im, Hookang; Ebalunode, Jerry; Strych, Ulrich; Benedik, Michael J; Briggs, James M; Kohn, Harold; Krause, Kurt L

2005-02-01

319

Structural Insights into the Quinolone Resistance Mechanism of Mycobacterium tuberculosis DNA Gyrase  

Microsoft Academic Search

Mycobacterium tuberculosis DNA gyrase, an indispensable nanomachine involved in the regulation of DNA topology, is the only type II topoisomerase present in this organism and is hence the sole target for quinolone action, a crucial drug active against multidrug-resistant tuberculosis. To understand at an atomic level the quinolone resistance mechanism, which emerges in extensively drug resistant tuberculosis, we performed combined

Jérémie Piton; Stéphanie Petrella; Marc Delarue; Gwénaëlle André-Leroux; Vincent Jarlier; Alexandra Aubry; Claudine Mayer; Hendrik W. van Veen

2010-01-01

320

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

E-print Network

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

Yeh, Syun-Ru

321

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

E-print Network

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

Kirschner, Denise

322

Tuberculosis screening and follow-up of asylum seekers in Norway: a cohort study  

Microsoft Academic Search

BACKGROUND: About 80% of new tuberculosis cases in Norway occur among immigrants from high incidence countries. On arrival to the country all asylum seekers are screened with Mantoux test and chest x-ray aimed to identify cases of active tuberculosis and, in the case of latent tuberculosis, to offer follow-up or prophylactic treatment. We assessed a national programme for screening, treatment

Ingunn Harstad; Einar Heldal; Sigurd L Steinshamn; Helge Garåsen; Geir W Jacobsen

2009-01-01

323

Pulmonary tuberculosis as differential diagnosis of lung cancer  

PubMed Central

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

Bhatt, MLB; Kant, Surya; Bhaskar, Ravi

2012-01-01

324

[Spleen and medullary tuberculosis].  

PubMed

Spleen is a rare extra-pulmonary tuberculosis manifestation. The spleen tuberculosis is caused by the blood derivative dissemination of mycobacteria. The symptoms can suggest a hematological disease, but it is difficult to make a diagnosis, especially when there are no pulmonary changes. The case of a 27-year-old woman with unclear etiology bone marrow hypoplasia was presented. The patient experienced: fever, body weight loss, pancytopenia and spleen enlargement with numerous focal echographic changes. The splenectomy revealed in a histopathologic examination productiva caseosa tuberculosis. The bone marrow trepanobiopsy revealed as well tuberculosis changes. The antimycobacteria treatment caused an improvement of the clinical state and the regression of symptoms. PMID:20229713

B?achnio, Maria; Zielonka, Tadeusz M; Rzewuska, Ewa; Mioduszewska, Olga; Maryniak, Renata; B?achnio, Antoni

2009-01-01

325

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

PubMed Central

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

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

2013-01-01

326

Update on latent tuberculosis infection.  

PubMed

Latent tuberculosis infection refers to an asymptomatic, nontransmissible infection with Mycobacterium tuberculosis, carrying a 5% to 10% lifetime risk of progressing to active disease. One-half of this risk occurs within the first two years after infection. High-risk groups include recent immigrants from high-incidence countries, health care professionals, persons living or working in institutional settings, and homeless persons. Risk factors for progression to active disease include immunodeficiency, recent exposure to tuberculosis, and chronic kidney disease requiring dialysis. Tuberculin skin testing has several limitations, including the need for multiple office visits and the potential for false-positive results in patients who have received the bacillus Calmette-Guérin vaccine or been exposed to environmental mycobacteria. Interferon-gamma release assays address these deficiencies but are limited by their cost and requirement for blood processing. Interferon-gamma release assays are preferred in immigrants exposed to bacillus Calmette-Guérin and in patients who are not likely to return for interpretation of skin test results. Tuberculin skin testing is preferred for children younger than five years. Active disease should be excluded before initiating treatment. The newest treatment option of 12 weekly doses of isoniazid and rifapentine has similar or better effectiveness than standard nine-month therapy with daily isoniazid. A four-month regimen of daily rifampin is another alternative. PMID:25077395

Hartman-Adams, Holly; Clark, Karen; Juckett, Gregory

2014-06-01

327

Ligand-dependent active-site closure revealed in the crystal structure of Mycobacterium tuberculosis MenB complexed with product analogues.  

PubMed

1,4-Dihydroxy-2-naphthoyl coenzyme A (DHNA-CoA) synthase catalyzes an essential intramolecular Claisen condensation in menaquinone biosynthesis and is an important target for the development of new antibiotics. This enzyme in Mycobacterium tuberculosis is cofactor-free and is classified as a type II DHNA-CoA synthase, differing from type I enzymes, which rely on exogenous bicarbonate for catalysis. Its crystal structures in complex with product analogues have been determined at high resolution to reveal ligand-dependent structural changes, which include the ordering of a 27-residue active-site loop (amino acids 107-133) and the reorientation of the carboxy-terminal helix (amino acids 289-301) that forms part of the active site from the opposing subunit across the trimer-trimer interface. These structural changes result in closure of the active site to the bulk solution, which is likely to take place through an induced-fit mechanism, similar to that observed for type I DHNA-CoA synthases. These findings demonstrate that the ligand-dependent conformational changes are a conserved feature of all DHNA-CoA synthases, providing new insights into the catalytic mechanism of this essential tubercular enzyme. PMID:25372686

Song, Haigang; Sung, Hoi Pang; Tse, Yuk Sing; Jiang, Ming; Guo, Zhihong

2014-11-01

328

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

PubMed

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

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

2014-09-01

329

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

330

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

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

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

2014-01-01

331

Fighting tuberculosis: An old disease with new challenges  

Microsoft Academic Search

Tuberculosis (TB), caused by Mycobacterium tuberculosis, a slow growing bacterium, evolved from soil bacterium more than 10,000 years ago is a respiratory transmission infectious disease. It is a single largest infectious disease in the world infecting nearly 32% of the world's population is infected with TB. Among the infected individuals approximately 8 million develop active TB, and almost 2 million

Rama P. Tripathi; Neetu Tewari; Namrata Dwivedi; Vinod K. Tiwari

2005-01-01

332

A luciferase-based assay for rapid assessment of drug activity against Mycobacterium tuberculosis including monitoring of macrophage viability.  

