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1

Evaluation of two pretreatment methods for the detection of Mycobacterium tuberculosis in suspected pulmonary tuberculosis.  

PubMed

The objective of the current study was to compare the efficacy of phenol ammonium sulphate (PhAS) and sodium hypochlorite (NaOCl) pretreatment methods for the direct microscopy with the Löwenstein-Jensen (LJ) culture to detect acid fast bacilli (AFB) from pulmonary tuberculosis suspected cases using sputum specimens. To evaluate PhAS and NaOCl methods, sputum specimens (n?=?1145) were studied and the performance of each method was compared with LJ media. The, PhAS centrifuged smear and NaOCl centrifuged smear method demonstrated higher sensitivity (71.47% and 77%), specificity (99.61% and 98%), positive predictive value (98.8% and 94.88%) and negative predictive value (88.35% and 90.25%), respectively, when compared to LJ culture. However, the direct AFB smears and PhAS centrifugation method was ineffective to detect few Mycobacterium tuberculosis cases from sputum specimens, particularly in blood tinged specimens with scanty bacilli. Interestingly, NaOCl method could efficiently detect the Mycobacterium tuberculosis cases from blood tinged sputum specimens with scanty bacilli. The current study concluded that NaOCl method could be the most efficient and sensitive method than direct AFB smear and PhAS centrifuged smear method for the direct detection of AFB in suspected cases of pulmonary tuberculosis. PMID:22733571

Shinu, Pottathil; Nair, Anroop; Jad, Beena; Singh, Varsha

2013-03-01

2

Diagnostic accuracy of chest radiography in detecting mediastinal lymphadenopathy in suspected pulmonary tuberculosis  

PubMed Central

Objective: To estimate the diagnostic accuracy of chest radiography in the detection of chest lymphadenopathy in children with clinically suspected pulmonary tuberculosis. Methods: Design: Prospective cross sectional study. Setting: A short stay ward in a children's hospital in South Africa. Patients: Consecutive children under 14 years of age admitted with suspected pulmonary tuberculosis. Diagnostic test: Antero-posterior and/or lateral chest x rays interpreted independently and blind to the reference standard by three primary care clinicians and three paediatricians, all with a special interest in tuberculosis. Reference standard: Spiral chest computed tomography (CT) with contrast injection. Results: One hundred children (median age 21.5 months) were enrolled. Lymphadenopathy was present in 46 of 100 reference CT scans and judged to be present in 47.1% of x ray assessments. Overall sensitivity was 67% and specificity 59%. Primary care clinicians were more sensitive (71.5% v 63.3%, p = 0.047) and less specific (49.8% v 68.9%, p<0.001) than paediatricians. Overall accuracy was higher for the paediatricians (diagnostic odds ratio 3.83 v 2.49, p = 0.008). The addition of a lateral to an antero-posterior view did not significantly increase accuracy (diagnostic odds ratio 3.09 v 3.73, p = 0.16). Chance adjusted inter-observer agreement (?) varied widely between viewer pairs, but was around 30%. Conclusions: Detection of mediastinal lymphadenopathy on chest x ray to diagnose pulmonary tuberculosis in children must be interpreted with caution. Diagnostic accuracy might be improved by refining radiological criteria for lymphadenopathy. PMID:16243870

Swingler, G; du Toit, G; Andronikou, S; van der Merwe, L; Zar, H

2005-01-01

3

Health care seeking among pulmonary tuberculosis suspects and patients in rural Ethiopia: a community-based study  

PubMed Central

Background Health care seeking is a dynamic process that is influenced by socio-demographic, cultural and other factors. In Ethiopia, there are limited studies regarding the health seeking behaviour of tuberculosis (TB) suspects and TB patients. However, a thorough understanding of patients' motivation and actions is crucial to understanding TB and the treatment of disease. Such insights would conceivably help to reduce delay in diagnosis, improve treatment adherence and thereby reduce transmission of TB in the community. The objective of this study was to describe and analyze health care seeking among TB suspects and pulmonary TB (PTB) cases in a rural district of the Amhara Region in Ethiopia. Methods Study kebeles were randomly selected in a cross-sectional study design. House-to-house visits were conducted in which individuals aged 15 years and above in all households of the kebeles were included. Subjects with symptoms suggestive of TB were interviewed about their health seeking behaviour, socio-demographic and clinical factors using a semi-structured questionnaire. Logistics regression analysis was employed to assess associations between the independent and outcome variables. Results The majority, 787 (78%), TB suspects and 33 (82.5%) PTB cases had taken health care actions for symptoms from sources outside their homes. The median delay before the first action was 30 days. In logistics regression, women (AOR 0.8, 95% CI 0.6, 0.9) were found to be less likely to visit a medical health provider than men. Those with a long duration of cough (AOR 1.5, 95% CI 1.03, 2.1) and those with a previous history of TB (AOR 1.5, 95% CI 1.03, 2.3) were more likely to visit a medical health provider compared to those with a shorter duration of cough and with no history of TB. Conclusion The majority of TB suspects and PTB cases had already taken health care actions for their symptoms at the time of the survey. The availability of a simple and rapid diagnostic TB test for use at the lowest level of health care and the involvement of all health providers in case finding activities are imperative for early TB case detection. PMID:20003219

2009-01-01

4

Antituberculosis IgG Antibodies as a Marker of Active Mycobacterium tuberculosis Disease  

PubMed Central

Anti-Mycobacterium tuberculosis IgG antibodies may aid in the diagnosis of active M. tuberculosis disease. We studied whether anti-M. tuberculosis IgG antibodies are elevated in active M. tuberculosis disease and assessed factors contributing to false-positive and -negative results. A retrospective study of 2,150 individuals tested by the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay was conducted at the University of Utah, ARUP Laboratories, November 2008 to December 2010. All samples were tested with the InBios Active TbDetect antituberculosis (anti-TB) IgG antibody assay. Of 1,044 patients with a positive QFT-GIT, 59 (5.7%) were positive for M. tuberculosis antibodies. Fourteen of 1,106 (1.3%) with a negative or indeterminate QFT-GIT were positive for M. tuberculosis antibodies. M. tuberculosis antibody tests were positive in 61.5% with confirmed active M. tuberculosis disease and other mycobacterial infections. Over half of the false-negative M. tuberculosis antibody tests occurred in patients ?90 years of age. False positives were seen in 12.9% of autoimmune patients. The odds ratio of being positive by the QFT-GIT and the InBios TB IgG assay increased with confirmed M. tuberculosis disease or highly suspected M. tuberculosis disease and was 86.7 (95% confidence interval [CI], 34.4 to 218.5) in these two groups compared to patients negative by both tests. Although anti-M. tuberculosis antibodies can be detected in patients with active M. tuberculosis disease, caution should be used with patients where immunoglobulin levels may be decreased or patients with autoantibodies. PMID:22301692

Welch, Ryan J.; Lawless, Kathleen M.

2012-01-01

5

Validation of Mycobacterium tuberculosis Rv1681 Protein as a Diagnostic Marker of Active Pulmonary Tuberculosis  

PubMed Central

The development of an accurate antigen detection assay for the diagnosis of active tuberculosis (TB) would represent a major clinical advance. Here, we demonstrate that the Mycobacterium tuberculosis Rv1681 protein is a biomarker for active TB with potential diagnostic utility. We initially identified, by mass spectroscopy, peptides from the Rv1681 protein in urine specimens from 4 patients with untreated active TB. Rabbit IgG anti-recombinant Rv1681 detected Rv1681 protein in lysates and culture filtrates of M. tuberculosis and immunoprecipitated it from pooled urine specimens from two TB patients. An enzyme-linked immunosorbent assay formatted with these antibodies detected Rv1681 protein in unconcentrated urine specimens from 11/25 (44%) TB patients and 1/21 (4.8%) subjects in whom TB was initially clinically suspected but then ruled out by conventional methods. Rv1681 protein was not detected in urine specimens from 10 subjects with Escherichia coli-positive urine cultures, 26 subjects with confirmed non-TB tropical diseases (11 with schistosomiasis, 5 with Chagas' disease, and 10 with cutaneous leishmaniasis), and 14 healthy subjects. These results provide strong validation of Rv1681 protein as a promising biomarker for TB diagnosis. PMID:23390284

Macovei, Lilia; Kanunfre, Kelly; Dhiman, Rakesh; Restrepo, Blanca I.; Zarate, Izelda; Pino, Paula A.; Mora-Guzman, Francisco; Fujiwara, Ricardo T.; Michel, Gerd; Kashino, Suely S.

2013-01-01

6

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

PubMed Central

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

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

2011-01-01

7

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

8

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

PubMed Central

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

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

2013-01-01

9

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

10

38 CFR 3.374 - Effect of diagnosis of active tuberculosis.  

...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...

2014-07-01

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, 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

13

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

14

Direct molecular detection of Mycobacterium tuberculosis suspected to be the specific infection in a case of recurrent tonsillitis.  

PubMed

We report a case of a 21-year-old man with recurrent tonsillitis caused by Mycobacterium tuberculosis. For a period of 5 months, the patient had tonsillitis seven times and was treated with several oral or parenteral antibiotics. On one of these occasions, tonsillitis was complicated with a peritonsillar abscess that was treated by incision. According to relevant bibliographic data, this is the first case of Mycobacterium tuberculosis confirmed by direct molecular microbiology methods from the tonsillar tissue of a young immunocompetent male reported in Europe. In a case of recurrent tonsillitis, Mycobacterium tuberculosis infection should be considered as a possible cause. PMID:23591525

Lukši?, Boris; Kljaji?, Zlatko; Roje, Zeljka; Forempoher, Gea; Grgi?, Duška; Jankovi?-Katalini?, Vera; Goi?-Bariši?, Ivana

2013-12-01

15

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

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

2007-01-01

16

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

Microsoft Academic Search

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

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

2010-01-01

17

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

E-print Network

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

Sali, Andrej

18

Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis  

Microsoft Academic Search

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

Andrea E. Debarber; Khisimuzi Mdluli; Marlein Bosman; Linda-Gail Bekker

2000-01-01

19

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

Code of Federal Regulations, 2012 CFR

... false Pulmonary tuberculosis shown by X-ray in active service. 3.370 Section 3...370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for...

2012-07-01

20

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

Code of Federal Regulations, 2010 CFR

... false Pulmonary tuberculosis shown by X-ray in active service. 3.370 Section 3...370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for...

2010-07-01

21

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

... false Pulmonary tuberculosis shown by X-ray in active service. 3.370 Section 3...370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for...

2014-07-01

22

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

Code of Federal Regulations, 2011 CFR

... false Pulmonary tuberculosis shown by X-ray in active service. 3.370 Section 3...370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for...

2011-07-01

23

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

Code of Federal Regulations, 2013 CFR

... false Pulmonary tuberculosis shown by X-ray in active service. 3.370 Section 3...370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for...

2013-07-01

24

Spooky Suspects  

ERIC Educational Resources Information Center

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

Pacifici, Lara

2011-01-01

25

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

PubMed Central

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

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

2013-01-01

26

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

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

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

...2014-07-01 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...

2014-07-01

29

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

30

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

31

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; González-Sapienza, Gualberto; Marin, Monica

2014-01-01

32

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

PubMed Central

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

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

2008-01-01

33

Sensitivity of direct versus concentrated sputum smear microscopy in HIV-infected patients suspected of having pulmonary tuberculosis  

PubMed Central

Background Sputum concentration increases the sensitivity of smear microscopy for the diagnosis of tuberculosis (TB), but few studies have investigated this method in human immunodeficiency virus (HIV)-infected individuals. Methods We performed a prospective, blinded evaluation of direct and concentrated Ziehl-Neelsen smear microscopy on a single early-morning sputum sample in HIV-infected patients with > 2 weeks of cough hospitalized in Kampala, Uganda. Direct and concentrated smear results were compared with results of Lowenstein-Jensen culture. Results Of 279 participants, 170 (61%) had culture-confirmed TB. The sensitivity of direct and concentrated smear microscopy was not significantly different (51% vs. 52%, difference 1%, 95% confidence interval (CI): [-7%, 10%], p = 0.88). However, when results of both direct and concentrated smears were considered together, sensitivity was significantly increased compared with either method alone (64%, 95% CI: [56%, 72%], p < 0.01 for both comparisons) and was similar to that of direct smear results from consecutive (spot and early-morning) specimens (64% vs. 63%, difference 1%, 95% CI: [-6%, 8%], p = 0.85). Among 109 patients with negative cultures, one had a positive direct smear and 12 had positive concentrated smears (specificity 99% vs. 89%, difference 10%, 95% CI: [2%, 18%], p = 0.003). Of these 13 patients, 5 (38%) had improved on TB therapy after two months. Conclusion Sputum concentration did not increase the sensitivity of light microscopy for TB diagnosis in this HIV-infected population. Given the resource requirements for sputum concentration, additional studies using maximal blinding, high-quality direct microscopy, and a rigorous gold standard should be conducted before universally recommending this technique. PMID:19419537

2009-01-01

34

Letter to the Editor (Case Report) Development of active tuberculosis following initiation of  

E-print Network

Letter to the Editor (Case Report) Development of active tuberculosis following initiation risk of active tuberculosis in patients treated with tumor necrosis factor antagonists (anti-TNF agents to the initiation of anti-TNF agents in patients with evidence of latent tuberculosis [2]. We present two rheumatoid

Raychaudhuri, Soumya

35

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

36

Combined Use of Mycobacterium tuberculosis-Specific CD4 and CD8 T-Cell Responses Is a Powerful Diagnostic Tool of Active Tuberculosis.  

PubMed

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

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

2015-02-01

37

Effect of pyrazinamidase activity on pyrazinamide resistance in Mycobacterium tuberculosis.  

PubMed

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

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

2009-03-01

38

Rv3168 phosphotransferase activity mediates kanamycin resistance in Mycobacterium tuberculosis.  

PubMed

Tuberculosis is a worldwide epidemic disease caused by Mycobacterium tuberculosis, with an estimated one-third of the human population currently affected. Treatment of this disease with aminoglycoside antibiotics has become less effective owing to antibiotic resistance. Recent determination of the crystal structure of the M. tuberculosis Rv3168 protein suggests a structure similar to that of Enterococcus faecalis APH(3')-IIIa, and that this protein may be an aminoglycoside phosphotransferase. To determine whether Rv3168 confers antibiotic resistance against kanamycin, we performed dose-response antibiotic resistance experiments using kanamycin. Expression of the Rv3168 protein in Escherichia coli conferred antibiotic resistance against 100 ?M kanamycin, a concentration that effected cell growth arrest in the parental E. coli strain and an E. coli strain expressing the Rv3168(D249A) mutant, in which the catalytic Asp249 residue was mutated to alanine. Furthermore, we detected phosphotransferase activity of Rv3168 against kanamycin as a substrate. Moreover, docking simulation of kanamycin into the Rv3168 structure suggests that kanamycin fits well into the substrate binding pocket of the protein, and that the phosphorylation-hydroxyl-group of kanamycin was located at a position similar to that in E. faecalis APH(3')-IIIa. On the basis of these results, we suggest that the Rv3168 mediates kanamycin resistance in M. tuberculosis, likely through phosphotransferase targeting of kanamycin. PMID:23928847

Ahn, Jae-Woo; Kim, Kyung-Jin

2013-11-28

39

Revisiting Anti-tuberculosis Activity of Pyrazinamide in Mice  

PubMed Central

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

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

2014-01-01

40

T-Cell Hyporesponsiveness Induced by Activated Macrophages through Nitric Oxide Production in Mice Infected with Mycobacterium tuberculosis  

Microsoft Academic Search

In active tuberculosis, T-cell response to Mycobacterium tuberculosis is known to be reduced. In the course of Mycobacterium tuberculosis infection in mice, we observed that T-cell proliferation in response to M. tuberculosis purified protein derivative (PPD) reached the maximum level on day 7, then declined to the minimal level on day 14, and persisted at a low level through day

SHIGEKI NABESHIMA; MARI NOMOTO; GORO MATSUZAKI; KENJI KISHIHARA; HATSUMI TANIGUCHI; SHIN-ICHI YOSHIDA; KIKUO NOMOTO

1999-01-01

41

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

NASA Technical Reports Server (NTRS)

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

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

1991-01-01

42

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

PubMed Central

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

Ryabova, Olga; Kaprelyants, Arseny; Makarov, Vadim

2014-01-01

43

Tuberculosis and Diabetes  

MedlinePLUS

TUBERCULOSIS & DIABETES COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES © WHO Sept 2011 For more information: ... Recommended collaborative activities for prevention and care of diabetes and tuberculosis • Indicators for evaluating collaborative activities • Implementing collaborative activities ...

44

Prevalence, Risk Factors and Social Context of Active Pulmonary Tuberculosis among Prison Inmates in Tajikistan  

PubMed Central

Setting Tuberculosis (TB) is highly prevalent in prisons of the former Soviet Union. Objective To understand the behavioral, demographic and biological factors placing inmates in Tajikistan at risk for active TB. Design We administered a behavioral and demographic survey to 1317 inmates in two prison facilities in Sughd province, Tajikistan along with radiographic screening for pulmonary TB. Suspected cases were confirmed bacteriologically. Inmates undergoing TB treatment were also surveyed. In-depth interviews were conducted with former prisoners to elicit relevant social and behavioral characteristics. Results We identified 59 cases of active pulmonary TB (prevalence 4.5%). Factors independently associated with increased prevalence of active TB were: HIV-infection by self-report (PR 7.88; 95%CI 3.40–18.28), history of previous TB (PR 10.21; 95%CI 6.27–16.63) and infrequent supplemental nutrition beyond scheduled meals (PR 3.00; 95%CI 1.67–5.62). Access to supplemental nutrition was associated with frequency of visits from friends and family and ability to rely on other inmates for help. Conclusion In prison facilities of Tajikistan, HIV-infection, injection drug use and low access to supplemental nutrition were associated with prevalent cases of active pulmonary TB. Policies that reduce HIV transmission among injection drug users and improve the nutritional status of socially isolated inmates may alleviate the TB burden in Tajikistan’s prisons. PMID:24465861

Winetsky, Daniel E.; Almukhamedov, Olga; Pulatov, Dilshod; Vezhnina, Natalia; Dooronbekova, Aizhan; Zhussupov, Baurzhan

2014-01-01

45

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

46

A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis  

Microsoft Academic Search

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

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

2005-01-01

47

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

PubMed Central

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

Bermudez, Luiz E.; Meek, Laura

2014-01-01

48

Analysis of Mycobacterium tuberculosis-Specific CD8 T-Cells in Patients with Active Tuberculosis and in Individuals with Latent Infection  

Microsoft Academic Search

CD8 T-cells contribute to control of Mycobacterium tuberculosis infection, but little is known about the quality of the CD8 T-cell response in subjects with latent infection and in patients with active tuberculosis disease. CD8 T-cells recognizing epitopes from 6 different proteins of Mycobacterium tuberculosis were detected by tetramer staining. Intracellular cytokines staining for specific production of IFN-? and IL-2 was

Nadia Caccamo; Giuliana Guggino; Serena Meraviglia; Giuseppe Gelsomino; Paola di Carlo; Lucina Titone; Marialuisa Bocchino; Domenico Galati; Alessandro Matarese; Jan Nouta; Michel R. Klein; Alfredo Salerno; Alessandro Sanduzzi; Francesco Dieli; Tom H. M. Ottenhoff; Madhukar Pai

2009-01-01

49

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

PubMed Central

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

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

2015-01-01

50

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...