PubMed

The intracellular (IC) effect of drugs against Mycobacterium tuberculosis (Mtb) is not well established but increasingly important to consider when combining current and future multidrug regimens into the best possible treatment strategies. For this purpose, we developed an IC model based on a genetically modified Mtb H37Rv strain, expressing the Vibrio harvei luciferase (H37Rv-lux) infecting the human macrophage like cell line THP-1. Cells were infected at a low multiplicity of infection (1:1) and subsequently exposed to isoniazid (INH), ethambutol (EMB), amikacin (AMI) or levofloxacin (LEV) for 5days in a 96-well format. Cell viability was evaluated by Calcein AM and was maintained throughout the experiment. The number of viable H37Rv-lux was determined by luminescence and verified by a colony forming unit analysis. The results were compared to the effects of the same drugs in broth cultures. AMI, EMB and LEV were significantly less effective intracellularly (MIC90: >4mg/L, 8mg/L and 2mg/L, respectively) compared to extracellularly (MIC90: 0.5mg/L for AMI and EMB; 0.25mg/L for LEV). The reverse was the case for INH (IC: 0.064mg/L vs EC: 0.25mg/L). In conclusion, this luciferase based method, in which monitoring of cell viability is included, has the potential to become a useful tool while evaluating the intracellular effects of anti-mycobacterial drugs. PMID:25194234

Larsson, Marie C; Lerm, Maria; Ängeby, Kristian; Nordvall, Michaela; Juréen, Pontus; Schön, Thomas

2014-11-01

333

A systems chemical biology study of malate synthase and isocitrate lyase inhibition in Mycobacterium tuberculosis during active and NRP growth.  

PubMed

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

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

2013-12-01

334

[Tuberculosis microepidemic in a commuter bus].  

PubMed

A tuberculosis microepidemic in a commuter bus was reported. Index patient was a 22-year-old woman who was an employee of an electronic company. An abnormal shadow was found on her chest roentgenogram during an annual medical check-up in June, 1996. As her sputum smear was Gaffky 6, she was admitted to our hospital for medication. Extraordinary examinations including PPD skin test and chest X-ray were carried out on 49 employees of the company in October, 1996. As the result of these examinations, the distribution of maximum diameters of erythema in PPD skin test showed bimodal distribution, and tuberculosis was discovered in two patients by Chest X-ray examination. Moreover, preventive administration of Isonicotinic acid hydrazide (INH) was indicated for 3 employees based on very strong skin reaction to PPD. These five employees were working separately from the index patient and had little contact with the patient in the work places, but using a same commuter bus. Therefore, we strongly suspect that they were infected from the index patient not in the work place but in the commuter bus. The air-conditioning of the bus used a closed recirculation system, hence insufficient ventilation in the bus contributed to the spread of tuberculosis infection. PMID:10423962

Yagi, T; Sasaki, Y; Yamagishi, F; Mizutani, F; Wada, A; Kuroda, F

1999-06-01

335

Breath-based biomarkers for tuberculosis  

NASA Astrophysics Data System (ADS)

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.

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

336

Zebrafishing for tuberculosis infection  

Microsoft Academic Search

Mycobacterium tuberculosis, also known as Koch’s bacillus, is the causative microbe of human tuberculosis (TB) that mainly involves lungs. For centuries, pulmonary TB, known as “lao” disease in Chinese, had been a brutal killer to human beings, as no drug was available to fight it. In the second half of the twentieth century, with the discovery and clinical application of

Liwei Wang

2010-01-01

337

Spinal tuberculosis: A review  

PubMed Central

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

Garg, Ravindra Kumar; Somvanshi, Dilip Singh

2011-01-01

338

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

PubMed Central

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

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

339

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

Microsoft Academic Search

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

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

340

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

Microsoft Academic Search

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

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

2003-01-01

341

Incidence of Active Pulmonary Tuberculosis in Patients with Coincident Filarial and/or Intestinal Helminth Infections Followed Longitudinally in South India  

PubMed Central

Background Filarial (and other helminth) infections are known to modulate mycobacteria-specific pro-inflammatory cytokine responses necessary for maintaining latency in tuberculosis (TB). We sought to address whether helminth co-infection alters progression to active pulmonary TB in a co-endemic area of South India. Methods/Principal Findings Incidence of active pulmonary TB was assessed in 5096 subjects from five villages among helminth-infected (hel+) and –uninfected (hel?) groups. Baseline stool examinations, circulating filarial antigen, and tuberculin skin testing (PPD) were performed along with chest radiographs, sputum microscopy, and culture. During three follow-up visits each 2.5 years, patients were assessed using PPD tests and questionnaires and—for those with potential symptoms of TB—sputum microscopy and culture. Of the 5096 subjects, 1923 were found to be hel+ and 3173 were hel?. Follow up interval stool examination could not be performed. In each group, 21 developed active TB over the course of the study. After adjusting for sex, age, BCG vaccination status, and PPD positivity, no difference was seen in active TB incidence between hel+ and hel? groups either at baseline (relative risk (RR) 1.60; 95% confidence interval (CI): 0.69, 3.71, P?=?0·27), or when followed prospectively (RR 1.24; 95% CI: 0.48, 3.18, P?=?0·66). Conclusions/Significance Our findings suggest that, despite the immunomodulatory effects of helminth infection, baseline co-morbid infection with these parasites had little effect on the clinical progression from latent to active pulmonary TB. PMID:24728010

Chatterjee, Soumya; Kolappan, Chockalingam; Subramani, Rangasamy; Gopi, Punnathanathu G.; Chandrasekaran, Vedhachalam; Fay, Michael P.; Babu, Subash; Kumaraswami, Vasanthapuram; Nutman, Thomas B.

2014-01-01

342

SUSPECT - The Online Supernova Spectrum Database  

NASA Astrophysics Data System (ADS)

We unveil SUSPECT, an online database for the uniform collection, storage and dissemination of supernova spectra. Observers may submit FITS format spectra by ftp or email. The spectra are stored and catalogued with a uniform header. An ADS-style web search interface makes supernova spectra available to anyone in a variety of formats, such as FITS, ASCII or GIF images. Visitors to the web site can search for spectra by date range, wavelength range or supernova type. Some searches combining several criteria are also possible. Original FITS headers are stored to maintain a complete history of each FITS spectrum, also available to visitors. Future enhancements to the database include web based spectrum submission, storage of noise spectra and photometry, and new ways of searching for spectra. The website of the SUSPECT database is http://www.nhn.ou.edu/\\ suspect.

Richardson, D.; Thomas, R. C.; Casebeer, D.; Blankenship, Z.; Ratowt, S.; Baron, E.; Branch, D.

2001-12-01

343

Inter-rater agreement in the assessment of abnormal chest X-ray findings for tuberculosis between two Asian countries  

PubMed Central

Background Inter-rater agreement in the interpretation of chest X-ray (CXR) films is crucial for clinical and epidemiological studies of tuberculosis. We compared the readings of CXR films used for a survey of tuberculosis between raters from two Asian countries. Methods Of the 11,624 people enrolled in a prevalence survey in Hanoi, Viet Nam, in 2003, we studied 258 individuals whose CXR films did not exclude the possibility of active tuberculosis. Follow-up films obtained from accessible individuals in 2006 were also analyzed. Two Japanese and two Vietnamese raters read the CXR films based on a coding system proposed by Den Boon et al. and another system newly developed in this study. Inter-rater agreement was evaluated by kappa statistics. Marginal homogeneity was evaluated by the generalized estimating equation (GEE). Results CXR findings suspected of tuberculosis differed between the four raters. The frequencies of infiltrates and fibrosis/scarring detected on the films significantly differed between the raters from the two countries (P < 0.0001 and P = 0.0082, respectively, by GEE). The definition of findings such as primary cavity, used in the coding systems also affected the degree of agreement. Conclusions CXR findings were inconsistent between the raters with different backgrounds. High inter-rater agreement is a component necessary for an optimal CXR coding system, particularly in international studies. An analysis of reading results and a thorough discussion to achieve a consensus would be necessary to achieve further consistency and high quality of reading. PMID:22296612

2012-01-01

344

Saudi guidelines for testing and treatment of latent tuberculosis infection  

PubMed Central

Pulmonary tuberculosis is a common disease in Saudi Arabia. As most cases of tuberculosis are due to reactivation of latent infection, identification of individuals with latent tuberculosis infection (LTBI) who are at increased risk of progression to active disease, is a key element of tuberculosis control programs. Whereas general screening of individuals for LTBI is not cost-effective, targeted testing of individuals at high risk of disease progression is the right approach. Treatment of those patients with LTBI can diminish the risk of progression to active tuberculosis disease in the majority of treated patients. This statement is the first Saudi guideline for testing and treatment of LTBI and is a result of the cooperative efforts of four local Saudi scientific societies. This Guideline is intended to provide physicians and allied health workers in Saudi Arabia with the standard of care for testing and treatment of LTBI. PMID:20103957

Al Jahdali, Hamdan H.; Baharoon, Salim; Abba, Abdullah A.; Memish, Ziad A.; Alrajhi, Abdulrahman A.; AlBarrak, Ali; Haddad, Qais A.; Al Hajjaj, Mohammad; Pai, Madhukar; Menzies, Dick

2010-01-01

345

Surveillance of Elderly Hospital Patients for Pulmonary Tuberculosis  

PubMed Central

A restrospective study of pulmonary tuberculosis in a general hospital showed that the diagnosis had been frequently overlooked in the middleaged or elderly because the patient also suffered from a more acute condition which preoccupied the attention of the doctor. The commonest error was to discount chest x-ray abnormalities by omitting sputum culture or serial radiography. Surveillance was carried out on all patients aged 60 or over admitted to a large general hospital whose routine chest radiograph showed signs of possible pulmonary tuberculosis whether apparently active or inactive. Three sputum samples from each patient were examined for Mycobacterium tuberculosis without reference to the clinical presentation. In a nine-month period six out of 81 patients proved to have active pulmonary tuberculosis (7·4%). It is suggested that this may be a useful method of screening the elderly hospital population for pulmonary tuberculosis. PMID:4203692

Cole, R. B.; Balmer, J. P.; Wilson, T. S.

1974-01-01

346

Diagnosis and management of miliary tuberculosis: current state and future perspectives  

PubMed Central

Tuberculosis (TB) remains one of the most important causes of death from an infectious disease, and it poses formidable challenges to global health at the public health, scientific, and political level. Miliary TB is a potentially fatal form of TB that results from massive lymphohematogenous dissemination of Mycobacterium tuberculosis bacilli. The epidemiology of miliary TB has been altered by the emergence of the human immunodeficiency virus (HIV) infection and widespread use of immunosuppressive drugs. Diagnosis of miliary TB is a challenge that can perplex even the most experienced clinicians. There are nonspecific clinical symptoms, and the chest radiographs do not always reveal classical miliary changes. Atypical presentations like cryptic miliary TB and acute respiratory distress syndrome often lead to delayed diagnosis. High-resolution computed tomography (HRCT) is relatively more sensitive and shows randomly distributed miliary nodules. In extrapulmonary locations, ultrasonography, CT, and magnetic resonance imaging are useful in discerning the extent of organ involvement by lesions of miliary TB. Recently, positron-emission tomographic CT has been investigated as a promising tool for evaluation of suspected TB. Fundus examination for choroid tubercles, histopathological examination of tissue biopsy specimens, and rapid culture methods for isolation of M. tuberculosis in sputum, body fluids, and other body tissues aid in confirming the diagnosis. Several novel diagnostic tests have recently become available for detecting active TB disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. A high index of clinical suspicion and early diagnosis and timely institution of antituberculosis treatment can be lifesaving. Response to first-line antituberculosis drugs is good, but drug-induced hepatotoxicity and drug–drug interactions in HIV/TB coinfected patients create significant problems during treatment. Data available from randomized controlled trials are insufficient to define the optimum regimen and duration of treatment in patients with drug-sensitive as well as drug-resistant miliary TB, including those with HIV/AIDS, and the role of adjunctive corticosteroid treatment has not been properly studied. Research is going on worldwide in an attempt to provide a more effective vaccine than bacille Calmette–Guérin. This review highlights the epidemiology and clinical manifestation of miliary TB, challenges, recent advances, needs, and opportunities related to TB diagnostics and treatment. PMID:23326198