51

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

PubMed

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

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

2015-02-01

52

Tuberculosis  

MedlinePLUS

... Skin tests, blood tests, x-rays, and other tests can tell if you have TB. If not treated properly, TB can be deadly. You can usually cure active TB by taking several medicines for a long period of time. NIH: National Institute of Allergy and Infectious Diseases

53

Host Targeted Activity of Pyrazinamide in Mycobacterium tuberculosis Infection  

PubMed Central

Pyrazinamide (PZA) is one of the first line antibiotics used for the treatment of tuberculosis (TB). In the present study, we have used in vitro and in vivo systems to investigate whether PZA, in addition to its known anti-mycobacterial properties, modulate the host immune response during Mycobacterium tuberculosis (Mtb) infection. In vitro we have examined the effect of PZA on cytokine and chemokine release by Mtb-infected or Toll-like receptor (TLR) -stimulated primary human monocytes. In vivo, we have investigated at the transcriptional levels using genome-wide microarray gene expression analysis, whether PZA treatment of Mtb-infected mice alters the host immune response to Mtb infection in the lungs. Here, we report that PZA treatment of Mtb-infected human monocytes and mice significantly reduces the release of pro-inflammatory cytokines and chemokines, including IL-1?, IL-6, TNF-? and MCP-1 at the protein and at the gene transcription levels, respectively. Data from microarray analysis also reveal that PZA treatment of Mtb-infected mice significantly alters the expression level of genes involved in the regulation of the pro-inflammatory mediators, lung inflammatory response and TLR signaling networks. Specifically, genes coding for adenylate cyclase and Peroxisome-Proliferator Activated Receptor (PPAR), molecules known for their anti-inflammatory effect, were found to be up-regulated in the lungs of PZA-treated Mtb-infected mice. Based on the microarray findings, we propose that PZA treatment modulates the host immune response to Mtb infection by reducing pro-inflammatory cytokine production, probably through PPAR- and NF-kB- dependent pathways. In addition, our results suggest that inclusion or exclusion of PZA in the TB treatment regimen could potentially affect the biomarker signature detected in the circulation of TB patients. PMID:24015316

Manca, Claudia; Koo, Mi-Sun; Peixoto, Blas; Fallows, Dorothy; Kaplan, Gilla; Subbian, Selvakumar

2013-01-01

54

Is IP10 a Better Biomarker for Active and Latent Tuberculosis in Children than IFN??  

Microsoft Academic Search

BackgroundThe blood based interferon-gamma release assays (IGRA) for the diagnosis of tuberculosis do not discriminate between active TB disease and latent TB infection (LTBI). The search for distinguishing biomarkers therefore continues, as the accurate diagnosis of tuberculosis is particularly challenging in children. IFN-?-inducible protein 10 (IP-10\\/CXCL10) has recently been evaluated as a marker for active TB in adults with promising

Elizabeth Whittaker; Andrea Gordon; Beate Kampmann

2008-01-01

55

Retrospective observational study of diagnostic accuracy of the Xpert® 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

56

Latent and Active Tuberculosis: Evaluation of Injecting Drug Users  

PubMed Central

Background There is a high risk of tuberculosis (TB) infection among injecting drug users (IDUs). Objectives This study aimed to determine the frequency of latent and active TB infection among IDUs. Materials and Methods In a cross-sectional study between 2008 and 2009, IDUs referred to the methadone maintenance treatment (MMT) centers in Hamedan-Iran, undergone tuberculin skin test (PPD; purified protein derivative) were recruited. The participants with positive results for PPD test (> 5 mm and > 10 mm in HIV positive and negative cases), undergone other complementary procedures such as chest-X-ray and sputum smear test. Results Overall, 268 IDUs between 18 and 70 (mean: 34.5 [8.2]) years were included in the study. PPD test had positive findings in 49 cases (18.3%). There was no significant difference of PPD positivity between HIV positive and negative participants (17.7% vs. 18.5%). An active TB was found among IDUs. Conclusions The high prevalence of latent and active TB among IDUs indicates the need for TB screening tests among this population. PMID:24616784

Mamani, Mojgan; Majzoobi, Mohammad Mahdi; Torabian, Saadat; Mihan, Ronak; Alizadeh, Kamyab

2013-01-01

57

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

Microsoft Academic Search

BackgroundNew 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.

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

2011-01-01

58

Elevated 1-? Hydroxylase Activity in Monocytes from Patients with Active Tuberculosis  

PubMed Central

A uremic patient developed hypercalcemia after tuberculosis infection, and his ionized calcium levels correlated with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) levels. We performed further studies to determine whether monocytes are alternative sites of 1,25(OH)2D3 conversion beyond renal tubular cells. Using an ex vivo bioassay, in this study, we found that 1-? hydroxylase (CYP27B1) activity in monocytes is significantly higher in patients with active tuberculosis (TB) than in those with frequent TB contact. However, when monocytes from patients with active TB were restimulated with antigen derived from Mycobacterium tuberculosis, less 1,25(OH)2D3 was observed. In contrast, the level of 1,25(OH)2D3 was unchanged in those with frequent TB contact. We conclude that monocytes may be an alternative source of 1-? hydroxylase that could convert 25-hydroxyvitamin D3 to the more active 1,25(OH)2D3. PMID:24371450

Tung, Yi-Ching; Ou, Tsan-Teng; Tsai, Wen-Chan

2013-01-01

59

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

PubMed Central

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

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

2014-01-01

60

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

PubMed Central

Background & objectives: Pyrazinamide is an essential component of first line anti-tuberculosis regimen as well as most of the second line regimens. This drug has a unique sterilizing activity against Mycobacterium tuberculosis. Its unique role in tuberculosis treatment has lead to the search and development of its structural analogues. One such analogue is 5-chloro-pyrazinamide (5-Cl-PZA) that has been tested under in vitro conditions against M. tuberculosis. The present study was designed with an aim to assess the activity of 5-Cl-PZA, alone and in combination with first-line drugs, against murine tuberculosis. Methods: The minimum inhibitory concentration (MIC) of 5-Cl-PZA in Middlebrook 7H9 broth (neutral pH) and the inhibitory titre of serum from mice that received a 300 mg/kg oral dose of 5-Cl-PZA 30 min before cardiac puncture were determined. To test the tolerability of orally administered 5-Cl-PZA, uninfected mice received doses up to 300 mg/kg for 2 wk. Four weeks after low-dose aerosol infection either with M. tuberculosis or M. bovis, mice were treated 5 days/wk with 5-Cl-PZA, at doses ranging from 37.5 to 150 mg/kg, either alone or in combination with isoniazid and rifampicin. Antimicrobial activity was assessed by colony-forming unit counts in lungs after 4 and 8 wk of treatment. Results: The MIC of 5-Cl-PZA against M. tuberculosis was between 12.5 and 25 ?g/ml and the serum inhibitory titre was 1:4. Under the same experimental conditions, the MIC of pyrazinamide was >100 ?g/ml and mouse serum had no inhibitory activity after a 300 mg/kg dose; 5-Cl-PZA was well tolerated in uninfected and infected mice up to 300 and 150 mg/kg, respectively. While PZA alone and in combination exhibited its usual antimicrobial activity in mice infected with M. tuberculosis and no activity in mice infected with M. bovis, 5-Cl-PZA exhibited antimicrobial activity neither in mice infected with M. tuberculosis nor in mice infected with M. bovis. Interpretation & conclusion: Our findings showed that 5-Cl-PZA at doses up to 150 mg/kg was not active in chronic murine TB model. Further studies need to be done to understand the mechanism and mode of inactivation in murine model of tuberculosis. PMID:23287128

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

2012-01-01

61

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

62

Mycobacterium tuberculosis alters the metalloprotease activity of the COP9 signalosome.  

PubMed

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

Danelishvili, Lia; Babrak, Lmar; Rose, Sasha J; Everman, Jamie; Bermudez, Luiz E

2014-01-01

63

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

64

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

PubMed

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

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

2014-01-25

65

Interferon-? Release Assays for Active Pulmonary Tuberculosis Diagnosis in Adults in Low- and Middle-Income Countries: Systematic Review and Meta-analysis  

PubMed Central

Background.?The diagnostic value of interferon-? release assays (IGRAs) for active tuberculosis in low- and middle-income countries is unclear. Methods.?We searched multiple databases for studies published through May 2010 that evaluated the diagnostic performance of QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB (T-SPOT) among adults with suspected active pulmonary tuberculosis or patients with confirmed cases in low- and middle-income countries. We summarized test performance characteristics with use of forest plots, hierarchical summary receiver operating characteristic (HSROC) curves, and bivariate random effects models. Results.?Our search identified 789 citations, of which 27 observational studies (17 QFT-GIT and 10 T-SPOT) evaluating 590 human immunodeficiency virus (HIV)–uninfected and 844 HIV-infected individuals met inclusion criteria. Among HIV-infected patients, HSROC/bivariate pooled sensitivity estimates (highest quality data) were 76% (95% confidence interval [CI], 45%–92%) for T-SPOT and 60% (95% CI, 34%–82%) for QFT-GIT. HSROC/bivariate pooled specificity estimates were low for both IGRA platforms among all participants (T-SPOT, 61% [95% CI, 40%–79%]; QFT-GIT, 52% [95% CI, 41%–62%]) and among HIV-infected persons (T-SPOT, 52% [95% CI, 40%–63%]; QFT-GIT, 50% [95% CI, 35%–65%]). There was no consistent evidence that either IGRA was more sensitive than the tuberculin skin test for active tuberculosis diagnosis. Conclusions.?In low- and middle-income countries, neither the tuberculin skin test nor IGRAs have value for active tuberculosis diagnosis in adults, especially in the context of HIV coinfection. PMID:21996694

Metcalfe, John Z.; Everett, Charles K.; Steingart, Karen R.; Cattamanchi, Adithya; Huang, Laurence; Hopewell, Philip C.

2011-01-01

66

Binding of activated isoniazid with acetyl-CoA carboxylase from Mycobacterium tuberculosis  

PubMed Central

AccD6 (acetyl coenzyme A (CoA) carboxylase), plays an important role in mycolic acid synthesis of Mycobacterium tuberculosis (Mtb). Induced gene expression by isoniazid (isonicotinylhydrazine - INH), anti-tuberculosis drug) shows the expression of accD6. It is our interest to study the binding of activated INH with the AccD6 model using molecular docking procedures. The study predicts a primary binding site for activated INH (isonicotinyl acyl radical) in AccD6 as a potential target. PMID:22125378

Unissa, Ameeruddin Nusrath; Sudha, Subramanian; Selvakumar, Nagamiah; Hassan, Sameer

2011-01-01

67

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

PubMed Central

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

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

2014-01-01

68

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

PubMed

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

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

2008-01-01

69

Stress and Host Immunity Amplify Mycobacterium tuberculosis Phenotypic Heterogeneity and Induce Nongrowing Metabolically Active Forms.  

PubMed

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

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

2015-01-14

70

Mycobacterium tuberculosis Dihydrofolate Reductase Is Not a Target Relevant to the Antitubercular Activity of Isoniazid?  

PubMed Central

Mycobacterium tuberculosis enoyl-acyl-ACP reductase (InhA) has been demonstrated to be the primary target of isoniazid (INH). Recently, it was postulated that M. tuberculosis dihydrofolate reductase (DHFR) is also a target of INH, based on the findings that a 4R-INH-NADP adduct synthesized from INH by a nonenzymatic approach showed strong inhibition of DHFR in vitro, and overexpression of M. tuberculosis dfrA in M. smegmatis conferred a 2-fold increase of resistance to INH. In the present study, a plasmid expressing M. tuberculosis dfrA was transformed into M. smegmatis and M. tuberculosis strains, respectively. The transformant strains were tested for their resistance to INH. Compared to the wild-type strains, overexpression of dfrA in M. smegmatis and M. tuberculosis did not confer any resistance to INH based on the MIC values. Similar negative results were obtained with 14 other overexpressed proteins that have been proposed to bind some form of INH-NAD(P) adduct. An Escherichia coli cell-based system was designed that allowed coexpression of both M. tuberculosis katG and dfrA genes in the presence of INH. The DHFR protein isolated from the experimental sample was not found bound with any INH-NADP adduct by enzyme inhibition assay and mass spectroscopic analysis. We also used whole-genome sequencing to determine whether polymorphisms in dfrA could be detected in six INH-resistant clinical isolates known to lack mutations in inhA and katG, but no such mutations were found. The dfrA overexpression experiments, together with the biochemical and sequencing studies, conclusively demonstrate that DHFR is not a target relevant to the antitubercular activity of INH. PMID:20566771

Wang, Feng; Jain, Paras; Gulten, Gulcin; Liu, Zhen; Feng, Yicheng; Ganesula, Krishna; Motiwala, Alifiya S.; Ioerger, Thomas R.; Alland, David; Vilchèze, Catherine; Jacobs, William R.; Sacchettini, James C.

2010-01-01

71

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

PubMed Central

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

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

2014-01-01

72

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

PubMed

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

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

2015-01-01

73

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

Microsoft Academic Search

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

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

1996-01-01

74

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

75

Clinical outcomes of active specific immunotherapy in advanced colorectal cancer and suspected minimal residual colorectal cancer: a meta-analysis and system review  

PubMed Central

Background To evaluate the objective clinical outcomes of active specific immunotherapy (ASI) in advanced colorectal cancer (advanced CRC) and suspected minimal residual colorectal cancer (suspected minimal residual CRC). Methods A search was conducted on Medline and Pub Med from January 1998 to January 2010 for original studies on ASI in colorectal cancer (CRC). All articles included in this study were assessed with the application of predetermined selection criteria and were divided into two groups: ASI in advanced CRC and ASI in suspected minimal residual CRC. For ASI in suspected minimal residual CRC, a meta-analysis was executed with results regarding the overall survival (OS) and disease-free survival (DFS). Regarding ASI in advanced colorectal cancer, a system review was performed with clinical outcomes. Results 1375 colorectal carcinoma patients with minimal residual disease have been enrolled in Meta-analysis. A significantly improved OS and DFS was noted for suspected minimal residual CRC patients utilizing ASI (For OS: HR = 0.76, P = 0.007; For DFS: HR = 0.76, P = 0.03). For ASI in stage II suspected minimal residual CRC, OS approached significance when compared with control (HR = 0.71, P = 0.09); however, the difference in DFS of ASI for the stage II suspected minimal residual CRC reached statistical significance (HR = 0.66, P = 0.02). For ASI in stage III suspected minimal residual CRC compared with control, The difference in both OS and DFS achieved statistical significance (For OS: HR = 0.76, P = 0.02; For DFS: HR = 0.81, P = 0.03). 656 advanced colorectal patients have been evaluated on ASI in advanced CRC. Eleven for CRs and PRs was reported, corresponding to an overall response rate of 1.68%. No serious adverse events have been observed in 2031 patients. Conclusions It is unlikely that ASI will provide a standard complementary therapeutic approach for advanced CRC in the near future. However, the clinical responses to ASI in patients with suspected minimal residual CRC have been encouraging, and it has become clear that immunotherapy works best in situations of patients with suspected minimal residual CRC. PMID:21272332

2011-01-01

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

Synergistic activities of clarithromycin and antituberculous drugs against multidrug-resistant Mycobacterium tuberculosis.  

PubMed Central

The rise of multidrug-resistant Mycobacterium tuberculosis has complicated therapy for tuberculosis and led us to search for a potentially active combination of drugs against these strains. The susceptibilities of 12 strains of multidrug-resistant M. tuberculosis to standard antituberculous drugs (isoniazid, rifampin, ethambutol, and pyrazinamide), clarithromycin, and its metabolite, 14-hydroxyclarithromycin, were determined by use of the BACTEC radiometric method. All strains were resistant to at least two of the antituberculous drugs. Clarithromycin and 14-hydroxyclarithromycin MICs were in the range indicating resistance at > or = 8.0 micrograms/ml for all strains. Combination testing by the BACTEC method was performed with various concentrations of isoniazid, rifampin, and ethambutol, and with clarithromycin/14-hydroxyclarithromycin at fixed concentrations of 2.0/0.5 micrograms/ml, respectively. Addition of clarithromycin/14-hydroxyclarithromycin to these antituberculous drug mixtures resulted in a 4- to 32-fold reduction in MICs of isoniazid, rifampin, and ethambutol and made resistant strains susceptible. Fractional inhibitory concentrations ranged from 0.23 to 0.50 for all strains, suggesting a synergistic interaction between standard antituberculous drugs and clarithromycin/14-hydroxyclarithromycin. The ability of clarithromycin/14-hydroxyclarithromycin to enhance the activities of isoniazid, ethambutol, and rifampin in vitro suggests that this combination may be efficacious in the treatment of multidrug-resistant M. tuberculosis infections. PMID:7492101

Cavalieri, S J; Biehle, J R; Sanders, W E

1995-01-01

78

Is IP-10 a Better Biomarker for Active and Latent Tuberculosis in Children than IFN??  

PubMed Central

Background The blood based interferon-gamma release assays (IGRA) for the diagnosis of tuberculosis do not discriminate between active TB disease and latent TB infection (LTBI). The search for distinguishing biomarkers therefore continues, as the accurate diagnosis of tuberculosis is particularly challenging in children. IFN-?-inducible protein 10 (IP-10/CXCL10) has recently been evaluated as a marker for active TB in adults with promising results. Aim To investigate this new biomarker for active TB and LTBI in paediatrics. Method We measured IP-10 levels using ELISA in supernatants of whole blood samples stimulated with TB-specific-antigens and negative control antigen. Results IP-10 is produced in high levels following mycobacterial antigen stimulation in active TB (n?=?17) and LTBI (n?=?16) compared to controls (n?=?16) and to IFN-?. The baseline levels of IP-10 are increased in active TB and in LTBI, but there is no significant difference of stimulated levels of IP-10 between active TB and LTBI. Conclusions IP-10 is a biomarker for tuberculosis in children. However like IFN?, IP-10 also does not distinguish between active TB and LTBI. PMID:19065267

Whittaker, Elizabeth; Gordon, Andrea; Kampmann, Beate

2008-01-01

79

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

80

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

81

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

PubMed Central

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

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

2013-01-01

82

Tuberculous pleurisy diagnosed by medical thoracoscopy in an adalimumab-treated rheumatoid arthritis patient after treatment of latent tuberculosis infection.  

PubMed

A 28-year-old rheumatoid arthritis woman treated with adalimumab was admitted with fever, cough, and right chest pain. X-ray showed right pleural effusion. By medical thoracoscopy, diffuse white nodules were observed, and biopsy specimen demonstrated epithelioid cell granulomas with necrosis and auramine-stained organisms, which suggested a diagnosis of tuberculous pleurisy. Medical thoracoscopy can be a potent diagnostic method when tuberculous pleurisy is suspected. Notably, despite latent tuberculosis treatment, active tuberculosis was not prevented. PMID:22911136

Nagafuchi, Yasuo; Shoda, Hirofumi; Fujio, Keishi; Ishii, Satoru; Sugiyama, Haruhito; Yamamoto, Kazuhiko

2013-09-01

83

In vitro and ex vivo activity of peptide deformylase inhibitors against Mycobacterium tuberculosis H37Rv.  

PubMed

Bacterial peptide deformylase (PDF) catalyses removal of the N-terminal formyl group of proteins and is essential for protein maturation, growth and survival of bacteria. Thus, PDF appears to be a good antimycobacterial drug target. In the present study, various well-known PDF inhibitors, such as BB-3497, actinonin, 1,10-phenanthroline, hydroxylamine hydrochloride and galardin, were selected to evaluate their inhibitory activity against Mycobacterium tuberculosis. All compounds were found to be active against M. tuberculosis, with MIC(90) values (lowest drug concentration at which 90% of growth was inhibited on the basis of CFU enumeration) ranging from 0.2 mg/L to 74 mg/L. BB-3497 and 1,10-phenanthroline exhibited potent in vitro antimycobacterial activity, and also showed synergism with isoniazid and rifampicin. All compounds showed a bacteriostatic mode of inhibition. Under ex vivo conditions and short-course chemotherapy, BB-3497 and actinonin were found to be significantly active, with BB-3497 exhibiting comparable efficacy to that of isoniazid. Collectively, promising activities of PDF inhibitors such as BB-3497 and actinonin suggest their potential use against M. tuberculosis. PMID:19505802

Sharma, Anshika; Sharma, Sadhna; Khuller, G K; Kanwar, A J

2009-09-01

84

Reduced NK activity correlates with active disease in HIV- patients with multidrug-resistant pulmonary tuberculosis.  

PubMed Central

There has been a global increase in the incidence of multidrug-resistant pulmonary tuberculosis (TB). As there are no previous reports of immune function in HIV- patients with multidrug-resistant pulmonary TB, a comprehensive assessment of cellular immunity in this setting was undertaken. This involved a prospective, case-controlled study which included five patients with active multidrug-resistant pulmonary TB and five matched controls with active non-resistant infection, and documented the changes in immune parameters which occurred upon clinical resolution. Patients with multidrug-resistant TB had significantly lower fresh natural killer (NK) cell activity than matched controls with non-resistant pulmonary TB (P < 0.05). This was a specific abnormality, as there were no significant differences in antigen-specific cytotoxicity or lymphocyte proliferation in the case-controlled study. Follow-up assessment of the patients with multidrug-resistant infections indicated that clinical improvement correlated with a moderate increase in NK cell activity. Impaired NK cell function may be involved in the pathogenesis of multidrug-resistant TB. PMID:8082292

Ratcliffe, L T; Lukey, P T; MacKenzie, C R; Ress, S R

1994-01-01

85

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

PubMed

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

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

2004-08-01

86

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

87

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

88

Guinea pig neutrophils infected with Mycobacterium tuberculosis produce cytokines which activate alveolar macrophages in noncontact cultures.  

PubMed

The early influx of neutrophils to the site of infection may be an important step in host resistance against Mycobacterium tuberculosis. In this study, we investigated the effect of M. tuberculosis infection on the ability of guinea pig neutrophils to produce interleukin-8 (IL-8; CXCL8) and tumor necrosis factor alpha (TNF-alpha) and to activate alveolar macrophages. Neutrophils and alveolar macrophages were isolated from naïve guinea pigs, cultured together or alone, and infected with virulent M. tuberculosis for 3, 12, and 24 h. IL-8 protein production in cocultures, as measured by using an enzyme-linked immunosorbent assay, was found to be additive at 24 h and significantly greater in M. tuberculosis-infected cocultures than in uninfected cocultures and in cultures of the infected neutrophils or macrophages alone. The IL-8 mRNA levels, determined by real-time reverse transcription-PCR, were elevated at 24 h in infected cocultures and infected cells cultured alone. In order to elucidate the contributions of neutrophils and their soluble mediators to the activation of alveolar macrophages, neutrophils and alveolar macrophages were cultured in a contact-independent manner by using a Transwell insert system. Neutrophils were infected with virulent M. tuberculosis in the upper wells, and alveolar macrophages were cultured in the lower wells. The release of hydrogen peroxide from alveolar macrophages exposed to soluble products from infected neutrophils was significantly increased compared to that from unexposed alveolar macrophages. Significant up-regulation of IL-1beta and TNF-alpha mRNA levels in alveolar macrophages was observed at 24 and 30 h, respectively, compared to those in cells not exposed to soluble neutrophil products. Treatment with anti-guinea pig TNF-alpha polyclonal antibody completely abolished the response of alveolar macrophages to neutrophil products. This finding suggests that TNF-alpha produced by infected neutrophils may be involved in the activation of alveolar macrophages and hence may contribute to the containment of M. tuberculosis infection during the early period of infection. PMID:17283104

Sawant, Kirti V; McMurray, David N

2007-04-01

89

Deregulated microRNAs in CD4+ T cells from individuals with latent tuberculosis versus active tuberculosis  

PubMed Central

The mechanisms of latent tuberculosis (TB) infection remain elusive. Roles of microRNA (miRNA) have been highlighted in pathogen–host interactions recently. To identify miRNAs involved in the immune response to TB, expression profiles of miRNAs in CD4+ T cells from patients with latent TB, active TB and healthy controls were investigated by microarray assay and validated by RT-qPCR. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to analyse the significant functions and involvement in signalling pathways of the differentially expressed miRNAs. To identify potential target genes for miR-29, interferon-? (IFN-?) mRNA expression was measured by RT-qPCR. Our results showed that 27 miRNAs were deregulated among the three groups. RT-qPCR results were generally consistent with the microarray data. We observed an inverse correlation between miR-29 level and IFN-? mRNA expression in CD4+ T cells. GO and KEGG pathway analysis showed that the possible target genes of deregulated miRNAs were significantly enriched in mitogen-activated protein kinase signalling pathway, focal adhesion and extracellular matrix receptor interaction, which might be involved in the transition from latent to active TB. In all, for the first time, our study revealed that some miRNAs in CD4+ T cells were altered in latent and active TB. Function and pathway analysis highlighted the possible involvement of miRNA-deregulated mRNAs in TB. The study might help to improve understanding of the relationship between miRNAs in CD4+ T cells and TB, and laid an important foundation for further identification of the underlying mechanisms of latent TB infection and its reactivation. PMID:24373112

Fu, Yurong; Yi, Zhengjun; Li, Jianhua; Li, Ruifang

2014-01-01

90

Unique Transcriptome Signature of Mycobacterium tuberculosis in Pulmonary Tuberculosis  

Microsoft Academic Search

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 identifi- cation of M. tuberculosis genes actively expressed during pulmonary tuberculosis. To obtain optimal informa- tion from our DNA

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

2006-01-01

91

Control of Mycobacterium tuberculosis growth by activated natural killer cells  

PubMed Central

We characterized the underlying mechanisms by which glutathione (GSH)-enhanced natural killer (NK) cells inhibit the growth of Mycobacterium tuberculosis (M. tb) inside human monocytes. We observed that in healthy individuals, treatment of NK cells with N-acetyl cysteine (NAC), a GSH prodrug in conjunction with cytokines such as interleukin (IL)-2 + IL-12, resulted in enhanced expression of NK cytotoxic ligands (FasL and CD40L) with concomitant stasis in the intracellular growth of M. tb. Neutralization of FasL and CD40L in IL-2 + IL-12 + NAC-treated NK cells resulted in abrogation in the growth inhibition of M. tb inside monocytes. Importantly, we observed that the levels of GSH are decreased significantly in NK cells derived from individuals with HIV infection compared to healthy subjects, and this decrease correlated with a several-fold increase in the growth of M. tb inside monocytes. This study describes a novel innate defence mechanism adopted by NK cells to control M. tb infection. PMID:22385249

Guerra, C; Johal, K; Morris, D; Moreno, S; Alvarado, O; Gray, D; Tanzil, M; Pearce, D; Venketaraman, V

2012-01-01

92

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; Martínez Gómez, Julia María; Ang, Michelle Lay Teng; Zainul Rahim, Siti Zarina; Tan, Mai Ping; Pethe, Kevin

2012-01-01

93

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

PubMed

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

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

2015-02-01

94

A Method for Extracting Suspected Parotid Lesions in CT Images using Feature-based Segmentation and Active Contours based on Stationary Wavelet Transform  

NASA Astrophysics Data System (ADS)

Automatic suspected lesion extraction is an important application in computer-aided diagnosis (CAD). In this paper, we propose a method to automatically extract the suspected parotid regions for clinical evaluation in head and neck CT images. The suspected lesion tissues in low contrast tissue regions can be localized with feature-based segmentation (FBS) based on local texture features, and can be delineated with accuracy by modified active contour models (ACM). At first, stationary wavelet transform (SWT) is introduced. The derived wavelet coefficients are applied to derive the local features for FBS, and to generate enhanced energy maps for ACM computation. Geometric shape features (GSFs) are proposed to analyze each soft tissue region segmented by FBS; the regions with higher similarity GSFs with the lesions are extracted and the information is also applied as the initial conditions for fine delineation computation. Consequently, the suspected lesions can be automatically localized and accurately delineated for aiding clinical diagnosis. The performance of the proposed method is evaluated by comparing with the results outlined by clinical experts. The experiments on 20 pathological CT data sets show that the true-positive (TP) rate on recognizing parotid lesions is about 94%, and the dimension accuracy of delineation results can also approach over 93%.

Wu, T. Y.; Lin, S. F.

2013-10-01

95

Gamma Interferon Release Assay for Monitoring of Treatment Response for Active Tuberculosis: an Explosion in the Spaghetti Factory  

PubMed Central

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

Denkinger, Claudia M.; Pai, Madhukar; Patel, Meena

2013-01-01

96

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

PubMed

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

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

2013-02-01

97

Rituximab seems to be a safer alternative in patients with active rheumatoid arthritis with tuberculosis  

PubMed Central

Demonstrating the efficiency and safety of rituximab (Rtx) in the treatment of active rheumatoid arthritis (RA) and tuberculosis (TB). Two cases of RA with active TB were followed up to 3?years following the initiation of Rtx. The former case presented with a history of concomitant diagnosis of both RA and TB and the latest one, also diagnosed with RA and reactivation of TB developed during the anti-tumour necrosis factor treatment. After a sufficient time of follow-up, we have observed that Rtx seems to be safer and efficient in the treatment of active RA and TB. PMID:23341582

Pehlivan, Yavuz; Kisacik, Bunyamin; Bosnak, Vuslat Kecik; Onat, Ahmet Mesut

2013-01-01

98

Gamma interferon reverses inhibition of leukocyte bactericidal activity by a 25-kilodalton fraction from Mycobacterium tuberculosis.  

PubMed Central

In this study we examined the effects of Mycobacterium tuberculosis cell extracts on the phagocytic activity of polymorphonuclear leukocytes and cultured peripheral blood monocytes. M. tuberculosis cell extracts were fractionated on Sephacryl S-200 columns, and a 25-kilodalton glycolipoprotein was shown to inhibit the intracellular killing ability of these leukocytes but had no effect on their phagocytic potential. This same fraction inhibited fusion of phagosomes with lysosomes, as assessed by noting the transfer of acridine orange from lysosomes to phagosomes. This fraction was shown to have a maximal inhibitory effect when it was in the form of an intact carbohydrate-lipid-protein complex. Gamma interferon (IFN-gamma), but not IFN-alpha, reversed the inhibitory effect of the mycobacterial component on bactericidal activity and on fusion of phagosomes and lysosomes. Thus, this 25-kilodalton fraction of M. tuberculosis cell extract may be important in protecting organisms against phagocytic degradation, an effect which can be reversed by IFN-gamma. PMID:3117692

Wadee, A A; Cohen, J D; Rabson, A R

1987-01-01

99

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

PubMed Central

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

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

2000-01-01

100

Direct inhibitors of InhA are active against Mycobacterium tuberculosis.  

PubMed

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

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

2015-01-01

101

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

PubMed Central

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

2014-01-01

102

Involvement of CD244 in regulating CD4+ T cell immunity in patients with active tuberculosis.  

PubMed

CD244 (2B4) is a member of the signaling lymphocyte activation molecule (SLAM) family of immune cell receptors and it plays an important role in modulating NK cell and CD8(+) T cell immunity. In this study, we investigated the expression and function of CD244/2B4 on CD4(+) T cells from active TB patients and latent infection individuals. Active TB patients had significantly elevated CD244/2B4 expression on M. tuberculosis antigen-specific CD4(+) T cells compared with latent infection individuals. The frequencies of CD244/2B4-expressing antigen-specific CD4(+) T cells were significantly higher in retreatment active TB patients than in new active TB patients. Compared with CD244/2B4-dull and -middle CD4(+) T cells, CD244/2B4-bright CD4(+) T cell subset had significantly reduced expression of IFN-?, suggesting that CD244/2B4 expression may modulate IFN-? production in M. tuberculosis antigen-responsive CD4(+) T cells. Activation of CD244/2B4 signaling by cross-linking led to significantly decreased production of IFN-?. Blockage of CD244/2B4 signaling pathway of T cells from patients with active TB resulted in significantly increased production of IFN-?, compared with isotype antibody control. In conclusion, CD244/2B4 signaling pathway has an inhibitory role on M. tuberculosis antigen-specific CD4(+) T cell function. PMID:23638187

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

2013-01-01

103

Involvement of CD244 in Regulating CD4+ T Cell Immunity in Patients with Active Tuberculosis  

PubMed Central

CD244 (2B4) is a member of the signaling lymphocyte activation molecule (SLAM) family of immune cell receptors and it plays an important role in modulating NK cell and CD8+ T cell immunity. In this study, we investigated the expression and function of CD244/2B4 on CD4+ T cells from active TB patients and latent infection individuals. Active TB patients had significantly elevated CD244/2B4 expression on M. tuberculosis antigen-specific CD4+ T cells compared with latent infection individuals. The frequencies of CD244/2B4-expressing antigen-specific CD4+ T cells were significantly higher in retreatment active TB patients than in new active TB patients. Compared with CD244/2B4-dull and -middle CD4+ T cells, CD244/2B4-bright CD4+ T cell subset had significantly reduced expression of IFN-?, suggesting that CD244/2B4 expression may modulate IFN-? production in M. tuberculosis antigen-responsive CD4+ T cells. Activation of CD244/2B4 signaling by cross-linking led to significantly decreased production of IFN-?. Blockage of CD244/2B4 signaling pathway of T cells from patients with active TB resulted in significantly increased production of IFN-?, compared with isotype antibody control. In conclusion, CD244/2B4 signaling pathway has an inhibitory role on M. tuberculosis antigen-specific CD4+ T cell function. PMID:23638187

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

2013-01-01

104

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

PubMed Central

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

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

2007-01-01

105

[Managment of tuberculosis in an University of Campania].  

PubMed

Tuberculosis (TBC) is an infectious disease with the highest mortality and morbidity by single pathogen, affecting about one third of worldwide population. Although Mantoux test is the most used, IGRA (Interferon-gamma Release Assays) tests seem to give good results for presumptive diagnosis of active or latent tuberculosis. From June 2011 to June 2012 we made about 1,000 visits for TBC prevention among the exposed to biological risks of our University. The management of suspected latent or active tuberculosis infection was carried out in collaboration with the pulmonologist, assessing the risk of contagion among exposed or affected operators. Health surveillance protocol and judgements of suitability for specific task were made not only in consideration of worker health, but also considerating the possible risk for patients, since this disease is a major problem for public health. PMID:23405647

Uccello, R; Monaco, M G L; Feola, D; Garzillo, E M; Muoio, M; Sannolo, N; Lamberti, M

2012-01-01

106

Proteome-Scale Antibody Responses and Outcome of Mycobacterium tuberculosis Infection in Nonhuman Primates and in Tuberculosis Patients  

PubMed Central

Background.Biomarkers of progression from latent Mycobacterium tuberculosis infection to active tuberculosis are needed. We assessed correlations between infection outcome and antibody responses in macaques and humans by high-throughput, proteome-scale serological studies. Methods.Mycobacterium tuberculosis proteome microarrays were probed with serial sera from macaques representing various infection outcomes and with single-point human sera from tuberculosis suspects. Fluorescence intensity data were analyzed by calculating Z scores and associated P values. Temporal changes in macaque antibody responses were analyzed by polynomial regression. Correlations between human responses and sputum bacillary burden were assessed by quantile and hurdle regression. Results.Macaque outcome groups exhibited distinct antibody profiles: early, transient responses in latent infection and stable antibody increase in active and reactivation disease. In humans, antibody levels and reactive protein numbers increased with bacillary burden. Responses to a subset of 10 proteins were more tightly associated with disease state than reactivity to the broader reactive proteome. Conclusions.Integration of macaque and human data reveals dynamic properties of antibody responses in relation to outcome and leads to actionable findings for translational research. These include the potential of antibody responses to detect acute infection and preclinical tuberculosis and to identify serodiagnostic proteins for the spectrum of bacillary burden in tuberculosis. PMID:22732925

Kunnath-Velayudhan, Shajo; Davidow, Amy L.; Wang, Hui-Yun; Molina, Douglas M.; Huynh, Vu T.; Salamon, Hugh; Pine, Richard; Michel, Gerd; Perkins, Mark D.; Xiaowu, Liang; Felgner, Philip L.; Flynn, JoAnne L.; Catanzaro, Antonino; Gennaro, Maria L.