Ray, Sayantan; Talukdar, Arunansu; Kundu, Supratip; Khanra, Dibbendhu; Sonthalia, Nikhil

2013-01-01

347

T Cell Activation and Cytokine Profile of Tuberculosis and HIV-Positive Individuals during Antituberculous Treatment and Efavirenz-Based Regimens  

PubMed Central

Introduction The profile of immune activation markers in tuberculosis and HIV-infected patients is already known. The impact of simultaneous infections on the immune parameters is still not fully explored. Methods We conducted a prospective study to estimate trajectories of activated T cell subsets and the profile of anti- and pro-inflammatory cytokines in a group of HIV-TB individuals, previously naïve for HAART, recruited from a randomized clinical trial during TB treatment and first antiretroviral therapy with efavirenz. Patients were evaluated according to the immunosuppression levels at baseline as group 1 (CD4<200 cells/mm3) and group 2 (CD4>200 cells/mm3). These parameters were measured at the time of HAART initiation (started about 30 days after the onset of TB treatment) and at the follow-up visits after 30, 60, 90 and 180 days. Trajectories were estimated using least squares estimates of the coefficients of a restricted cubic spline function in time after adjusting for subject effects, bootstrapping it 500 times. Results Increase of CD4 T cell counts and suppression of HIV viral load were observed for all patients under HAART and TB treatment. Descendent trajectories were observed for the activated CD8+/CD38+ and CD3+/HLA-DR+ T cell subsets, and for plasma concentration of gamma- interferon (IFN-?). Except for TNF-? and IL-2 discrete variations were observed for the other cytokines. Differences in the trajectories of these parameters were observed for groups 1 and 2. Higher values of IFN-?, IL-2, IL-6 and IL-10 were observed for group 1 from the baseline to two months after treatment initiation, whereas reduced levels of TNF-? were observed for this group between 60 and 120 days of HAART. Conclusion Independent of the immunosuppression profile at baseline, HIV-TB patients under HAART were able to recover the CD4+ T cell counts, and control viral replication and immune activation parameters over time. PMID:23840403

da Silva, Tatiana P.; Giacoia-Gripp, Carmem B. W.; Schmaltz, Carolina A.; Sant` Anna, Flavia M.; Rolla, Valeria; Morgado, Mariza G.

2013-01-01

348

Drug tolerance in Mycobacterium tuberculosis.  

PubMed

Although Mycobacterium tuberculosis is eradicated rapidly during therapy in some patients with pulmonary tuberculosis, it can persist for many months in others. This study examined the relationship between mycobacterial drug tolerance (delayed killing in vitro), persistence, and relapse. It was performed with 39 fully drug-susceptible isolates from a prospective trial of standard short-course antituberculous therapy with sputum smear-positive, human immunodeficiency virus-uninfected subjects with pulmonary tuberculosis in Brazil and Uganda. The rate of killing in vitro was determined by monitoring the growth index (GI) in BACTEC 12B medium after addition of drug to established cultures and was measured as the number of days required for 99% sterilization. Drugs differed significantly in bactericidal activity, in the following order from greatest to least, rifampin > isoniazid-ethambutol > ethambutol (P < 0.001). Isolates from subjects who had relapses (n = 2) or in whom persistence was prolonged (n = 1) were significantly more tolerant of isoniazid-ethambutol and rifampin than isolates from other subjects (P < 0.01). More generally, the duration of persistence during therapy was predicted by strain tolerance to isoniazid and rifampin (P = 0.012 and 0.026, respectively). Tolerance to isoniazid-ethambutol and tolerance to rifampin were highly correlated (P < 0.001). Tolerant isolates did not differ from others with respect to the MIC of isoniazid; the rate of killing of a tolerant isolate by isoniazid-ethambutol was not increased at higher drug concentrations. These observations suggest that tolerance may not be due to drug-specific mechanisms. Tolerance was of the phenotypic type, although increased tolerance appeared to emerge after prolonged drug exposure in vivo. This study suggests that drug tolerance may be an important determinant of the outcome of therapy for tuberculosis. PMID:10543735

Wallis, R S; Patil, S; Cheon, S H; Edmonds, K; Phillips, M; Perkins, M D; Joloba, M; Namale, A; Johnson, J L; Teixeira, L; Dietze, R; Siddiqi, S; Mugerwa, R D; Eisenach, K; Ellner, J J

1999-11-01

349

Suspected Child Maltreatment: Recognize and Respond  

ERIC Educational Resources Information Center

Early childhood educators spend extensive amounts of time with young children, so they are often the first adults to notice signs that a child may be abused or neglected. All educators are required by law to report suspected maltreatment, and can play an important role in preventing and responding to abuse and neglect of young children. What is…

Kemple, Kristen Mary; Kim, Hae Kyoung

2011-01-01

350

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

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).

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

351

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

PubMed Central

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

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

2014-01-01

352

Isolated Coccygeal Tuberculosis  

PubMed Central

Isolated tuberculosis of the coccyx is extremely rare. A 35-year-old man presented with a 3-month history of coccygeal and gluteal pain. Computed tomography and magnetic resonance imaging revealed osseous destruction and a large enhancing mass involving the coccyx with anterior and posterior extension. Pathologic examination of the surgical specimen revealed necrosis, chronic granulomatous inflammation, and multinucleated giant cells consistent with tuberculosis. This case highlights the importance of considering tuberculosis as a diagnosis even though unusual sites are involved. PMID:23323174

Kim, Do Un; Ju, Chang IL

2012-01-01

353

Transforming the fight against tuberculosis: targeting catalysts of transmission.  