2012-01-01

107

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

PubMed Central

Objective: This is the new comparative geogenetic molecular evolution research of M. tuberculosis in Iran and Belarus. Thus, we researched the genetic patterns of samples collected in the first survey of anti-tuberculosis drug-resistance by gene coding of RNA polymerase as part of the international project of on tuberculosis. Method: DNA extraction and amplification of rpoB gene was performed. All PCR products of gene were sequenced using the Amersham auto sequencer. For analysing phenogram has been demonstrated by method UPGMA and Neighbour-Joining. Clinical isolates (70/473) were analyzed by using sequencing gene rpoB and genotyped by program DNAMAN and MEGA. Results: The all data were compared with the international database of national center for biotechnology information website. Multi drug resistant of tuberculosis patient (MDR-TB) was 92% in never treated and 8% in previously treated. Mutations in rpoB gene and katG genes were showed in 95% and 84% of the MDR isolates, respectively. Two clusters were found to be identical by the four different analysis methods, presumably representing cases of recent transmission of MDR tuberculosis. The other isolates are divided in Iran into 2 groups: group A – similar to the Eastern strains (China, Taiwan) and group B – strains of another genotype. And 3 groups in Belarus: group A - Strains of the first group are more similar to the standard European and Eastern ones China and Taiwan) which diverged in the last 10 years (Genetic evolution rate), i.e. they are relatively new ones, and that is confirmed by the mutations, group B - Strains of the second group diverged earlier; they are older than the strains of the first group (16 years old- time and rate of evolution) and group C - Strains of the third group are similar to European strains and only circulate in Brest region. They are grouped separately on the phenogram and became prevalent in Iran (they are called Iranian residential strains and also is genetic analogy between group A from Iran and Belarusian isolates. Conclusion: This research gives a first result on genetic evolution of the M. tuberculosis strains distributing in the Iran and Belarus during the first survey of anti-tuberculosis drug-resistance and is homologies between groups A from Iran with group A from Belarus. It may aid in the creation of a national database that will be a valuable support for further studies. PMID:21760866

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

2011-01-01

108

Safety and bactericidal activity of rifalazil in patients with pulmonary tuberculosis.  

PubMed

Rifalazil, also known as KRM-1648 or benzoxazinorifamycin, is a new semisynthetic rifamycin with a long half-life of approximately 60 h. Rifalazil has potent bactericidal activity against Mycobacterium tuberculosis in vitro and in animal models of tuberculosis (TB). Prior studies in healthy volunteers showed that once-weekly doses of 25 to 50 mg of rifalazil were well tolerated. In this randomized, open-label, active-controlled phase II clinical trial, 65 subjects with sputum smear-positive pulmonary TB received one of the following regimens for the first 2 weeks of therapy: 16 subjects received isoniazid (INH) (5 mg/kg of body weight) daily; 16 received INH (5 mg/kg) and rifampin (10 mg/kg) daily; 17 received INH (5 mg/kg) daily plus 10 mg of rifalazil once weekly; and 16 received INH (5 mg/kg) daily and 25 mg of rifalazil once weekly. All subjects were then put on 6 months of standard TB therapy. Pretreatment and day 15 sputum CFU of M. tuberculosis were measured to assess the bactericidal activity of each regimen. The number of drug-related adverse experiences was low and not significantly different among treatment arms. A transient decrease in absolute neutrophil count to less than 2,000 cells/mm(3) was detected in 10 to 20% of patients in the rifalazil- and rifampin-containing treatment arms without clinical consequences. Decreases in CFU counts were comparable among the four treatment arms; however, the CFU results were statistically inconclusive due to the variability in the control arms. Acquired drug resistance did not occur in any patient. Studies focused on determining a maximum tolerated dose will help elucidate the full anti-TB effect of rifalazil. PMID:11408210

Dietze, R; Teixeira, L; Rocha, L M; Palaci, M; Johnson, J L; Wells, C; Rose, L; Eisenach, K; Ellner, J J

2001-07-01

109

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

PubMed

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

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

2015-02-01

110

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

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

2014-01-01

111

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

2009-01-01

112

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

PubMed

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

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

2010-02-01

113

The MprB extracytoplasmic domain negatively regulates activation of the Mycobacterium tuberculosis MprAB two-component system.  

PubMed

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; Zahrt, Thomas C

2014-01-01

114

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

115

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

Microsoft Academic Search

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

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

2007-01-01

116

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

PubMed Central

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

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

2012-01-01

117

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

118

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

119

Phosphorylation control of protein tyrosine phosphatase A activity in Mycobacterium tuberculosis.  

PubMed

Protein tyrosine phosphatase A (PtpA) has been shown to play a key role in human macrophage infection by Mycobacterium tuberculosis (Mtb). Protein tyrosine kinase A (PtkA) was the first protein tyrosine kinase shown to phosphorylate PtpA. Here, we found that PtkA-mediated phosphorylation of PtPA on Tyr-128 and Tyr-129 enhances the PtPA phosphatase activity. Moreover, ex-vivo protein-protein interaction assays showed that PtpA can be phosphorylated by several eukaryotic-like Ser/Thr protein kinases, such as protein kinase A (PknA). PknA was found to regulate PtpA phosphatase activity through Thr-45 phosphorylation. These results indicate that members of two independent families of protein kinases tune PtpA activity in Mtb. PMID:25535696

Zhou, Peifu; Li, Wu; Wong, Dennis; Xie, Jianping; Av-Gay, Yossef

2015-01-30

120

Prevalence of respiratory symptoms and cases suspicious for tuberculosis among public health clinic patients in Afghanistan,  

E-print Network

Prevalence of respiratory symptoms and cases suspicious for tuberculosis among public health clinic of suspected pulmonary tuberculosis (TB) among patients with respiratory complaints attending Comprehensive Health Centers (CHCs) in Afghanistan. methods Consecutive consenting patients presenting with respiratory

Scharfstein, Daniel

121

Access channel residues Ser315 and Asp137 in Mycobacterium tuberculosis catalase-peroxidase (KatG) control peroxidatic activation of the pro-drug isoniazid  

PubMed Central

Peroxidatic activation of the anti-tuberculosis pro-drug isoniazid by Mycobacterium tuberculosis catalase-peroxidase (KatG) is regulated by gating residues of a heme access channel. The steric restriction at the bottleneck of this channel is alleviated by replacement of residue Asp137 with Ser, according to crystallographic and kinetic studies. PMID:24185282

Zhao, Xiangbo; Hersleth, Hans-Petter; Zhu, Janan; Andersson, K. Kristoffer; Magliozzo, Richard S.

2013-01-01

122

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

123

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

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, José G.; Fryling, Nicole A.; Franzblau, Scott G.; Cho, Sang Hyun; Stamets, Paul E.; Wang, Yuehong; Pauli, Guido F.

2013-01-01

125

Dynamic antibody responses to the Mycobacterium tuberculosis proteome  

PubMed Central

Considerable effort has been directed toward controlling tuberculosis, which kills almost two million people yearly. High on the research agenda is the discovery of biomarkers of active tuberculosis (TB) for diagnosis and for monitoring treatment outcome. Rational biomarker discovery requires understanding host–pathogen interactions leading to biomarker expression. Here we report a systems immunology approach integrating clinical data and bacterial metabolic and regulatory information with high-throughput detection in human serum of antibodies to the entire Mycobacterium tuberculosis proteome. Sera from worldwide TB suspects recognized approximately 10% of the bacterial proteome. This result defines the M. tuberculosis immunoproteome, which is rich in membrane-associated and extracellular proteins. Additional analyses revealed that during active tuberculosis (i) antibody responses focused on an approximately 0.5% of the proteome enriched for extracellular proteins, (ii) relative target preference varied among patients, and (iii) responses correlated with bacillary burden. These results indicate that the B cell response tracks the evolution of infection and the pathogen burden and replicative state and suggest functions associated with B cell-rich foci seen in tuberculous lung granulomas. Our integrated proteome-scale approach is applicable to other chronic infections characterized by diverse antibody target recognition. PMID:20668240

Kunnath-Velayudhan, Shajo; Salamon, Hugh; Wang, Hui-Yun; Davidow, Amy L.; Molina, Douglas M.; Huynh, Vu T.; Cirillo, Daniela M.; Michel, Gerd; Talbot, Elizabeth A.; Perkins, Mark D.; Felgner, Philip L.; Liang, Xiaowu; Gennaro, Maria L.

2010-01-01

126

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

127

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

PubMed Central

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

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

2012-01-01

128

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

PubMed Central

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

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

2014-01-01

129

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

130

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

131

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

132

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

133

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

PubMed

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

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

2015-02-12

134

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

PubMed Central

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

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

2015-01-01

135

Antimycobacterial activity of DNA intercalator inhibitors of Mycobacterium tuberculosis primase DnaG.  

PubMed

Owing to the rise in drug resistance in tuberculosis combined with the global spread of its causative pathogen, Mycobacterium tuberculosis (Mtb), innovative anti mycobacterial agents are urgently needed. Recently, we developed a novel primase-pyrophosphatase assay and used it to discover inhibitors of an essential Mtb enzyme, primase DnaG (Mtb DnaG), a promising and unexplored potential target for novel antituberculosis chemotherapeutics. Doxorubicin, an anthracycline antibiotic used as an anticancer drug, was found to be a potent inhibitor of Mtb DnaG. In this study, we investigated both inhibition of Mtb DnaG and the inhibitory activity against in vitro growth of Mtb and M. smegmatis (Msm) by other anthracyclines, daunorubicin and idarubicin, as well as by less cytotoxic DNA intercalators: aloe-emodin, rhein and a mitoxantrone derivative. Generally, low-?M inhibition of Mtb DnaG by the anthracyclines was correlated with their low-?M minimum inhibitory concentrations. Aloe-emodin displayed threefold weaker potency than doxorubicin against Mtb DnaG and similar inhibition of Msm (but not Mtb) in the mid-?M range, whereas rhein (a close analog of aloe-emodin) and a di-glucosylated mitoxantrone derivative did not show significant inhibition of Mtb DnaG or antimycobacterial activity. Taken together, these observations strongly suggest that several clinically used anthracyclines and aloe-emodin target mycobacterial primase, setting the stage for a more extensive exploration of this enzyme as an antibacterial target.The Journal of Antibiotics advance online publication, 24 September 2014; doi:10.1038/ja.2014.131. PMID:25248725

Gajadeera, Chathurada; Willby, Melisa J; Green, Keith D; Shaul, Pazit; Fridman, Micha; Garneau-Tsodikova, Sylvie; Posey, James E; Tsodikov, Oleg V

2014-09-24

136

[A tuberculosis epidemic in one hospital].  

PubMed

A Tuberculosis epidemic occurred in a hospital in Fukushima prefecture, 1993. It was detected after the diagnosis of two tuberculosis cases among nurses working in the hospital. A contact survey in the hospital revealed two another cases of tuberculosis, one from the nurse, and the other one from the patient admitted to the hospital. In addition, two more nurses in the same hospital were suspected of having tuberculosis, but they do not yet started treatment by the time of the survey. Though the source of the infection could not be identified, the doctor's delay in detecting cases was suspected on the background of the epidemic. Deficiency in the health care system of nursing school was also suspected. PMID:8523850

Yamaguchi, Y; Suzuki, S

1995-10-01

137

Global chemical composition and antioxidant and anti-tuberculosis activities of various extracts of Globularia alypum L. (Globulariaceae) leaves.  

PubMed

In this work, an evaluation of the biological activities of Globularia alypum L. extracts and their global chemical composition was realized. Extracts from G. alypum were obtained by two extraction methods. The composition of polyphenols (8.5-139.95 g gallic acid equivalent/Kg of dry mass), tannins (1.39-18.65 g catechin equivalent/Kg of dry mass), anthocyanins (8.17-70.69 mg cyanidin equivalent/Kg of dry mass) and flavonoids (0.31-19.28 g quercetin equivalent/Kg of dry mass) was evaluated. The samples were subjected to a screening for their antioxidant activities using the DPPH* and ABTS*+ assays. For the first time, the anti-tuberculosis activity (H(37)Rv) for G. alypum was tested against Mycobacterium tuberculosis. The strongest antioxidant activity was obtained for the methanol extract (IC(50 ) = 15.58 ± 0.168 mg/L) and the best anti-tuberculosis activity was obtained for the petroleum ether extract (IC(50 )= 77 mg/L). We have found a positive correlation between the total phenolics content and the antioxidant activity R2 = 0.88 (DPPH*) and R2 = 0.97 (ABTS*+). We have found also a positive correlation between the flavonoid content and the antioxidant activity R2 = 0.91 (DPPH*) and R2 = 0.91 (ABTS*+). PMID:22183884

Khlifi, Daycem; Hamdi, Moktar; El Hayouni, Akrem; Cazaux, Sylvie; Souchard, Jean Pierre; Couderc, François; Bouajila, Jalloul

2011-01-01

138

Structure of Mycobacterium tuberculosis PknB supports a universal activation mechanism for Ser\\/Thr protein kinases  

Microsoft Academic Search

A family of eukaryotic-like Ser\\/Thr protein kinases occurs in bacteria, but little is known about the structures and functions of these proteins. Here we characterize PknB, a transmembrane signaling kinase from Mycobacterium tuberculosis. The intracellular PknB kinase domain is active autonomously, and the active enzyme is phosphorylated on residues homologous to regulatory phospho-acceptors in eukaryotic Ser\\/Thr kinases. The crystal structure

Tracy A. Young; Benedicte Delagoutte; James A. Endrizzi; Arnold M. Falick; Tom Alber

2003-01-01

139

Cytokine Levels Correlate with a Radiologic Score in Active Pulmonary Tuberculosis  

Microsoft Academic Search

Pulmonary tuberculosis is an infectious disease caused by Mycobacterium tuberculosis . This microor- ganism is capable of inducing a delayed hypersensitivity reaction in the lung, with subsequent ex- pression of the disease. This reaction depends on the presence of different cytokines that exert spe- cific functions. The aim of this study was to evaluate the presence and the concentrations of

MASSIMO CASARINI; FRANCO AMEGLIO; LUCILLA ALEMANNO; PROFETA ZANGRILLI; PAOLO MATTIA; GREGORINO PAONE; ALBERTO BISETTI; SANDRO GIOSUÈ

1999-01-01

140

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

PubMed

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

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

2010-08-01

141

Bactericidal activity of an imidazo[1, 2-a]pyridine using a mouse M. tuberculosis infection model.  

PubMed

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

142

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

143

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

PubMed

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

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

2015-01-01

144

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

PubMed

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

2014-05-01

145

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

PubMed Central

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

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

2014-01-01

146

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

147

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

PubMed Central

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

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

2013-01-01

148

Suspected Pesticide Poisoning  

PubMed Central

Of 1125 calls to a regional poison control center about suspected pesticide poisonings, more than half concerned children younger than 6 years, most of whom had ingested small amounts and required no treatment other than drinking fluids. Adults represented a small proportion of victims, but were more likely to have consumed moderate or large quantities, to have symptoms, and to need referral. PMID:21228985

Sellar, Christine; Ferguson, Joyce A.

1991-01-01

149

Cordilleran suspect terranes  

USGS Publications Warehouse

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

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

1980-01-01

150

Contrast-Enhanced Ultrasound in the Diagnosis of Patients Suspected of Having Active Crohn's Disease: Meta-analysis.  

PubMed

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

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

2015-03-01

151

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

PubMed Central

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

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

2012-01-01

152

The timing of TNF and IFN-? signaling affects macrophage activation strategies during Mycobacterium tuberculosis infection  

PubMed Central

During most infections, the population of immune cells known as macrophages are key to taking up and killing bacteria as an integral part of the immune response. However, during infection with Mycobacterium tuberculosis (Mtb), host macrophages serve as the preferred environment for mycobacterial growth. Further, killing of Mtb by macrophages is impaired unless they become activated. Activation is induced by stimulation from bacterial antigens and inflammatory cytokines derived from helper T cells. The key macrophage-activating cytokines in Mtb infection are tumor necrosis factor-? (TNF) and interferon (IFN)-?. Due to differences in cellular sources and secretion pathways for TNF and IFN- ?, the possibility of heterogeneous cytokine distributions exists, suggesting that the timing of macrophage activation from these signals may affect activation kinetics and thus impact the outcome of Mtb infection. Here we use a mathematical model to show that negative feedback from production of nitric oxide (the key mediator of mycobacterial killing) that typically optimizes macrophage responses to activating stimuli may reduce effective killing of Mtb. Statistical sensitivity analysis predicts that if TNF and IFN-? signals precede infection, the level of negative feedback may have a strong effect on how effectively macrophages kill Mtb. However, this effect is relaxed when IFN-? or TNF + IFN-? signals are received coincident with infection. Under these conditions, the model suggests that negative feedback induces fast responses and an initial overshoot of nitric oxide production for given doses of TNF and IFN-?, favoring killing of Mtb. Together, our results suggest that direct entry of macrophages into a granuloma site (and not distal to it) from lung vascular sources represents a preferred host strategy for mycobacterial control. We examine implications of these results in establishment of latent Mtb infection. PMID:18321531

Ray, J. Christian J.; Wang, Jian; Chan, John; Kirschnera, Denise E.

2008-01-01

153

Efficient synthesis and in vitro antitubercular activity of 1,2,3-triazoles as inhibitors of Mycobacterium tuberculosis  

Microsoft Academic Search

Efficient and rapid synthesis of 1,2,3-triazole derivatives has been achieved via Huisgen’s 1,3-dipolar cycloaddition between alkyl\\/arylazides and diethyl\\/dimethyl acetylenedicarboxylate in excellent yields under solvent-free conditions. The environmentally friendly solvent-free protocol overcomes the limitations associated with the prevailing time-consuming solution phase protocols and affords the triazoles just in 1–3min. In vitro antitubercular activity of these triazoles was screened against Mycobacterium tuberculosis

Poovan Shanmugavelan; Sangaraiah Nagarajan; Murugan Sathishkumar; Alagusundaram Ponnuswamy; Perumal Yogeeswari; Dharmarajan Sriram

154

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

PubMed

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

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

2013-03-22

155

Dynamic active site protection by the M. tuberculosis protein tyrosine phosphatase PtpB lid domain  

PubMed Central

The Mycobacterium tuberculosis protein tyrosine phosphatase PtpB shows resistance to the oxidative conditions that prevail within an infected host macrophage, but the mechanism of this molecular adaptation is unknown. Crystal structures of PtpB revealed previously that a closed, two-helix lid covers the active site. By measuring single-molecule Förster-type resonance energy transfer to probe the dynamics of two helices that constitute the lid, we obtained direct evidence for large, spontaneous opening transitions of PtpB with the closed form of both helices favored ~3:1. Despite similar populations of conformers, the two helices move asynchronously as demonstrated by different opening and closing rates under our experimental conditions. Assuming that lid closure excludes oxidant, the rates of opening and closing quantitatively accounted for the slow observed rate of oxidative inactivation. Increasing solvent viscosity using glycerol but not PEG8000 resulted in higher rates of oxidative inactivation due to an increase in the population of open conformers. These results establish that the rapid conformational gating of the PtpB lid constitutes a reversible physical blockade that transiently masks the active site and retards oxidative inactivation. PMID:20230004

Megan Flynn, E.; Hanson, Jeffrey A.; Alber, Tom; Yang, Haw

2010-01-01

156

Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis.  

PubMed

Biotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high-throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counterscreen in biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counterscreen proved crucial to filter out compounds whose whole-cell activity was off target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were cocrystallized with BioA to provide a framework for future structure-based drug design efforts. PMID:25556942

Park, Sae Woong; Casalena, Dominick E; Wilson, Daniel J; Dai, Ran; Nag, Partha P; Liu, Feng; Boyce, Jim P; Bittker, Joshua A; Schreiber, Stuart L; Finzel, Barry C; Schnappinger, Dirk; Aldrich, Courtney C

2015-01-22

157

Sterilizing activities of novel combinations lacking first- and second-line drugs in a murine model of tuberculosis.  

PubMed

Novel oral regimens composed of new drugs with potent activity against Mycobacterium tuberculosis and no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine ? clofazimine ? rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further. PMID:22470112

Williams, Kathy; Minkowski, Austin; Amoabeng, Opokua; Peloquin, Charles A; Taylor, Dinesh; Andries, Koen; Wallis, Robert S; Mdluli, Khisimuzi E; Nuermberger, Eric L

2012-06-01

158

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

159

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

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

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

PubMed Central

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

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

2013-01-01

162

Isoniazid Activation Defects in Recombinant Mycobacterium tuberculosis Catalase-Peroxidase (KatG) Mutants Evident in InhA Inhibitor Production  

Microsoft Academic Search

Mycobacterium tuberculosis KatG catalyzes the activation of the antitubercular agent isoniazid to yield an inhibitor targeting enoyl reductase (InhA). However, no firm biochemical link between many KatG variants and isoniazid resistance has been established. In the present study, six distinct KatG variants identified in clinical Mycobacterium tuberculosis isolates resistant to isoniazid were generated by site-directed mutagenesis, and the recombinant mutant

Chih-Jen Wei; Benfang Lei; James M. Musser; Shiao-Chun Tu

2003-01-01

163

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

Microsoft Academic Search

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

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

164

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

Microsoft Academic Search

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

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

2008-01-01

165

Enzymatic activities and DNA substrate specificity of Mycobacterium tuberculosis DNA helicase XPB.  

PubMed

XPB, also known as ERCC3 and RAD25, is a 3' ? 5' DNA repair helicase belonging to the superfamily 2 of helicases. XPB is an essential core subunit of the eukaryotic basal transcription factor complex TFIIH. It has two well-established functions: in the context of damaged DNA, XPB facilitates nucleotide excision repair by unwinding double stranded DNA (dsDNA) surrounding a DNA lesion; while in the context of actively transcribing genes, XPB facilitates initiation of RNA polymerase II transcription at gene promoters. Human and other eukaryotic XPB homologs are relatively well characterized compared to conserved homologs found in mycobacteria and archaea. However, more insight into the function of bacterial helicases is central to understanding the mechanism of DNA metabolism and pathogenesis in general. Here, we characterized Mycobacterium tuberculosis XPB (Mtb XPB), a 3'?5' DNA helicase with DNA-dependent ATPase activity. Mtb XPB efficiently catalyzed DNA unwinding in the presence of significant excess of enzyme. The unwinding activity was fueled by ATP or dATP in the presence of Mg(2+)/Mn(2+). Consistent with the 3'?5' polarity of this bacterial XPB helicase, the enzyme required a DNA substrate with a 3' overhang of 15 nucleotides or more. Although Mtb XPB efficiently unwound DNA model substrates with a 3' DNA tail, it was not active on substrates containing a 3' RNA tail. We also found that Mtb XPB efficiently catalyzed ATP-independent annealing of complementary DNA strands. These observations significantly enhance our understanding of the biological roles of Mtb XPB. PMID:22615856

Balasingham, Seetha V; Zegeye, Ephrem Debebe; Homberset, Håvard; Rossi, Marie L; Laerdahl, Jon K; Bohr, Vilhelm A; Tønjum, Tone

2012-01-01

166

Tuberculosis (For Parents)  

MedlinePLUS

... resolves on its own as a child develops immunity over a 6- to 10-week period. But ... conditions become favorable (for instance, due to lowered immunity), the bacteria become active. Tuberculosis in older kids ...

167

Isoniazid induces apoptosis of activated CD4+ T cells: implications for post-therapy tuberculosis reactivation and reinfection.  

PubMed

Tuberculosis (TB) remains the second highest killer from a single infectious disease worldwide. Current therapy of TB is lengthy and consists of multiple expensive antibiotics, in a strategy referred to as Directly Observed Treatment, Short Course (DOTS). Although this therapy is effective, it has serious disadvantages. These therapeutic agents are toxic and are associated with the development of a variety of drug-resistant TB strains. Furthermore, patients treated with DOTS exhibit enhanced post-treatment susceptibility to TB reactivation and reinfection, suggesting therapy-related immune impairment. Here we show that Isoniazid (INH) treatment dramatically reduces Mycobacterium tuberculosis antigen-specific immune responses, induces apoptosis in activated CD4(+) T cells, and renders treated animals vulnerable to TB reactivation and reinfection. Consequently, our findings suggest that TB treatment is associated with immune impairment. PMID:25202011

Tousif, Sultan; Singh, Dhiraj Kumar; Ahmad, Shaheer; Moodley, Prashini; Bhattacharyya, Maitree; Van Kaer, Luc; Das, Gobardhan

2014-10-31

168

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

PubMed Central

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.

2014-01-01

169

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

PubMed Central

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, we show that both microaerophilic stationary-phase M. tuberculosis treated with a high dose of rifampin in vitro and pyrazinamide-induced persistent bacteria in mice are nonculturable yet still contain 16S rRNA and mRNA transcripts. Also, the in vitro persistent, plate culture-negative bacteria incorporate radioactive uridine into their RNA in the presence of rifampin and can rapidly up-regulate gene transcription after the replacement of the drug with fresh medium and in response to heat shock. Our results show that persistent M. tuberculosis has transcriptional activity. This finding provides a molecular basis for the rational design of drugs targeted at persistent bacteria. PMID:11053379

Hu, Yanmin; Mangan, Joseph A.; Dhillon, Jasvir; Sole, Kath M.; Mitchison, Denis A.; Butcher, Philip D.; Coates, Anthony R. M.

2000-01-01

170

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

171

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

PubMed

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

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

2014-06-01

172

[HIV infection and tuberculosis].  

PubMed

The number of people infected with human immunodeficiency virus (HIV) is gradually increasing in Japan, and the morbidity rate from tuberculosis in the Japanese people is high. Accordingly, the number of cases with both infections is considered to increase in the future. Our hospital has already encountered 31 cases of HIV associated tuberculosis. HIV infects mainly CD4-positive cells. The extreme decrease in the cell count results in serious cellular immunological disorder. CD4-positive cell disorder induces disorders of B lymphocytes, cytotoxic T cells, natural killer cells, and macrophage functions. These destructive conditions show the state of immunodeficiency including macrophage that are most important for defense of acid-fast bacterial infection. Migration and activation of macrophages with cytokines derived from T cells are impaired to induce the following phenomena: hypoplasia of granuloma, failure of tubercule bacillus suppression, the spread to regional lymph nodes (hilar or mediastinal lymph nodes), and hematogenous dissemination. On this occasion, caseous necrosis and cavitation are unlikely to occur, and false-negative tuberculin reaction is often observed. The incidence of severe cases, which include miliary tuberculosis, tuberculous meningitis, etc., and extrapulmonary tuberculosis, are high among acquired immunodeficiency syndrome (AIDS)-associated tuberculosis cases. HIV-infected tuberculosis cases are generally regarded as endogenous exacerbation, but they include primary infection and reinfection as well. Even during the treatment for drug-sensitive strains particularly, some cases may have reinfection with multidrug-resistant bacteria, suggesting that caution should be taken against this point. Conversely, the association of tuberculosis is a factor for the poor prognosis of HIV infection, since it facilitates the development of HIV infection. If the bacteria belong to a drug-sensitive strain, the infection with them responds well to antituberculous drugs, the same as in tuberculosis cases without HIV infection, showing a favorable prognosis. However, the mortality rate of infection with multi-drug-resistant tuberculosis is extremely high. The combined use of a protease inhibitor, i.e., anti-HIV drug, with rifampicin is regarded as contraindication for the treatment because rifampicin strongly induces hepatic cytochrome P-450 and increases the metabolism of protease inhibitors and nonnucleoside reverse transcriptases to markedly decrease the blood concentrations. Accordingly, the treatment for tuberculosis should take priority over that for HIV infection in HIV-infected tuberculosis, and highly active antiretroviral therapy (HAART) may be administered after the treatment of tuberculosis. When HAART is necessary for the treatment during the tuberculosis treatment, rifampicin had better be exchanged to rifabutin because the effect of rifabutin to induce cytochrome P-450 is less potent than that of rifampicin. A report has recently shown that the exacerbation of pyrexia and chest X-ray findings was transiently observed approximately 2 weeks after potent anti-HIV therapy for HIV-infected tuberculosis, which included a protease inhibitor. The reason for the exacerbation has been believed to be that the impaired function of CD4-positive cells is improved by the administration of anti-HIV drugs to raise temporarily the reaction of the vital part to M. tuberculosis. A tuberculin skin test (TST) reaction size of > or = 5 mm of induration is considered positive (i.e., indicative of M. tuberculosis infection) in persons who are infected with HIV. Persons with a TST reaction size > or = 5 mm who have not previously received treatment for M. tuberculosis infection should receive tuberculosis preventive treatment. Prevention by BCG vaccination is regarded as contraindications for HIV-infected patients, because disseminated M. bovis infection may be associated with them. Many HIV-positive patients infected with tuberculosis show uneventful healing, when M. tuberculosis is the sensitive strain. However, since

Nagai, Hideaki

2003-01-01

173

Mean platelet volume as an inflammation marker in active pulmonary tuberculosis  

PubMed Central

Background The mean platelet volume (MPV) reflects the size of platelets. It has been shown to be inversely correlated with level of the inflammation in some chronic inflammatory diseases. This prospective study aims to show the usability of MPV as an inflammation marker in patients with active pulmonary tuberculosis (PTB) by comparison with healthy controls. In addition, its relationships with other inflammatory markers such as C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) as well as with the radiological extent of disease were examined. Methods This study included 82 patients with active PTB and 95 healthy subjects (control group). Whole blood counts, CRP level, and ESR were compared between the two groups. In the PTB group, the relationships between the radiological extent of disease and the MPV and other inflammation markers were investigated. Results The MPV was 7.74 ± 1.33/?L in the PTB group and 8.20 ± 1.13/?L in the control group (p = 0.005). The blood platelet count, CRP level, and ESR were significantly higher in the active PTB group than in the control group (p < 0.0001). In the PTB group, CRP levels (r = 0.26, p = 0.003) and ESR (r = 0.39, p = 0.003), but not MPV (p = 0.80), were significantly correlated with the radiologic extent of the disease. Conclusions The MPV was lower in patients with PTB than in healthy controls, however, the difference was limited. The MPV does not reflect the severity of the disease. The use of MPV as an inflammation marker and a negative acute-phase reactant in PTB does not seem to be reliable. PMID:24581084

2014-01-01

174

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.; Pérez de la Lastra, José M.; Moreno-Cid, Juan A.; Fernández de Mera, Isabel G.; Alberdi, Pilar; Santos, Gracia; Ballesteros, Cristina; Lyashchenko, Konstantin P.; Minguijón, Esmeralda; Romero, Beatriz; de Juan, Lucía; Domínguez, Lucas; Juste, Ramón; Gortazar, Christian

2014-01-01

175

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

PubMed

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

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

2000-09-01

176

[The diagnosis of pulmonary tuberculosis].  

PubMed

Mycobacterium tuberculosis (M. tuberculosis) infects all organs in the body; however, lung infection is the primary lesion. The total number of infections is decreasing, but the percentage of infections in older people is rising. Because this disease is due to infection with M. tuberculosis, the diagnosis requires the presence of M. tuberculosis. Chest X-ray and CT are very powerful tools to suggest the presence of M. tuberculosis infection. Pathological examination of the tissues also shows the typical findings of M. tuberculosis infection; however, the presence of the bacterium was not proven in certain cases of M. tuberculosis infection, and especially in cases of latent infection. Recently, the whole-blood interferon--gamma test (QuantiFERON-TB, QFT) became more popular than the tuberculin skin test. It is reported that the specificity and sensitivity of QFT are similar to or better than the tuberculin skin test. However, it should be noted that QFT positive does not automatically lead to a diagnosis of active M. tuberculosis infection and that QFT is one of the supplementary tests in the diagnosis of M. tuberculosis infection. Currently, massive infection with M. tuberculosis is increasing. The precise responsible linkage in massive infection with M. tuberculosis needs DNA polymorphism analysis using variable numbers of tandem repeats (VNTR) or restricted fragment length polymorphism (RFLP). PMID:23198540

Koyama, Sekiya; Sakaguchi, Nobuki; Hotta, Jyunnichi

2012-08-01

177

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

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

2009-01-01

178

Tuberculosis Fluoroscopy  

Cancer.gov

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

179

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

180

Bovine Tuberculosis  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

181

Zn(II) stimulation of Fe(II)-activated repression in the iron-dependent repressor from Mycobacterium tuberculosis.  

PubMed

Thermodynamic measurements of Fe(II) binding and activation of repressor function in the iron-dependent repressor from Mycobacterium tuberculosis (IdeR) are reported. IdeR, a member of the diphtheria toxin repressor family of proteins, regulates iron homeostasis and contributes to the virulence response in M. tuberculosis. Although iron is the physiological ligand, this is the first detailed analysis of iron binding and activation in this protein. The results showed that IdeR binds 2 equiv of Fe(II) with dissociation constants that differ by a factor of 25. The high- and low-affinity iron binding sites were assigned to physical binding sites I and II, respectively, using metal binding site mutants. IdeR was also found to contain a high-affinity Zn(II) binding site that was assigned to physical metal binding site II through the use of binding site mutants and metal competition assays. Fe(II) binding was modestly weaker in the presence of Zn(II), but the coupled metal binding-DNA binding affinity was significantly stronger, requiring 30-fold less Fe(II) to activate DNA binding compared to Fe(II) alone. Together, these results suggest that IdeR is a mixed-metal repressor, where Zn(II) acts as a structural metal and Fe(II) acts to trigger the physiologically relevant promoter binding. This new model for IdeR activation provides a better understanding of IdeR and the biology of iron homeostasis in M. tuberculosis. PMID:23432191

Stapleton, Brian; Walker, Lawrence R; Logan, Timothy M

2013-03-19

182

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

PubMed Central

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

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

2011-01-01

183

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

PubMed Central

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

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

2014-01-01

184

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

185

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

PubMed Central

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

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

2010-01-01

186

Catalase-peroxidase (Mycobacterium tuberculosis KatG) catalysis and isoniazid activation.  

PubMed

Resonance Raman spectra of native, overexpressed M. tuberculosis catalase-peroxidase (KatG), the enzyme responsible for activation of the antituberculosis antibiotic isoniazid (isonicotinic acid hydrazide), have confirmed that the heme iron in the resting (ferric) enzyme is high-spin five-coordinate. Difference Raman spectra did not reveal a change in coordination number upon binding of isoniazid to KatG. Stopped-flow spectrophotometric studies of the reaction of KatG with stoichiometric equivalents or small excesses of hydrogen peroxide revealed only the optical spectrum of the ferric enzyme with no hypervalent iron intermediates detected. Large excesses of hydrogen peroxide generated oxyferrous KatG, which was unstable and rapidly decayed to the ferric enzyme. Formation of a pseudo-stable intermediate sharing optical characteristics with the porphyrin pi-cation radical-ferryl iron species (Compound I) of horseradish peroxidase was observed upon reaction of KatG with excess 3-chloroperoxybenzoic acid, peroxyacetic acid, or tert-butylhydroperoxide (apparent second-order rate constants of 3.1 x 10(4), 1.2 x 10(4), and 25 M(-1) s(-1), respectively). Identification of the intermediate as KatG Compound I was confirmed using low-temperature electron paramagnetic resonance spectroscopy. Isoniazid, as well as ascorbate and potassium ferrocyanide, reduced KatG Compound I to the ferric enzyme without detectable formation of Compound II in stopped-flow measurements. This result differed from the reaction of horseradish peroxidase Compound I with isoniazid, during which Compound II was stably generated. These results demonstrate important mechanistic differences between a bacterial catalase-peroxidase and the homologous plant peroxidases and yeast cytochrome c peroxidase, in its reactions with peroxides as well as substrates. PMID:10933818

Chouchane, S; Lippai, I; Magliozzo, R S

2000-08-15

187

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

188

Tuberculosis in the elderly  

Microsoft Academic Search

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

S. Rajagopalan; T. T. Yoshikawa

2000-01-01

189

resistant strains of Mycobacterium tuberculosis  

Microsoft Academic Search

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

Ying Zhang; Steven Denkin; Dmitriy Volokhov; Vladimir Chizhikov

190

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

191

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

PubMed Central

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

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

2013-01-01

192

miRNA signatures in sera of patients with active pulmonary tuberculosis.  