PubMed

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

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

2014-10-15

354

Tuberculosis spine: Therapeutically refractory disease  

PubMed Central

Background: India ranks second amongst the high-burden multi drug resistant tuberculosis (MDR-TB) countries, with an estimated incidence of 2.3% MDR-TB cases amongst the new cases and 17.2% amongst the previously treated cases. The diagnosis and treatment protocol for MDR-TB of the spine are not clearly established. We report outcome of a series of 15 cases of TB spine who were suspected to be therapeutically refractory cases (MDR-TB) on the basis of clinicoradiological failures of initial treatment. Materials and Methods: Fifteen cases of TB spine from C2 to L5 spine were suspected to be the cases of MDR-TB (therapeutically refractory cases) on the basis of failures of adequate clinicoradiological healing response at 5 months or more on antitubercular treatment (ATT). None of the patient was immunocompromised. Thirteen out of 15 patients had tissue samples sent for histopathology, culture and sensitivity, smear, BACTEC, and polymerase chain reaction (PCR). All patients were put on second line ATT and followed up fortnightly with regular liver and kidney function tests, erythrocyte sedimentation rate (ESR), and plain X-ray. Healing was documented as subjective improvement of symptoms, reduction in ESR, and observations on contrast enhanced magnetic resonance imaging (MRI) such as resolution of marrow edema, fatty replacement of bone marrow and resolution of abscesses. Ambiguous MRI observations in a few patients were resolved on positron emission tomography (PET) scan. Patients were monitored continuously for 2 years after stopping ATT. Results: We could demonstrate a positive culture in three cases. Two of them had multi drug resistance. We could achieve healing status in 13 out of 14 patients after starting second line drugs, one patient is still on treatment while other patient with no drug resistance is responding well on ATT. Conclusions: The suspicion of therapeutically refractory case is of paramount importance. Once suspected, surgery to procure tissue for diagnosis and culture is to be undertaken. The demonstration of drug resistance on culture may not be achieved in all TB spine cases and empiric drug regimen for MDR-TB is to be started. We have achieved the healed status with immunomodulation and second line ATT. The length of treatment needs to be monitored with MRI and PET scan. PMID:22448055

Jain, Anil K; Dhammi, Ish K; Modi, Prashant; Kumar, Jaswant; Sreenivasan, Ravi; Saini, Namita Singh

2012-01-01

355

The sampling of ignitable liquids on suspects' hands.  

PubMed

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

Montani, Isabelle; Comment, Stéfane; Delémont, Olivier

2010-01-30

356

Cystic tuberculosis of the scapula in a young boy: a case report and review of the literature  

PubMed Central

Introduction Tuberculosis of the flat bones is rare and only a small percentage involves the scapular bone. Case presentation We report a rare case of tuberculosis of the scapula in a 14-year-old. Diagnostic clues include lytic areas with low density seen in the body of the scapula involving a glenoid margin associated with typical clinical features. Treatment should include a regimen of four antitubercular drugs along with surgical debridement if required. Conclusion Although rare, tuberculosis should be suspected in patients presenting with a chronic sinus in the scapular region, particularly in the developing world. PMID:19830202

2009-01-01

357

Tuberculosis in the elderly.  

PubMed

Tuberculosis (TB) today remains one of the world's most lethal infectious diseases. An estimated one-third of the world's 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 as harboring Mtb without evidence of active infection, and TB disease is active infection without Mtb based on clinical and laboratory findings. Recognizing that TB has been one of the most neglected international health problems and that the TB epidemic is rampant in many parts of the world, the World Health Organization (WHO) declared TB to be a global health emergency in 1993 (23). Despite the steady decline in TB cases since this time resulting from the overall implementation of more effective infection control practices, directly observed therapy (DOT), and efforts to control the human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) epidemic, preventive and control strategies among other high-risk populations such as the elderly evidently remain a clinical and epidemiological challenge. The geriatric population among all ethnic groups and both genders, represent the largest reservoir of TB infection, particularly in developed nations (9). Clinical features of TB in older adults may be atypical, non-specific, and confused with concomitant age-related diseases (28). Underlying acute or chronic diseases, malnutrition, and the biological changes with aging, can disrupt integumental barriers, impair microbial clearance mechanisms, and contribute to the expected age-associated decline in cellular immune responses to infecting agents such as Mtb. Diagnosis of TB can be difficult and consequently overlooked; this treatable infection may unfortunately be recognized only at autopsy. Furthermore, therapy of TB in the elderly is challenging because of the increased incidence of adverse drug reactions. Optimal treatment of associated chronic diseases, minimization of invasive procedures, limitation of polypharmacy, and adequate nutritional support are essential for this vulnerable population. The institutionalized elderly in addition are especially at high risk for reactivation of latent TB as well as susceptible to new TB infection. This article will discuss the global epidemiology, pathogenesis and immunologic aspects, unique clinical consideration, treatment and prevention of TB, briefly inclusive of the recent published guidelines for targeted tuberculin testing and treatment of latent TB infection as it pertains to the elderly. PMID:11130191

Rajagopalan, S; Yoshikawa, T T

2000-10-01

358

[Tuberculosis and malaria global prophylaxis in the light of decisions of the Big Eight].  