PubMed

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

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

2013-01-01

193

miRNA Signatures in Sera of Patients with Active Pulmonary Tuberculosis  

PubMed Central

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

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

2013-01-01

194

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

PubMed

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

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

2009-12-01

195

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

PubMed Central

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

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

2009-01-01

196

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

PubMed Central

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

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

2013-01-01

197

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

198

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

PubMed

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

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

2015-01-01

199

38 CFR 3.959 - Tuberculosis.  

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

2014-07-01

200

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

201

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

202

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

203

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

204

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

205

Whole Blood Interferon-? Release Assay Is Insufficient for the Diagnosis of Sputum Smear Negative Pulmonary Tuberculosis  

PubMed Central

Purpose We investigated the value of an interferon-? release assay (IGRA) for the diagnosis of active pulmonary tuberculosis (PTB) among sputum smear negative PTB suspects in an environment with intermediate burden of PTB and high Bacillus Calmette-Guérin (BCG) vaccination rate. Materials and Methods We retrospectively reviewed IGRA, medical records, chest PA and CT scan of PTB suspects seen at Gangnam Severance Hospital, Seoul, Korea from Oct. 2007 to Apr. 2013. "Active PTB" was diagnosed when 1) M. tuberculosis culture positive, 2) confirmation by pathologic examination; or 3) clinical findings compatible with TB. Results Of 224 sputum smear negative PTB suspects, 94 were confirmed as having active PTB. There were no statistically significant differences in the diagnostic yield of IGRA between immunocompromised and immunocompetent sputum smear negative PTB suspects. IGRA did show superior sensitivity [81.9%, 95% confidence interval (CI); 74.13-89.70%] in the diagnosis of sputum smear negative PTB when compared with chest high-resolution computed tomography (HRCT), tuberculin skin test (TST), and chest X-ray (p<0.001). Also, IGRA showed highest negative predictive value (82.7%, 95% CI; 75.16-90.15%) when compared with HRCT, TST and chest X-ray (p=0.023). However, combining the results of IGRA with those of HRCT, TST, or both did not increase any diagnostic parameters. Conclusion Failure to increase diagnostic yields by combination with other diagnostic modalities suggests that additional enforcement with IGRA may be insufficient to exclude other diagnoses in sputum smear negative PTB suspects and to screen active PTB in an environment with intermediate TB prevalence and a high BCG vaccination rate. PMID:24719140

Park, HeeJin; Shin, Jung Ar; Kim, Hyung Jung; Ahn, Chul Min

2014-01-01

206

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

207

Characterization of Activity and Expression of Isocitrate Lyase in Mycobacterium avium and Mycobacterium tuberculosis  

Microsoft Academic Search

Analysis by two-dimensional gel electrophoresis revealed that Mycobacterium avium expresses several pro- teins 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

KERSTIN HONER; ANDRAS MICZAK; DANA L. SWENSON

1999-01-01

208

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

209

[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

210

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

PubMed Central

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. Results A new protocol for expression and purification of recombinant M. tuberculosis DNA topoisomerase I (MtTOP) has been developed to produce enzyme of much higher specific activity than previously characterized recombinant enzyme. MtTOP was found to be less efficient than E. coli DNA topoisomerase I (EcTOP) in removal of remaining negative supercoils from partially relaxed DNA. DNA cleavage by MtTOP was characterized for the first time. Comparison of DNA cleavage site selectivity with EcTOP showed differences in cleavage site preferences, but the preferred sites of both enzymes have a C nucleotide in the -4 position. Conclusion Recombinant M. tuberculosis DNA topoisomerase I can be expressed as a soluble protein and purified in high yield from E. coli host with a new protocol. Analysis of DNA cleavage with M. tuberculosis DNA substrate showed that the preferred DNA cleavage sites have a C nucleotide in the -4 position. PMID:19519900

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

2009-01-01

211

Simple and rapid method for detection of nitrate reductase activity of Mycobacterium tuberculosis and Mycobacterium canettii grown in the Bactec MGIT960 system.  

PubMed

Mycobacterium tuberculosis reduces nitrate very strongly as compared to Mycobacterium bovis and M. bovis BCG. Nitrate reductase, in conjunction with niacin accumulation, constitutes one of the major biochemical tests used in clinical microbiology laboratories to differentiate M. tuberculosis from other members of the M. tuberculosis complex, as well as nontuberculous Mycobacteria. Determination of nitrate reductase activity is currently performed using cultures grown on solid media with a slow detection time and the need for large quantities of bacilli, as otherwise the test is not reliable. Hereby, we propose a nitrate reduction test coupled to Bactec MGIT960 system as a simple, rapid and economic method with a total gain of time of about 3 to 4weeks over the conventional solid medium. In our study, almost all the M. tuberculosis and Mycobacterium canettii strains gave a strongly positive nitrate reductase result within 1day of positive detection by the MGIT960 system. In contrast, M. bovis, M. bovis BCG and M. africanum strains remained negative even after 14days of incubation. The possibility to detect nitrate reductase within 1 to 3days of a positive culture using MGIT960 opens new perspectives with the possibility of confirming M. tuberculosis - starting directly from pathological specimens. PMID:20298726

Goh, Khye Seng; Rastogi, Nalin

2010-05-01

212

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

213

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

PubMed Central

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 Å and its C-terminal DNA-binding domain at 1.7 Å 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 (??)4 topology instead of the canonical (??)5 fold observed in other response regulators. The linker region adopts a unique conformation which 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 ?10 which provides 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 ?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. PMID:18353359

Wisedchaisri, Goragot; Wu, Meiting; Sherman, David R.; Hol, Wim G. J.

2008-01-01

214

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

215

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

216

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

217

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

218

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

Code of Federal Regulations, 2011 CFR

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

2011-07-01

219

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

Code of Federal Regulations, 2010 CFR

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

2010-07-01

220

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

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

2014-07-01

221

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

Code of Federal Regulations, 2013 CFR

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

2013-07-01

222

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

Code of Federal Regulations, 2012 CFR

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

2012-07-01

223

Primary gastric tuberculosis – report of 5 cases  

PubMed Central

Background Gastric tuberculosis is rare, and usually associated with pulmonary tuberculosis or an immunodeficient state. Here, we report five cases of gastric tuberculosis in immunocompetent patients without evidence of pulmonary involvement. Case presentation Three patients presented with gastric outlet obstruction that required surgery to relieve the obstruction as well as to confirm the diagnosis. The remaining two had involvement of gastroesophageal junction. All of them responded well to standard antitubercular treatment. Conclusion Though gastric tuberculosis is rare, it should be considered a possibility when patients present with gastric outlet obstruction or with endoscopic evidence of diffuse chronic inflammatory activity, particularly in areas endemic for tuberculosis. PMID:12703983

Amarapurkar, Deepak N; Patel, Nikhil D; Amarapurkar, Anjali D

2003-01-01

224

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

Microsoft Academic Search

BackgroundLeucocyte activating chemokines such as CCL2, CCL3, and CXCL8 together with proinflammatory IFN?, TNF? and downmodulatory IL10 play a central role in the restriction of M. tuberculosis infections, but is unclear whether these markers are indicative of tuberculosis disease severity.MethodologyWe investigated live M. tuberculosis- and M. bovis BCG- induced peripheral blood mononuclear cell responses in patients with tuberculosis (TB) and

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

2009-01-01

225

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

PubMed Central

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

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

1992-01-01

226

[Present and future of tuberculosis care in regions].  

PubMed

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

Shigeto, Eriko

2012-12-01

227

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

PubMed Central

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

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

2011-01-01

228

A case of skeletal tuberculosis and psoas abscess: disease activity evaluated using 18?F-fluorodeoxyglucose positron emission tomography-computed tomography  

PubMed Central

Background Psoas abscess complicating tuberculous spondylitis is a rare morbidity in extrapulmonary tuberculosis. There are no established guidelines for evaluating the clinical response of psoas abscess. Although several studies have shown that positron emission tomography-computed tomography with 18?F-fluorodeoxyglucose can play a potential role in diagnosing multifocal tuberculosis and monitoring the clinical response of pulmonary tuberculosis, to our knowledge, this is the first report demonstrating that positron emission tomography-computed tomography is useful for evaluating local inflammation and disease activity of a tuberculous psoas abscess. Case presentation We report a case of multifocal bone and lymph node tuberculosis with concomitant lumbar psoas abscess in a 77-year-old man, along with a literature review. An initial positron emission tomography-computed tomography scan showed intense 18?F-fluorodeoxyglucose accumulation in the sternum, ribs, vertebrae, and lymph nodes. The patient was successfully treated with antitubercular agents and computed tomography-guided drainage therapy. A follow-up positron emission tomography-computed tomography after abscess drainage and 9 months of antitubercular drug treatment revealed that the majority of lesions improved; however, protracted inflammation surrounding the psoas abscess was still observed. These results indicate that disease activity of psoas abscess can remain, even after successful drainage and antitubercular medication regime of appropriate duration. Conclusion We have successfully followed up the extent of skeletal tuberculosis complicated with psoas abscess by positron emission tomography-computed tomography. In this patient, positron emission tomography-computed tomography is useful for evaluating the disease activity of tuberculous psoas abscess and for assessing the appropriate duration of antitubercular drug therapy in psoas abscess. PMID:24225333

2013-01-01

229

MyD88 Primes Macrophages for Full-Scale Activation by Interferon-? yet Mediates Few Responses to Mycobacterium tuberculosis  

PubMed Central

Macrophages are activated from a resting state by a combination of cytokines and microbial products. Microbes are often sensed through Toll-like receptors signaling through MyD88. We used large-scale microarrays in multiple replicate experiments followed by stringent statistical analysis to compare gene expression in wild-type (WT) and MyD88?/? macrophages. We confirmed key results by quantitative reverse transcription polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. Surprisingly, many genes, such as inducible nitric oxide synthase, IRG-1, IP-10, MIG, RANTES, and interleukin 6 were induced by interferon (IFN)-? from 5- to 100-fold less extensively in MyD88?/? macrophages than in WT macrophages. Thus, widespread, full-scale activation of macrophages by IFN-? requires MyD88. Analysis of the mechanism revealed that MyD88 mediates a process of self-priming by which resting macrophages produce a low level of tumor necrosis factor. This and other factors lead to basal activation of nuclear factor ?B, which synergizes with IFN-? for gene induction. In contrast, infection by live, virulent Mycobacterium tuberculosis (Mtb) activated macrophages largely through MyD88-independent pathways, and macrophages did not need MyD88 to kill Mtb in vitro. Thus, MyD88 plays a dynamic role in resting macrophages that supports IFN-?–dependent activation, whereas macrophages can respond to a complex microbial stimulus, the tubercle bacillus, chiefly by other routes. PMID:14517275

Shi, Shuangping; Nathan, Carl; Schnappinger, Dirk; Drenkow, Jörg; Fuortes, Michele; Block, Ellen; Ding, Aihao; Gingeras, Thomas R.; Schoolnik, Gary; Akira, Shizuo; Takeda, Kiyoshi; Ehrt, Sabine

2003-01-01

230

[Extrapulmonary tuberculosis.  

PubMed

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

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

2014-08-14

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

Ferritin Structure from Mycobacterium tuberculosis: Comparative Study with Homologues Identifies Extended C-Terminus Involved in Ferroxidase Activity  

PubMed Central

Ferritins are recognized as key players in the iron storage and detoxification processes. Iron acquisition in the case of pathogenic bacteria has long been established as an important virulence mechanism. Here, we report a 3.0 Å crystal structure of a ferritin, annotated as Bacterioferritin B (BfrB), from Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis that continues to be one of the world's deadliest diseases. Similar to the other members of ferritin family, the Mtb BfrB subunit exhibits the characteristic fold of a four-helical bundle that possesses the ferroxidase catalytic centre. We compare the structure of Mtb BfrB with representatives of the ferritin family belonging to the archaea, eubacteria and eukarya. Unlike most other ferritins, Mtb BfrB has an extended C-terminus. To dissect the role of this extended C-terminus, truncated Mtb BfrB was purified and biochemical studies implicate this region in ferroxidase activity and iron release in addition to providing stability to the protein. Functionally important regions in a protein of known 3D-structure can be determined by estimating the degree of conservation of the amino-acid sites with its close homologues. Based on the comparative studies, we identify the slowly evolving conserved sites as well as the rapidly evolving variable sites and analyze their role in relation to structure and function of Mtb BfrB. Further, electrostatic computations demonstrate that although the electrostatic environment of catalytic residues is preserved within the family, extensive variability is exhibited by residues defining the channels and pores, in all likelihood keeping up with the diverse functions executed by these ferritins in varied environments. PMID:21494619

Khare, Garima; Gupta, Vibha; Nangpal, Prachi; Gupta, Rakesh K.; Sauter, Nicholas K.; Tyagi, Anil K.

2011-01-01

233

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

234

Early Immunologic Failure is Associated With Early Mortality Among Advanced HIV–Infected Adults Initiating Antiretroviral Therapy With Active Tuberculosis  

PubMed Central

Background.?The relationship between antiretroviral therapy (ART) response and early mortality after ART initiation is unknown. We hypothesized that early mortality is associated with decreased early immunologic response to ART. Methods.?We prospectively determined the association between changes in plasma human immunodeficiency virus type 1 (HIV-1) RNA and CD4+ T-cell counts (CD4 count) after 4 weeks of ART and early mortality in adults with pulmonary tuberculosis and pre-ART CD4 counts ?125 cells/µL. Purified protein derivative (PPD)–specific immune recovery was determined by interferon-? enzyme-linked immunosorbent spot assays. Levels of interleukin 6, C-reactive protein, and soluble CD14 were assessed. Patients with CD4 count and viral load values at baseline and week 4 were analyzed using multiple logistic regression. Results.?Early immunologic response, but not pre-ART CD4 counts or virologic response, was related to early mortality (8 [interquartile range {IQR}, ?18 to 43] vs 68 [IQR, 24–131] cells/µL, P = .002). In a logistic regression model, every 20 cells/µL increase in the CD4 count from baseline to week 4 was independently associated with a 40% reduction in the odds of death (odds ratio, 0.59 [95% confidence interval, .41–.87]). PPD-specific immune recovery was lower, whereas levels of immune activation were higher, among deaths. Conclusions.?Early immunologic failure despite virologic suppression is associated with early mortality after ART initiation in advanced HIV/tuberculosis. PMID:23908475

Ravimohan, Shruthi; Tamuhla, Neo; Steenhoff, Andrew P.; Letlhogile, Rona; Makutu, Didimalang Kgomotso; Nfanyana, Kebatshabile; Rantleru, Tumelo; Tierney, Ann; Nkakana, Kelebogile; Schwartz, Adam B.; Gross, Robert; MacGregor, Rob Roy; Bellamy, Scarlett L.; Frank, Ian; Weissman, Drew; Bisson, Gregory P.

2013-01-01

235

Ferritin Structure from Mycobacterium tuberculosis: Comparative Study with Homologues Identifies Extended C-Terminus Involved in Ferroxidase Activity  

Microsoft Academic Search

Ferritins are recognized as key players in the iron storage and detoxification processes. Iron acquisition in the case of pathogenic bacteria has long been established as an important virulence mechanism. Here, we report a 3.0 Å crystal structure of a ferritin, annotated as Bacterioferritin B (BfrB), from Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis that continues to be one

Garima Khare; Vibha Gupta; Prachi Nangpal; Rakesh K. Gupta; Nicholas K. Sauter; Anil K. Tyagi; Javed N. Agrewala

2011-01-01

236

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

PubMed

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

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

2014-10-20

237

Sternal tuberculosis.  

PubMed

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

2013-11-01

238

Exploring serological classification tree model of active pulmonary tuberculosis by magnetic beads pretreatment and MALDI-TOF MS analysis.  

PubMed

Pulmonary tuberculosis (TB) is an infectious disease disturbing status of public health, and accurate diagnosis of TB would effectively help control the disturbance. Our study tried to establish a classification tree model that distinguished active TB from non-TB individuals. We used matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) combined with weak cationic exchange (WCX) magnetic beads to analyse 178 serum samples containing 75 patients with active TB and 103 non-TB individuals (43 patients with common pulmonary diseases and 60 healthy controls). Samples were randomly divided into a training set and a test set. Statistical softwares were applied to construct this model. An amount of 48 differential expressed peaks (P < 0.05) were identified by the training set, and our model was set up by three of them, m/z 7626, 8561 and 8608. This model can discriminate patients with active TB from patients with non-TB with a sensitivity of 98.3% and a specificity of 84.4%. The test set was used to verify the performance, which demonstrated good sensitivity and specificity: 85.7% and 83.3%, respectively. Differential expressed peaks between smear-positive and smear-negative active TB also have been analysed. It came out that m/z 8561 and 8608 not only acted as vital factors in the pathogenesis of active TB but also played an important role in regulating different active TB status. In conclusion, MALDI-TOF MS combined with WCX magnetic beads was a powerful technology for constructing classification tree model, and the model we built could serve as a potential diagnostic tool for active TB. PMID:21668462

Deng, C; Lin, M; Hu, C; Li, Y; Gao, Y; Cheng, X; Zhang, F; Dong, M; Li, Y

2011-10-01

239

GeneXpert MTB/RIF Testing in the Management of Patients with Active Tuberculosis; A Real Life Experience from Saudi Arabia  

PubMed Central

Background GeneXpert MTB/RIF is a real-time PCR assay with established diagnostic performance in pulmonary and extra-pulmonary forms of tuberculosis. The aim of this study was to assess the contribution of GeneXpert MTB/RIF assay to the management of patients with any form of active tuberculosis in a single large tertiary center in Saudi Arabia, with a special focus on the impact on time to start of antituberculous therapy compared with Ziehl-Neelsen (ZN) smears and mycobacterial cultures. Materials and Methods Clinical, radiological and laboratory records for all patients who were commenced on antituberculous therapy between March 2011 and February 2013 were retrospectively reviewed. Results A total of 140 patients were included, 38.6% of which had pulmonary tuberculosis. GeneXpert MTB/RIF was requested for only 39.2% of patients and was the only reason for starting antituberculous therapy for only 12.1%. The median time to a positive GeneXpert MTB/RIF result was 0 days (IQR 3) compared with 0 day (IQR 1) for smear microscopy (P > 0.999) and 22 days (IQR 21) for mycobacterial cultures (P < 0.001). No patients discontinued antituberculous therapy because of a negative GeneXpert MTB/RIF result. Conclusions In a setting wherein physicians are highly experienced in the diagnosis and treatment of tuberculosis, GeneXpert MTB/RIF was remarkably under-utilized and had only a limited impact on decisions related to starting or stopping antituberculous therapy. Cost-effectiveness and clinical utility of routine testing of all smear-negative clinical samples submitted for tuberculosis investigations by GeneXpert MTB/RIF warrant further study. PMID:24693467

Al-Otaibi, Mohammed F.; Al-Ateah, Souad M.; Al-Onazi, Fahad M.; Baig, Kamran; El-Khizzi, Noura A.; Albarrak, Ali M.

2014-01-01

240

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

241

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

PubMed Central

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

Wadee, A A; Clara, A M

1989-01-01

242

A tuberculosis survey in Kenya*  

PubMed Central

The Government of Kenya, wanting to assess the extent of the tuberculosis problem in the Colony and Protectorate as an essential preliminary to a control programme, requested the assistance of WHO in carrying out a survey. The purpose was to establish the over-all prevalence for Kenya of tuberculous infection and pulmonary tuberculosis. From a population of about six million people, 8700 were selected at random for tuberculin testing, chest X-ray and bacteriological examination. The results of examination of this small sample indicate that among the 3.5 million Africans aged 10 years and over there are approximately 110 000 cases and suspected cases of pulmonary tuberculosis, and that 3% of the children aged 0-4 years and 13% of those aged 5-9 are infected. The problem of tuberculosis control in Kenya is undoubtedly a big one, the population being scattered over vast areas. However, the excellent co-operation of the population throughout the present survey suggests that mass control measures might meet with considerable success. PMID:14493266

Roelsgaard, E.; Nyboe, J.

1961-01-01

243

Childhood Tuberculosis in General Practice.  

PubMed

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

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

2014-10-01

244

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, Gözde; te Riele, Hein

2013-01-01

245

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

PubMed Central

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

2013-01-01

246

Composition of three essential oils, and their mammalian cell toxicity and antimycobacterial activity against drug resistant-tuberculosis and nontuberculous mycobacteria strains.  

PubMed

Tuberculosis (TB) is the most ancient epidemic disease in the world and a serious opportunistic disease in HIV/AIDS patients. The increase in multidrug resistant Mycobacterium tuberculosis (MDR-TB, XDR-TB) demands the search for novel antimycobacterial drugs. Essential oils (EOs) have been widely used in medicine and some EOs and their major components have been shown to be active against M. tuberculosis. The aim of this work was to evaluate the antimycobacterial and cell toxicity activities of three EOs derived from Salvia aratocensis, Turnera diffusa and Lippia americana, aromatics plants collected in Colombia. The EOs were isolated by hydrodistillation and analyzed by GC/MS techniques. The EOs were tested against 15 Mycobacterium spp using a colorimetric macrodilution method and against mammalian Vero and THP-1 cells by MTT. The activity was expressed as minimal concentration in microg/mL that inhibits growth, and the concentration that is cytotoxic for 50 or 90% of the cells (CC50 and CC90). The major components were epi-alpha-cadinol (20.1%) and 1,10-di-epi-cubenol (14.2%) for Salvia aratocensis; drima-7,9(11)-diene (22.9%) and viridiflorene (6.6%) for Turnera diffusa; and germacrene D (15.4%) and trans-beta- caryophyllene (11.3%) for Lippia americana. The most active EO was obtained from S. aratocensis, with MIC values below 125 microg mL(-1) for M. tuberculosis Beijing genotype strains, and 200 to 500 microg mL(-1) for nontuberculous mycobacterial strains. The EOs were either partially or non toxic to Vero and THP-1 mammalian cells with CC50 values from 30 to > 100 microg mL(-1), and a CC90 > 100 microg mL(-1). The EOs obtained from the three aromatic Colombian plants are an important source of potential compounds against TB. Future studies using the major EO components are recommended. PMID:22224302

Bueno, Juan; Escobar, Patricia; Martínez, Jairo René; Leal, Sandra Milena; Stashenko, Elena E

2011-11-01

247

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

Microsoft Academic Search

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

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

1999-01-01

248

Xpert MTB/RIF Testing of Stool Samples for the Diagnosis of Pulmonary Tuberculosis in Children  

PubMed Central

In a pilot accuracy study, stool Xpert testing from 115 children with suspected pulmonary tuberculosis (PTB) detected 8/17 (47%) culture-confirmed tuberculosis cases, including 4/5 (80%) HIV-infected and 4/12 (33%) HIV-uninfected children. Sputum Xpert detected 11/17 (65%) cases. Stool holds promise for PTB diagnosis in HIV-infected children. PMID:23580738

Nicol, Mark P.; Spiers, Karalene; Workman, Lesley; Isaacs, Washiefa; Munro, Jacinta; Black, Faye; Zemanay, Widaad; Zar, Heather J.

2013-01-01

249

Xpert MTB/RIF testing of stool samples for the diagnosis of pulmonary tuberculosis in children.  

PubMed

In a pilot accuracy study, stool Xpert testing from 115 children with suspected pulmonary tuberculosis (PTB) detected 8/17 (47%) culture-confirmed tuberculosis cases, including 4/5 (80%) HIV-infected and 4/12 (33%) HIV-uninfected children. Sputum Xpert detected 11/17 (65%) cases. Stool holds promise for PTB diagnosis in HIV-infected children. PMID:23580738

Nicol, Mark P; Spiers, Karalene; Workman, Lesley; Isaacs, Washiefa; Munro, Jacinta; Black, Faye; Zemanay, Widaad; Zar, Heather J

2013-08-01

250

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

251

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

Microsoft Academic Search

The emergence of total drug-resistant tuberculosis (TDRTB) has made the discovery of new therapies for tuberculosis urgent.\\u000a The cytoplasmic enzymes of peptidoglycan biosynthesis have generated renewed interest as attractive targets for the development\\u000a of new anti-mycobacterials. One of the cytoplasmic enzymes, uridine diphosphate (UDP)-MurNAc-tripeptide ligase (MurE), catalyses\\u000a the addition of meso-diaminopimelic acid (m-DAP) into peptidoglycan in Mycobacterium tuberculosis coupled to

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

2010-01-01

252

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

PubMed

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

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

2008-01-01

253

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

254

Prime Suspect, Second Row Center  

ERIC Educational Resources Information Center

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

Laird, Ellen A.

2011-01-01

255

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

PubMed

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

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

2015-02-01

256

Domain Orientation in the Inactive Response Regulator Mycobacterium tuberculosis MtrA Provides a Barrier to Activation†‡  

PubMed Central

The structure of MtrA, an essential gene product for the human pathogen Mycobacterium tuberculosis, has been solved to a resolution of 2.1 Å. MtrA is a member of the OmpR/PhoB family of response regulators and represents the fourth family member for which a structure of the protein in its inactive state has been determined. As is true for all OmpR/PhoB family members, MtrA possesses an N-terminal regulatory domain and a C-terminal winged helix-turn-helix DNA-binding domain, with phosphorylation of the regulatory domain modulating the activity of the protein. In the inactive form of MtrA these two domains form an extensive interface that is composed of the ?4-?5-?5 face of the regulatory domain and the C-terminal end of the positioning helix, the trans-activation loop, and the recognition helix of the DNA-binding domain. This domain orientation suggests a mechanism of mutual inhibition by the two domains. Activation of MtrA would require a disruption of this interface to allow the ?4-?5-?5 face of the regulatory domain to form the inter-molecule interactions that are associated with the active state and to allow the recognition helix to interact with DNA. Furthermore, the interface appears to stabilize the inactive conformation of MtrA, potentially reducing the rate of phosphorylation of the N-terminal domain. This combination of effects may form a switch regulating the activity of MtrA. The domain orientation exhibited by MtrA also provides a rationale for the variation in linker length that is observed within the OmpR/PhoB family of response regulators. PMID:17511470

Friedland, Natalia; Mack, Timothy R.; Yu, Minmin; Hung, Li-Wei; Terwilliger, Thomas C.; Waldo, Geoffrey S.; Stock, Ann M.

2008-01-01

257

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

258

Prevalent tuberculosis and mortality among HAART initiators  

PubMed Central

The effect of tuberculosis on mortality in people initiating highly active antiretroviral treatment (HAART) remains unclear; here, we strengthened a previous cohort analysis. Multivariate Cox proportional hazards models were used to assess the association of baseline tuberculosis and time to all-cause mortality among HAART initiators. In reanalysis, treatment for tuberculosis at time of HAART initiation remained unassociated with increased risks of all-cause mortality, with adjusted hazard ratios ranging from 1.00 to 1.09. PMID:22313956

Westreich, Daniel; Fox, Matthew P.; Van Rie, Annelies; Maskew, Mhairi

2012-01-01

259

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

Microsoft Academic Search

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

Amit Nayyar; Alpeshkumar Malde; Evans Coutinho; Rahul Jain

2006-01-01

260

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

261

Abdominal Tuberculosis  

Microsoft Academic Search

. Throughout the world tuberculosis is\\u000a \\u000a associated with poverty, deprivation, and human immunodeficiency virus\\u000a \\u000a infection. Abdominal tuberculosis is usually of insidious onset with\\u000a \\u000a diverse symptoms and signs. A few present with acute complications of\\u000a \\u000a perforation, obstruction, or bleeding. The diagnosis is difficult,\\u000a \\u000a especially in areas where the disease is less common, as many patients\\u000a \\u000a do not have evidence of pulmonary

Niall O. Aston

1997-01-01

262

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

PubMed

Biomarkers that can identify tuberculosis (TB) disease and serve as markers for efficient therapy are requested. We have studied T cell cytokine production (IFN-?, IL-2, TNF-?) and degranulation (CD107a) as well as subsets of CD4+ T regulatory cells (Tregs) after in vitro Mtb antigen stimulation (ESAT-6, CFP-10, Ag85) in 32 patients with active TB disease throughout 24 weeks of effective TB treatment. A significant decline in the fraction of Mtb specific total IFN-? and single IFN-? producing T cells was observed already after 2 weeks of treatment, whereas the pool of single IL-2+ cells increased over time for both CD4+ and CD8+ T cells. The Treg subsets CD25(high) CD127(low) , CD25(high) CD147(++) and CD25(high) CD127(low) CD161(+) expanded significantly after Mtb antigen stimulation in vitro at all time-points, whereas the CD25(high) CD127(low) CD39(+) Tregs remained unchanged. The fraction of CD25(high) CD127(low) Tregs increased after 8 weeks of treatment. Thus, we revealed an opposing shift of Tregs and intracellular cytokine production during treatment. This may indicate that functional signatures of the CD4+ and CD8+ T cells can serve as immunological correlates of early curative host responses. Whether such signatures can be used as biomarkers in monitoring and follow-up of TB treatment needs to be further explored. PMID:25313008

Feruglio, Siri L; Tonby, Kristian; Kvale, Dag; Dyrhol-Riise, Anne Ma

2014-10-14

263

Mycobacterium microti--pulmonary tuberculosis in an immunocompetent patient.  

PubMed

Human tuberculosis is caused by members of the Mycobacterium tuberculosis complex, which includes M. tuberculosis, M. bovis, M. africanum and M. bovis BCG. However there are increasing reports of rarely occurring genetic variants such as M. canettii, M. microti and M. pinipedii. The natural reservoir, mode of transmission and potential modification of host interaction of these species is not yet fully elucidated. We report a rare case of extensive cavitary smear-positive tuberculosis of the left lung caused by M. microti in an immunocompetent tuberculin-negative 68-year-old man. Transmission by a raccoon dog or raccoon as a novel M. microti reservoir was suspected. Spoligotyping of the isolate revealed the llama subtype. The strain exhibited no detectable drug resistance. Response to standard tuberculosis treatment, initially comprising isoniacid, rifampicin, pyrazinamide and ethambutol, was excellent. Delayed growth on solid media, specific phenotypic features and contact with animals should raise suspicion for this rare mycobacterial infection. PMID:19562286

Frank, Wolfgang; Reisinger, Emil C; Brandt-Hamerla, Wiltrud; Schwede, Ilona; Handrick, Werner

2009-01-01

264

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

PubMed Central

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

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

1995-01-01

265

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

PubMed Central

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

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

2011-01-01

266

A community and workplace outbreak of tuberculosis in Hawke's Bay in 2002  

Microsoft Academic Search

Aims To describe a community and workplace outbreak of tuberculosis in Hawke's Bay in 2002. Methods Contact tracing and case definitions used in this study followed New Zealand guidelines for tuberculosis control. DNA fingerprinting of Mycobacterium tuberculosis isolates was performed by restriction fragment length polymorphism (RFLP). Results 19 new cases of active tuberculosis disease (TBD) and 42 cases of latent

Caroline McElnay; Craig Thornley; Rob Armstrong

267

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

PubMed Central

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

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

2014-01-01

268

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

269

Synthesis of new sugar derivatives and evaluation of their antibacterial activities against Mycobacterium tuberculosis.  

PubMed

A series of sugar derivatives (1-13) were synthesized and evaluated for antibacterial activity against Mycobacteriumtuberculosis (MTB), especially multi-drug resistant (MDR) MTB, and the structure-activity relationships of these compounds were studied. The results showed that the compound OCT313 (2-acetamido-2deoxy-beta-D-glucopyranosyl N,N-dimethyldithiocarbamate) (4) exhibited significant in vitro bactericidal activity, and that the dithiocarbamate group at C-1 position of the glucopyranoside ring was requisite for the antibacterial activity. PMID:19828313

Horita, Yasuhiro; Takii, Takemasa; Chiba, Taku; Kuroishi, Ryuji; Maeda, Yasuhiro; Kurono, Yukihisa; Inagaki, Emi; Nishimura, Kenji; Yamamoto, Yoshifumi; Abe, Chiyoji; Mori, Masami; Onozaki, Kikuo

2009-11-15

270

A comparative study on the activities of six combination regimens against multidrug-resistant Mycobacterium tuberculosis infection in BALB/c mice.  

PubMed

The objective of the present study was to compare the activities of six combination regimens in a murine tuberculosis model infected with a multidrug-resistant tuberculosis isolate. After 1 month of treatment, all the combination regimens dramatically reduced CFU counts in the spleens and lungs, especially the regimens containing six drugs which had no visible counts in either organ. After 2 months of treatment, the spleens of mice treated with the six regimens all became culture negative, but for the lungs, only those treated with the regimens containing six drugs became culture negative. When levofloxacin was replaced by moxifloxacin, the regimen displayed a better activity. The activity of amikacin is closely related to the dosage. Despite in vitro resistance, isoniazid showed moderate activity. Clofazimine was able to improve the combination therapy results. Three months post-treatment, both the spleens and lungs of mice treated with the two regimens containing six drugs remained culture negative, while the spleens of mice treated with the other four regimens became culture positive. The activity of the regimens improved as more drugs were added. PMID:23684355

Zheng, Meiqin; Jin, Haixia; Fu, Lei; Xu, Jian; Wang, Bin; Zhao, Weijie; Zhu, Hui; Li, Peng; Lu, Yu; Li, Qi

2013-04-01

271

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

272

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

PubMed Central

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

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

2015-01-01

273

Usefulness of Sputum Induction with Hypertonic Saline in a Real Clinical Practice for Bacteriological Yields of Active Pulmonary Tuberculosis  

PubMed Central

Background Mycobacterial identification in active pulmonary tuberculosis (APTB) is confirmative, even though successful rates using self-expectorated sputum are limited. Sputum specimens collected by hypertonic saline nebulization showed higher bacteriologic diagnostic sensitivities over those of self-expectoration, mostly studied in smear-negative or sputum-scarce patients. The efficacy of induced sputum was rarely assessed in real clinical settings. Methods A prospective randomized case-control study was performed in one hospital. The subjects highly suspicious of APTB were asked to provide 3 pairs of sputum specimens in 3 consecutive days. The first pairs of the specimens were obtained either by self-expectoration (ES) from the next day of the visit or sputum induction with 7% saline nebulization in clinic (SI), and the other specimens were collected in the same way. The samples were tested in microscopy, culture, and polymerase chain reaction (PCR). The outcomes of the bacteriological diagnosis were compared. Results Seventy six patients were assigned to either ES (38 subjects, median age of 51, 65.8% male) or SI (38 subjects, median age of 55, 52.6% male). APTB was clinically confirmed in 51 patients (70.8%), 27 in ES and 24 in SI. Among the APTB, more adequate specimens were collected from SI (41/65, 63.1%) than ES (34/80, 42.5%) (p=0.01). Bacteriological confirmation was achieved in 14 (58.3%) patients in SI, and 13 (48.1%) in ES (p=0.46). In the same-day bacteriological diagnosis with microscopy and PCR, there were positive results for 9 patients (37.5%) in SI and 7 patients (25.9%) in ES (p=0.37). Conclusion Sputum induction improves sputum specimen adequacy. It may be useful for the same-day bacteriological diagnosis with microscopic examination and PCR. PMID:24851129

Seong, Gil Myeong; Lee, Jong Hoo; Kim, Jeong Hong; Kim, Miok

2014-01-01

274

Hepatobiliary tuberculosis.  

PubMed

Hepatobiliary tuberculosis refers to the localized form of hepatic tuberculosis and is a distinct entity in which hepatobiliary involvement overwhelmingly dominates the clinical picture. Presentations are often delayed, and manifestations can be nonspecific. Fever is the most common symptom followed by abdominal pain, and hepatomegaly is the most common abnormality found on clinical examination. Abnormalities of the liver function tests are non-specific and hence not diagnostic. Ultrasound or computed tomography reveals single or complex masses, and guided biopsy is diagnostic either by demonstrating caseating granuloma or the organism by staining and culture. Treatment is with standard first-line antituberculous drugs. Endoscopic stenting gives an excellent outcome for symptomatic biliary strictures. The outcome in patients infected with Human Immunodeficiency virus depends on the level of underlying immunosuppression. PMID:24640207

Bandyopadhyay, Sanjay; Maity, Pranab K

2013-06-01

275

Can we control tuberculosis in high HIV prevalence settings?  

PubMed

The overlap between the epidemiology of HIV and tuberculosis and consequent rapid rise in numbers of patients with tuberculosis in many African countries has put a huge burden on health systems. The stigma of HIV has increased the existing stigma surrounding tuberculosis. There are three mechanisms by which we may reduce the number of cases of tuberculosis in a community: reducing transmission of tuberculosis, reducing reactivation of latent tuberculosis infection and reducing HIV transmission. Reinforcing the existing health service to find more cases, active case-finding in communities or enhanced case-finding in specific groups will reduce transmission of tuberculosis. However, health services that find it difficult to find cases efficiently will also find it difficult to support patients throughout treatment to achieve a cure. Partnership with traditional healers, community-based organizations and private practitioners could reduce this burden. Reactivation of tuberculosis among people living with HIV can be reduced by tuberculosis preventive therapy or by antiretroviral therapy. Programmes that identify people living with HIV can also implement enhanced tuberculosis case-finding increasing the benefits of the programme. However, the impact of widespread use of antiretroviral therapy may be to increase the number of people in a community who are mildly immunocompromised and the incidence of tuberculosis at a community level might rise. Any strategy that successfully reduces HIV transmission will benefit tuberculosis control, since around a third of all HIV-positive individuals will develop tuberculosis before they die. To control tuberculosis in high HIV prevalence settings, we must strengthen health systems to include not only expansion of the DOTS strategy but also full-blooded implementation of voluntary counselling and testing, enhanced and active tuberculosis case-finding, preventive therapy and better care for people living with HIV including antiretroviral therapy. The approach needed to control tuberculosis needs also to be integrated into broader development and poverty reduction goals. PMID:12758192

Godfrey-Faussett, Peter; Ayles, Helen

2003-01-01

276

Dermatomyositis masquerading musculoskeletal tuberculosis.  

PubMed

Dermatomyositis is a rare rheumatic disease which predominantly affects the muscles and skin requiring a protracted course of immunosuppressants which may predispose the patients to opportunistic infections. A 49-year-old lady was diagnosed to have dermatomyositis in August 2010 based on history, significantly raised creatine kinase level and muscle biopsy findings. She had recurrent admissions due to fever, myalgia and muscle weakness. She had spiking temperature despite high dose steroids, broad-spectrum antibiotics and antifungal agents. This prompted extensive investigation which leads us to the additional diagnosis of disseminated tuberculosis involving the lungs, muscles and bones. This case demonstrates the challenge in controlling the disease activity of dermatomyositis with immunosuppressants in the setting of disseminated tuberculosis. PMID:22675098

Rajalingham, Sakthiswary; Said, Mohd Shahrir Mohd; Shaharir, Syahrul Sazliyana; AbAziz, Aini; Periyasamy, Petrick; Anshar, Fauzi Md

2011-01-01

277

Dermatomyositis masquerading musculoskeletal tuberculosis  

PubMed Central

Dermatomyositis is a rare rheumatic disease which predominantly affects the muscles and skin requiring a protracted course of immunosuppressants which may predispose the patients to opportunistic infections. A 49-year-old lady was diagnosed to have dermatomyositis in August 2010 based on history, significantly raised creatine kinase level and muscle biopsy findings. She had recurrent admissions due to fever, myalgia and muscle weakness. She had spiking temperature despite high dose steroids, broad-spectrum antibiotics and antifungal agents. This prompted extensive investigation which leads us to the additional diagnosis of disseminated tuberculosis involving the lungs, muscles and bones. This case demonstrates the challenge in controlling the disease activity of dermatomyositis with immunosuppressants in the setting of disseminated tuberculosis. PMID:22675098

Rajalingham, Sakthiswary; Mohd Said, Mohd Shahrir; Shaharir, Syahrul Sazliyana; AbAziz, Aini; Periyasamy, Petrick; Md Anshar, Fauzi

2011-01-01

278

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

279

A Novel in vitro Human Macrophage Model to Study the Persistence of Mycobacterium tuberculosis Using Vitamin D(3) and Retinoic Acid Activated THP-1 Macrophages.  