PubMed

At the present time about two million people, one third of the Earth's population, are carriers of tuberculosis agent. Though tuberculosis is curable disease, it continues to take away lives of about 4400 persons; most of them are young and are in the most productive age. The most active incidence rate of tuberculosis occurs in the countries of Africa to the south of Sahara (29% of all cases of tuberculosis per head); half of new cases of tuberculosis fall on Asian countries: Bangladesh, China, India, Indonesia, Pakistan, Philippines. The governments of Big Eight maintain activities that have stabilized morbidity of tuberculosis on a world scale. Over 11 years (1995 - 2006) World Health Organization (WHO) implemented the DOTS strategy (Directly Observed Treatment with Short course of chemotherapy) in 183 countries and tested it on 26 millions patients with tuberculosis. Global data acquisition in 2005 found out morbidity of tuberculosis in 59% (the aim is 70%) and successful cure in 84% cases (the aim is 85 %). In 2006 WHO started realization of the Global Plan "Stop tuberculosis" (2006 - 2012). At the present time Global Fund use about 17% its resources to finance programs against tuberculosis. These funds help to reveal 5 millions extra cases of tuberculosis and cure 3 millions patients in the network of DOTS. PMID:18426014

Onishchenko, G G

2008-01-01

359

The Human Antibody Response to the Surface of Mycobacterium tuberculosis  

PubMed Central

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

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

2014-01-01

360

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

PubMed

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

Singh, Upasana; Sarkar, Dhiman

2006-12-01

361

[Cutaneous tuberculosis: case report].  

PubMed

Cutaneous tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis. It is not very frequent and particularly difficult to diagnose. It incidence ranges between 1.5 and 4% of all extrapulmonary tuberculosis, according to bibliography. The clinic presentations depend on the arrival via of the bacillus to the skin, the patient's immune state and the environment. We show a cutaneous tuberculosis on a child with chronic dermatologic lesions, with torpid evolution, without response to treatments; the skin biopsy showed caseous granulomas. The aim is to show a patient with an infrequent clinic presentation of this disease, to emphasize the importance of an early recognition and treatment, avoiding the appearance of complications and sequels. PMID:24862824

Bisero, Elsa; Luque, Graciela; Melillo, Karina; Favier, María Inés; Zapata, Alejandra; Cuello, María Soledad

2014-06-01

362

Update on cutaneous tuberculosis*  

PubMed Central

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

Dias, Maria Fernanda Reis Gavazzoni; Bernardes Filho, Fred; Quaresma, Maria Victoria; do Nascimento, Leninha Valerio; Nery, Jose Augusto da Costa; Azulay, David Rubem

2014-01-01

363

Update on cutaneous tuberculosis.  

PubMed

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

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

2014-12-01

364

Global Tuberculosis (TB)  

MedlinePLUS

... Peru, Philippines, Russia, Rwanda, South Africa, Thailand, and Vietnam. Learn More » Data and Statistics Reported Tuberculosis in ... Lesotho Mozambique Peru Philippines Rwanda South Africa Thailand Vietnam TB Disease Screening and Diagnosis in People with ...

365

[Epidemiologic trends in tuberculosis].  

PubMed

More than 90% of all tuberculosis cases occur in developing countries. Incidence rates estimated by WHO vary from 23 per 100,000 in industrialized countries to 191 per 100,000 in Africa and 237 per 100,000 in South East Asia. the downward trend observed in most industrialized counties in the 1970's and 1980's caused a neglect that nearly made tuberculosis a forgotten disease among the medical profession and policy makers. Ths neglect has led to a catastrophe in certain large cities in the United States. The resurgence of tuberculosis can not be attributed to the HIV/AIDS epidemic alone but also to the dismantling of health care structures responsible for tuberculosis control in certain countries. PMID:8794615

Billo, N E

1996-06-01

366

Tuberculosis in tropical Africa  

PubMed Central

Up to the end of the nineteenth century the tubercle bacillus apparently had little opportunity of disseminating among the rather isolated tribes of tropical Africa. With the creation of large centres of trade and industry in the wake of European colonization, tuberculosis seems to have spread rapidly over the continent and is today found everywhere. In a number of tuberculosis prevalence surveys conducted by WHO during 1955-60, randomly selected population groups were tuberculin tested, X-rayed and had sputa examined by direct microscopy. The three methods of examination were applied independently of one another. Data collected during the surveys have been analysed with a view to discovering common epidemiological features of tuberculosis in tropical Africa, assessing the reliability of the diagnostic methods employed and discussing their usefulness in future tuberculosis control programmes. PMID:14178027

Roelsgaard, E.; Iversen, E.; Bløcher, C.

1964-01-01

367

[Tuberculosis control programme in Tunisia: efficacy assessment].  

PubMed

The aim of this study was to assess the efficacy of the national Tuberculosis Control Programme in Tunisia, by applying the 8-stage model proposed by Piot (1967). Two retrospective cohorts of tuberculosis cases, including all new smear-positive cases detected by all laboratories in the study area during the study period, were selected at least 2 years after treatment began. The real number of new active cases during the study period was estimated at 142, the case detection rate at 61%. In all, 70% of patients started tuberculosis treatment, and regular use of the home treatment varied from 87% (including irregular use) to 71% (excluding irregular use). The low global efficacy of the program, which ranged from 26 to 31%, indicates the need for improved application of the strategy by programme managers. PMID:20685638

Kouni Chahed, Mohamed; Bellali, Hédia; Dhouibi, Sassia; Ben Alaya, Nissaf; Zouari, Béchir

2010-01-01

368

Database resources for the Tuberculosis community  

PubMed Central

Summary Access to online repositories for genomic and associated “-omics” datasets is now an essential part of everyday research activity. It is important therefore that the Tuberculosis community is aware of the databases and tools available to them online, as well as for the database hosts to know what the needs of the research community are. One of the goals of the Tuberculosis Annotation Jamboree, held in Washington DC on March 7th–8th 2012, was therefore to provide an overview of the current status of three key Tuberculosis resources, TubercuList (tuberculist.epfl.ch), TB Database (www.tbdb.org), and Pathosystems Resource Integration Center (PATRIC, www.patricbrc.org). Here we summarize some key updates and upcoming features in TubercuList, and provide an overview of the PATRIC site and its online tools for pathogen RNA-Seq analysis. PMID:23332401

Lew, Jocelyne M.; Mao, Chunhong; Shukla, Maulik; Warren, Andrew; Will, Rebecca; Kuznetsov, Dmitry; Xenarios, Ioannis; Robertson, Brian D.; Gordon, Stephen V.; Schnappinger, Dirk; Cole, Stewart T.; Sobral, Bruno

2013-01-01

369

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

PubMed Central

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

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

2013-01-01

370

Vaccine shortages and suspect online pharmacy sellers.  

PubMed

Vaccines represent half the products on the FDA Biologics Product Shortages list. As a result, providers and patients may purchase them online, a process rife with patient safety risks. We examined vaccine online availability by assessing up to 5 identified online sellers. We determined if sites were accredited by the National Association of Boards of Pharmacy (NABP) VIPPS program, listed as US or international, employed social media linking to suspect online pharmacies, and if they were on the NABP Not Recommended list. All vaccines were advertised by online pharmacies and through data aggregation and social media sites, none were VIPPS-accredited, and most were on the NABP Not Recommended list. We found some online sellers advertising vaccines as over-the-counter. We extended our analysis to WHO Essential Medicines List vaccines and found all are also available online from suspect, non-VIPPS accredited sellers. Stakeholders should be aware of these online patient safety dangers. PMID:22094281

Liang, Bryan A; Mackey, Tim K

2012-01-01

371

[Pulmonary manifestations of tuberculosis in children].  

PubMed

The occurrence of tuberculosis in children is dependent on a contagious bacillus carrying adult. Among 500 cases notified annually, perhaps 5 or 6% of the total infectious reservoir in France, 75% have parenchymal pulmonary disease and/or lymph nodes. These tuberculous diseases only represent 10% of the pulmonary disorders: 90% remain primary infections (PI active) or latent infections. These are most often asymptomatic (PI Latent) or of low grade activity (PI active). The CT scanner and fibreoptic bronchoscopy are indispensable complementary investigations in tuberculous disease. Whatever the clinical picture the diagnosis rests on bacteriological confirmation (but only 30% of cultures are positive) and most often rests on a body of evidence: for example a contagious adult living in proximity or a contagious family, or other risk factors are present. The evidence of a child with whatever form of pulmonary tuberculosis, even a latent primary infection, requires treatment which is adapted in such a way to enable a cure and to protect against subsequent endogenous re-activation. A coherent system of co-operation between the hospital and community service and between paediatricians and adult physicians is indispensable to find the index adult case to break the chain of contagion. There are two specific aspects in children, first congenital tuberculosis when a diagnosis is difficult and secondly tuberculosis in a child who is HIV positive when the management can be delicate. PMID:9496592

Olivier, C

1997-12-01

372

PICTURES OF A SUSPECT-TRU RETRIEVAL  

SciTech Connect

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

GADD, R.R.

2007-05-24

373

Analysis of regulated suspected allergens in waters.  

PubMed

Fragrance suspected allergens including those regulated by the EU Directive 76/768/EEC have been determined in different types of waters using solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS). The procedure was based on headspace sampling (HS-SPME) using polydimethylsiloxane/divinylbenzene (PDMS/DVB) fibers and has been optimized by an experimental design approach. The method performance has been studied showing good linearity (R ? 0.994) as well as good intra-day and inter-day precision (RSD ? 12%). Detection limits (S/N=3) ranged from 0.001 to 0.3 ng mL(-1). Reliability was demonstrated through the quantitative recoveries of the compounds in real water samples, including baby bathwaters, swimming pool waters, and wastewaters. The absence of matrix effects allowed quantification of the compounds by external aqueous calibration. The analysis of 35 samples of different types of waters showed the presence of suspected allergens in all the analyzed samples. All targets were found in the samples, with the exception of methyl eugenol and amyl cinnamic alcohol. Highest concentrations of suspected allergens were present in baby bathwaters, containing from 5 to 15 of the compounds at concentrations ranging from few pg mL(-1) to several hundreds of ng mL(-1). PMID:21111161

Becerril, Elias; Lamas, J Pablo; Sanchez-Prado, Lucia; Llompart, Maria; Lores, Marta; Garcia-Jares, Carmen

2010-12-15

374

Performance of QuantiFERON-TB Gold In-Tube (QFTGIT) for the diagnosis of Mycobacterium tuberculosis (Mtb) infection in Afar Pastoralists, Ethiopia  

PubMed Central

Background Currently, T-cell based gamma interferon (IFN?) release assays (IGRAs) are acknowledged as the best methods available for the screening of latent tuberculosis infection (LTBI) and also as aid for the diagnosis of active tuberculosis (TB). To our information, the performance of these diagnostic tests has not been evaluated in Ethiopia. Therefore, the intent of this study was to evaluate the performance of QuantiFERON-TB Gold In-Tube (QFTGIT) in patients clinically suspected of active pulmonary TB (PTB) as well as in healthy subjects prior to its utilization for the epidemiological study of active TB and LTBI in Afar pastoralists. Methods The sensitivity of QFTGIT was evaluated in 140 subjects who were clinically suspected of PTB using the cut-off value recommended by the manufacturer (? 0.35 IU/ml) and disease-specific cut-off value. Sputum culture result was used as a gold standard. The specificity of the test was evaluated both in patients and in 55 tuberculin skin test (TST) negative healthy subjects. Results Out of the 140 study participants, 37 (26.4%) were positive for active PTB by culture. Out of the 37 subjects who had positive results by culture, 6 individuals were HIV-seropositive. Out of the 103 subjects who were negative by culture, 6 subjects had indeterminate results and 21 were HIV-seropositive. The performance of the test was assessed using data from 107 (31 culture positive and 76 culture negative) individuals who were clinically suspected of PTB and HIV-seronegatives. Using the manufacturer recommended cut-off value, the sensitivity of the test was 64.5% (20/31), while its specificity was 36.8% (28/76). The sensitivity of the test was increased to 77.4%, while the specificity was reduced to 23.7% using a cut-off value ? 0.1 IU/ml of IFN? as disease-specific cut-off value. In TST negative healthy subjects, the specificity of the test was 58.2%. Conclusion Our findings revealed a low sensitivity of QFTGIT in the diagnosis of Mycobacterium tuberculosis (Mtb) infection in the present study area using the cut-off value recommended by the manufacturer. Nevertheless, the sensitivity increased from 64.5% to 77.4% by lowering the cut-off value recommended by the manufacturer to ? 0.1 IU/ml of IFN? level. Hence, it is of practical importance to evaluate the performance of QFTGIT in population under different settings prior to its application either for the diagnosis of active TB or LTBI. PMID:21162756

2010-01-01

375

Tuberculosis part 3: HIV-tuberculosis co-infection.  

PubMed

Tuberculosis is the most common opportunistic infection in HIV-seropositive persons. Tuberculosis may occur at any stage of HIV disease but the prevalence of TB increases with the progressive diminution of CD4+ T cell numbers. There is a synergistic relationship between tuberculosis and HIV infection as each accelerates the progression of the other. PMID:20034289

Feller, L; Wood, N H; Chikte, U M E; Khammissa, R A G; Meyerov, R; Lemmer, J

2009-09-01

376

Tuberculosis: A Problem for Lifeguards?  

ERIC Educational Resources Information Center

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…

Skaros, Susan

1996-01-01

377

New drug candidates and therapeutic targets for tuberculosis therapy.  

PubMed

Despite advances in chemotherapy and the BCG (Bacillus Calmette-Guérin) vaccine, tuberculosis remains a significant infectious disease. Although it can be cured, the therapy takes at least 6-9 months, and the laborious and lengthy treatment brings with it dangers of noncompliance, significant toxicity and drug resistance. The increasing emergence of drug resistance and the problem of mycobacterial persistence highlight the need to develop novel TB drugs that are active against drug resistant bacteria but, more importantly, kill persistent bacteria and shorten the length of treatment. Recent new and exciting developments in tuberculosis drug discovery show good promise of a possible revolution in the chemotherapy of tuberculosis. PMID:16478687

Zhang, Ying; Post-Martens, Katrin; Denkin, Steven

2006-01-01

378

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

E-print Network

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

Cohen, Ted

379

Incidence of Serious Side Effects from First-Line Antituberculosis Drugs among Patients Treated for Active Tuberculosis  

Microsoft Academic Search

Major adverse reactions to antituberculosis drugs can cause signifi- less certain because they are seldom used alone. The inci- cant morbidity, and compromise treatment regimens for tuberculo- dence of major side effects associated with pyrazinamide sis (TB). Among patients treated for active TB we estimated the (PZA), is somewhat controversial. Authoritative treatment incidence, and risk factors, of major side effects

Daphne Yee; Chantal Valiquette; Marthe Pelletier; Isabelle Parisien; Isabelle Rocher; Dick Menzies

380

48 CFR 1403.806 - Processing suspected violations.  

Code of Federal Regulations, 2011 CFR

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

2011-10-01

381

48 CFR 1403.806 - Processing suspected violations.  

Code of Federal Regulations, 2010 CFR

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

2010-10-01

382

EXPERIMENTAL EPIDEMIOLOGY OF TUBERCULOSIS  

PubMed Central

1. Ultraviolet irradiation of the air of a room exercises a protective influence against natural air-borne contagion of tuberculosis in rabbits. 2. When the radiant energy is of low intensity it reduces considerably the incidence of tuberculosis. (a) It completely protects rabbits of high natural resistance from acquiring demonstrable disease though they become tuberculin sensitive. (b) It fails to protect a small proportion of rabbits of low natural resistance from fatal tuberculosis. 3. When the radiant energy is of high intensity all rabbits, whether of high or of low natural resistance, are almost completely protected from a contagion so severe that it is fatal to the great majority of rabbits of the same genetic constitution not protected by these rays. The protected rabbits do not develop tuberculin sensitivity. 4. The contagion of tuberculosis in these studies is air-borne and the radiant energy exercises its protective influence by its bactericidal properties. It is probable that ultraviolet irradiation may control air-borne contagion of human tuberculosis. PMID:19871387

Lurie, Max B.

1944-01-01

383

Multidrug-resistant tuberculosis in an adult with cystic fibrosis.  

PubMed

Mycobacterium tuberculosis infection in patients with cystic fibrosis (CF) is rare. We report a 22-year-old CF patient with high fever, dyspnea and weight loss that progressively worsened over 2 weeks before admission. The patient suffered from liver cirrhosis, was colonized with Pseudomonas aeruginosa and had been repeatedly hospitalized for pulmonary infections. The patient was treated initially as for an exacerbation of P. aeruginosa infection, but tuberculosis (TBC) was suspected due to lack of improvement. A CT of the chest revealed enlarged bilateral cavities in the upper and middle lobes. A tuberculin skin test was positive, and M. tuberculosis nucleic acid was isolated from sputum samples. After receiving first-line anti-TBC drugs for 1 month, the patient's condition continued to worsen so molecular drug susceptibility testing was performed. Multidrug-resistant TBC was discovered, leading to a change in regimen. The patient was treated with ethionamide, moxifloxacin, linezolid, amikacin, imipenem/cilastatin and rifabutin and showed a remarkable clinical improvement. Although nontuberculous mycobacteria are more common in CF, the possibility of TBC should not be ignored. In that setting, early suspicion of infection due to resistant M. tuberculosis can be life saving. PMID:22869452

Manika, K; Giouleka, P; Zarogoulidis, K; Kioumis, I

2013-01-01

384

Renal Tuberculosis in the Modern Era  

PubMed Central

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

De Francesco Daher, Elizabeth; Bezerra da Silva Junior, Geraldo; Barros, Elvino Jose Guardao

2013-01-01

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Efficiency of a third serial sputum smear examination in the diagnosis of tuberculosis in Moldova and Uganda  

Microsoft Academic Search

SETTING: Twenty-four and 30 tuberculosis (TB) micros- copy laboratories in Moldova and Uganda, respectively. OBJECTIVE: To estimate the workload required to iden- tify one additional case of TB with a third serial sputum smear examination. METHODS: Retrospective laboratory register study to determine the prevalence and the incremental yield of TB cases from a third serial sputum smear examination among suspects

A. Katamba; D. Laticevschi; H. L. Rieder