PubMed

Mycobacterium tuberculosis (Mtb) replicates within the human macrophages and we investigated the activating effects of retinoic acid (RA) and vitamin D(3) (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

2011-01-01

280

Autocrine IL-10 induces hallmarks of alternative activation in macrophages and suppresses anti-tuberculosis effector mechanisms without compromising T cell immunity1  

PubMed Central

Elevated IL-10 has been implicated in reactivation tuberculosis (TB). Since macrophages rather than T cells were reported to be the major source of IL-10 in TB, we analyzed the consequences of a macrophage-specific overexpression of IL-10 in transgenic mice (macIL-10-transgenic) after aerosol infection with Mycobacterium tuberculosis (Mtb). MacIL-10-transgenic mice were more susceptible to chronic Mtb infection than non-transgenic littermates, exhibiting higher bacterial loads in the lung after 12 weeks of infection and dying significantly earlier than controls. The differentiation, recruitment and activation of TH1 cells as well as the induction of IFN-gamma-dependent effector genes against Mtb were not affected by macrophage-derived IL-10. However, microarray analysis of pulmonary gene expression revealed patterns characteristic of alternative macrophage activation that were overrepresented in Mtb-infected macIL-10-transgenic mice. Importantly, arginase-1 gene expression and activity were strikingly enhanced in transgenic mice accompanied by a reduced production of reactive nitrogen intermediates. Moreover, IL-10-dependent arginase-1 induction diminished anti-mycobacterial effector mechanisms in macrophages. Together, macrophage-derived IL-10 triggers aspects of alternative macrophage activation and promotes Mtb recrudescence independent of overt effects on anti-TB T cell immunity. PMID:19561100

Schreiber, Tanja; Ehlers, Stefan; Heitmann, Lisa; Rausch, Alexandra; Mages, Jörg; Murray, Peter J.; Lang, Roland; Hölscher, Christoph

2009-01-01

281

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

282

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

Microsoft Academic Search

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

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

2002-01-01

283

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  

Microsoft Academic Search

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.

MICHAEL V. TULLIUS; GUNTER HARTH; MARCUS A. HORWITZ

2001-01-01

284

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

285

Mycobacterium tuberculosis RpfB drives Th1-type T cell immunity via a TLR4-dependent activation of dendritic cells.  

PubMed

The failure of Mycobacterium bovis BCG as a TB vaccine against TB reactivation suggests that latency-associated proteins should be included in alternative TB vaccine development. Further, antigens known to generate protective immunity against the strong Th1 stimulatory response to reactivated TB should be included in novel vaccine design. Recent studies have emphasized the importance of Rpfs from Mycobacterium tuberculosis in the reactivation process and cellular immunity. However, little is known about how RpfB mediates protective immunity against M. tuberculosis. Here, we investigated the functional roles and signaling mechanisms of RpfB in DCs and its implications in the development of T cell immunity. DCs treated with RpfB displayed features of mature and functional status, with elevated expression of cell surface molecules (CD80, CD86, and MHC class I and II) and proinflammatory cytokine production (TNF-?, IL-1?, IL-6, and IL-12p70). Activation of DCs was mediated by direct binding of RpfB to TLR4, followed by MyD88/TRIF-dependent signaling to MAPKs and NF-?B signaling pathways. Specifically, we found that the RpfB G5 domain is the most important part in RpfB binding to TLR4. RpfB-treated DCs effectively polarized naïve CD4(+) and CD8(+) T cells to secrete IFN-? and IL-2. Importantly, RpfB induced the expansion of memory CD4(+)/CD8(+)CD44(high)CD62L(low) T cells in the spleen of M. tuberculosis-infected mice. Our data suggest that RpfB regulates innate immunity and activates adaptive immunity through TLR4, a finding that may help in the design of more effective vaccines. PMID:23825389

Kim, Jong-Seok; Kim, Woo Sik; Choi, Han-Gyu; Jang, Byungki; Lee, Keehoon; Park, Jong-Hwan; Kim, Hwa-Jung; Cho, Sang-Nae; Shin, Sung Jae

2013-10-01

286

Active tuberculosis is characterized by an antigen specific and strictly localized expansion of effector T cells at the site of infection.  

PubMed

Mycobacterium tuberculosis (MTB)-specific cytokine responses in the peripheral blood and at the site of infection may differ significantly within the same individual, but the under-lying T-cell subset changes are largely unknown. Here, we measured effector and memory T-cell markers on CD4? T cells (CD45RO, cysteine chemokine receptor (CCR)7, and CD27) in peripheral blood and at the site of active tuberculosis (TB). Additionally, T cells were stimulated overnight with purified protein derivative (PPD) and early secretory antigenic target (ESAT)-6 to determine which T-cell subset produces MTB-specific interferon (IFN)-?. A striking decrease in CCR7 and CD27 expression on T cells was noted at the site of active TB. Likewise, IFN-? expressing, ESAT-6 specific CD4?CD45RO?CD27? T cells were dramatically increased at the site of infection but were not detectable in peripheral blood. An antigen-specific expansion of differentiated T cells at the site of active TB infection was poorly reflected in peripheral blood. Insight in these changes in MTB-specific effector T cells in different compartments of the body could lead to new approaches for immune-based diagnosis and interventions. PMID:22821397

Nemeth, Johannes; Rumetshofer, Rudolf; Winkler, Heide-Maria; Burghuber, Otto C; Müller, Catharina; Winkler, Stefan

2012-11-01

287

Nude rat (F344/N-rnu) tuberculosis.  

PubMed

As many mononuclear cells from Mycobacterium tuberculosis-infected lung tissues are not available for fluorescence-activated cell sorter (FACS) analysis and the tuberculin test is not feasible in a mouse tuberculosis model, we attempted to develop a rat tuberculosis model. We have previously reported that rat tuberculosis is associated with granulomas that lack central necrosis. In order to develop a better animal model of tuberculosis in immunocompromised humans (tuberculosis associated with HIV infection or tuberculosis of the elderly), we infected F344/N-rnu nude rats with M. tuberculosis via the airborne route. The animals developed pulmonary granulomas with central necrosis encapsulated by dense collagen fibres, closely resembling those of human tuberculosis. The nude rats died of disseminated tuberculosis by the 85th day after aerosol infection, while F344 wild-type rats did not. Interestingly, T-cells that were reactive with anti-CD4 antibody and anti-CD8 antibody, indicating the presence of remnant thymus, were observed in the infected lung tissues of the nude rats. Therefore, T-cell precursors may be present in nude rats. The nude rat tuberculosis model mimics tuberculosis in immunocompromised humans and may provide a suitable model for immunological studies in vivo. PMID:16548891

Sugawara, Isamu; Yamada, Hiroyuki; Mizuno, Satoru

2006-04-01

288

Discrimination between active and latent tuberculosis based on the ratio of antigen-specific to mitogen-induced IP-10 production.  

PubMed

Mycobacterium tuberculosis (Mtb) is the major causative agent of tuberculosis (TB). The IFN-? release assay (IGRA) has been widely used to diagnose TB by testing cell-mediated immune responses but has no capacity for distinguishing between active TB and latent TB infection (LTBI). This study aims to identify a parameter that will help to discriminate active TB and LTBI. Whole blood samples from 33 active TB patients and 20 individuals with LTBI, and 26 non-TB controls were applied to the commercial IFN-? release assay QuantiFERON-TB Gold In Tube, and the plasma was analyzed for IL-2, IL-6, IL-8, IL-10, IL-13, TNF-?, IFN-?, MIG, IP-10, I-TAG, and MCP-1 by using a commercial cytometric bead array. Mtb antigen-specific production of most of the assayed cytokines and chemokines was higher in active TB than in LTBI. Mitogen-induced responses were lower in the active TB than in LTBI group. When the ratio of TB-specific to mitogen-induced responses was calculated, IL-2, IL-6, IL-10, IL-13, TNF-?, IFN-?, MIG, and IP-10 were more useful in discriminating active TB from LTBI. In particular, most patients showed higher IP-10 production to Mtb antigens than to mitogen at individual level, and the ratio for IP-10 was the strongest indicator of active infection vs. LTBI with 93.9% sensitivity and 90% specificity. In conclusion, the ratio of TB-specific to mitogen-induced IP-10 responses showed the most promising accuracy for discriminating active TB vs. LTBI, and should be further studied whether it can serve as a biomarker that can help clinicians administer appropriate treatments. PMID:25428147

Jeong, Yun Hee; Hur, Yun-Gyoung; Lee, Hyejon; Kim, Sunghyun; Cho, Jang-Eun; Chang, Jun; Shin, Sung Jae; Lee, Hyeyoung; Kang, Young Ae; Cho, Sang-Nae; Ha, Sang-Jun

2014-11-26

289

Evaluation of tuberculosis diagnostics in children: 1. Proposed clinical case definitions for classification of intrathoracic tuberculosis disease. Consensus from an expert panel.  

PubMed

There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis. PMID:22448023

Graham, Stephen M; Ahmed, Tahmeed; Amanullah, Farhana; Browning, Renee; Cardenas, Vicky; Casenghi, Martina; Cuevas, Luis E; Gale, Marianne; Gie, Robert P; Grzemska, Malgosia; Handelsman, Ed; Hatherill, Mark; Hesseling, Anneke C; Jean-Philippe, Patrick; Kampmann, Beate; Kabra, Sushil Kumar; Lienhardt, Christian; Lighter-Fisher, Jennifer; Madhi, Shabir; Makhene, Mamodikoe; Marais, Ben J; McNeeley, David F; Menzies, Heather; Mitchell, Charles; Modi, Surbhi; Mofenson, Lynne; Musoke, Philippa; Nachman, Sharon; Powell, Clydette; Rigaud, Mona; Rouzier, Vanessa; Starke, Jeffrey R; Swaminathan, Soumya; Wingfield, Claire

2012-05-15

290

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

291

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

PubMed

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

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

2015-02-15

292

Development of a Selective Activity-Based Probe for Adenylating Enzymes: Profiling MbtA Involved in Siderophore Biosynthesis from Mycobacterium tuberculosis  

PubMed Central

MbtA is an adenylating enzyme from Mycobacterium tuberculosis that catalyzes the first step in the biosynthesis of the mycobactins. A potent bisubstrate inhibitor (Sal-AMS) of MbtA was previously described that displays potent antitubercular activity under iron-replete as well as iron-deficient growth conditions. This finding is surprising since mycobactin biosynthesis is not required under iron-replete conditions and suggests off-target inhibition of additional biochemical pathways. As a first step towards a complete understanding of the mechanism of action of Sal-AMS, we have designed and validated an activity-based probe (ABP) for studying Sal-AMS inhibition in M. tuberculosis. This probe labels pure MbtA as well as MbtA in mycobacterial lysate and labeling can be completely inhibited by preincubation with Sal-AMS. Furthermore, this probe provides a prototypical core scaffold for the creation of ABPs to profile any of the other 66 adenylating enzymes in Mtb or the multitude of adenylating enzymes in other pathogenic bacteria. PMID:22796950

Duckworth, Benjamin P.; Wilson, Daniel J.; Nelson, Kathryn M.; Boshoff, Helena I.; Barry, Clifton E.; Aldrich, Courtney C.

2012-01-01

293

Development of a selective activity-based probe for adenylating enzymes: profiling MbtA Involved in siderophore biosynthesis from Mycobacterium tuberculosis.  

PubMed

MbtA is an adenylating enzyme from Mycobacterium tuberculosis that catalyzes the first step in the biosynthesis of the mycobactins. A bisubstrate inhibitor of MbtA (Sal-AMS) was previously described that displays potent antitubercular activity under iron-replete as well as iron-deficient growth conditions. This finding is surprising since mycobactin biosynthesis is not required under iron-replete conditions and suggests off-target inhibition of additional biochemical pathways. As a first step toward a complete understanding of the mechanism of action of Sal-AMS, we have designed and validated an activity-based probe (ABP) for studying Sal-AMS inhibition in M. tuberculosis. This probe labels pure MbtA as well as MbtA in mycobacterial lysate, and labeling can be completely inhibited by preincubation with Sal-AMS. Furthermore, this probe provides a prototypical core scaffold for the creation of ABPs to profile any of the other 66 adenylating enzymes in Mtb or the multitude of adenylating enzymes in other pathogenic bacteria. PMID:22796950

Duckworth, Benjamin P; Wilson, Daniel J; Nelson, Kathryn M; Boshoff, Helena I; Barry, Clifton E; Aldrich, Courtney C

2012-10-19

294

Active Case Finding of Pulmonary Tuberculosis through Screening of Respiratory Symptomatics Using Sputum Microscopy: Is It Time to Change the Paradigm?  

PubMed Central

Background. One of the main strategies for the early detection of pulmonary tuberculosis (PTB) is through the screening of individuals with symptoms compatible with PTB. Although this is programmatic strategy for active case finding, its yield is not well known. Objective. To determine the yield of pulmonary tuberculosis active case finding through the screening of respiratory symptomatic (RS) patients at a general hospital. Methods. RS patients were defined as subjects complaining of cough and/or sputum for a period of 2 or more weeks. Outpatients and their companions were approached while they waited in the outpatient care areas of the hospital to detect RS. Two samples from different days or 2 samples taken 2 hours apart on the same day were collected. Results. 122 RS patients were identified. Fifty-seven patients (46.7%) had at least one sputum sample analyzed. Three patients presented a positive smear and 2 were culture positive; neither had upper airway symptoms. None of the patients with productive cough and upper airway symptoms had a positive smear (P = 0.07). Only 19 (33.3%) returned to the laboratory to retrieve their results. Conclusion. Current strategy to screen RS patients based only on clinical data has a low compliance. Specific strategies to increase compliance (removal of barriers, incentives, etc.) should be implemented. PMID:23533747

del Portillo-Mustieles, Eva Carolina; Laniado-Laborín, Rafael

2013-01-01

295

The antimicrobial activity of copper and copper alloys against nosocomial pathogens and Mycobacterium tuberculosis isolated from healthcare facilities in the Western Cape: an in-vitro study.  

PubMed

Clinical isolates of meticillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Candida albicans and Mycobacterium tuberculosis (MTB) were tested against copper (Cu) and its alloys. Stainless steel and polyvinylchloride (PVC) were used as controls. The amount of Cu required to inhibit test isolates at room temperature (24 degrees C) and at 4 degrees C was determined. At room temperature, Cu, DZR Brass (Cu 62%, Pb 2.5%, arsenate 0.13% and Zn 22.5%) and Brass 70/30 (Cu 70% and zinc 30%) inhibited C. albicans and K. pneumoniae at 60 min; nickel silver (NiAg) inhibited C. albicans at 60 min and K. pneumoniae at 270 min. P. aeruginosa was inhibited by Brass 70/30 and nickel silver (NiAg) at 180 min and at 270 min by Cu and DZR. Cu and DZR inhibited A. baumannii at 180 min while the other alloys were effective at 360 min. Stainless steel and PVC showed little or no inhibitory activity. Two M. tuberculosis strains, one isoniazid resistant (R267) and the other multidrug resistant (R432), demonstrated growth inhibition with Cu of 98% and 88% respectively compared with PVC; the other alloys were less active. Time to positivity (TTP) for R267 was >15 days with Cu and 11 days for the other alloys; with R432 it was 5 days. Effective inhibition of nosocomial pathogens and MTB by Cu and alloys was best when the Cu content was >55%. PMID:18069086

Mehtar, S; Wiid, I; Todorov, S D

2008-01-01

296

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

PubMed Central

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

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

2014-01-01

297

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

298

Central nervous system tuberculosis.  

PubMed

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

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

2014-06-01

299

[Tuberculosis--a neverending story].  

PubMed

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

Dziecio?owska-Baran, Edyta; Gawlikowska-Sroka, Aleksandra

2013-01-01

300

Advances in the Diagnosis of Pulmonary Tuberculosis in HIV-Infected and HIV-Uninfected Children  

PubMed Central

The identification of improved diagnostic tests for tuberculosis has been identified as a global research priority. Over the past decade, there has been renewed interest in the development and validation of novel diagnostic tools for pulmonary tuberculosis that are applicable to resource-poor settings. These techniques are aimed primarily at improving detection of the organism or a specific host immune response. Although most studies have focused on determining the accuracy of novel tests in adults, it is likely they will also have the capacity to significantly improve the diagnosis of childhood tuberculosis. Improving the quality of clinical samples obtained from children with suspected tuberculosis remains an important research priority while awaiting validation of novel diagnostic tests. This review will focus on a number of recent developments for the diagnosis of tuberculosis, with a specific emphasis on the application of these new tests to children in settings where tuberculosis is endemic. PMID:21996697

Connell, Tom G.; Zar, Heather J.

2011-01-01

301

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

PubMed Central

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

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

2011-01-01

302

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

303

Prospective evaluation and characteristics of patients with suspected primary hyperaldosteronism  

Microsoft Academic Search

Primary hyperaldosteronism (PH), resulting in hypokalaemic hypertension, may be due to an aldos- terone-producing adenoma (APA) or bilateral zona glomerulosa hyperplasia. Six patients with suspect- ed PH were identified at the University Hospital of the West Indies and standardized screening was car- ried out. Plasma renin activity (PRA) and serum aldosterone concentrations (SAC) were measured, fol- lowed by confirmatory intravenous

CA McKenzie; R Wright-Pascoe; Boyne

2007-01-01

304

[Recent advances in tuberculosis immunity].  

PubMed

Primary tuberculosis infection is acquired by the inhalation of droplets containing Mycobacterium tuberculosis (MTB) bacilli. Only 5-10% of those individuals infected by MTB develop clinical diseases, and disease presentation itself is heterogeneous, suggesting that host factors play a large role in disease susceptibility. Protective immunity in the lung against MTB consist of the innate immunity in which alveolar macrophages play an central role, and the acquired immunity including various type of effector T cells. Recent studies show that the important roles of the receptors which recognize MTB for the development of protective immunity, the difference in the anti-MTB activity of macrophages between human and mice, the macrophage-heterogeneity that affects the anti-MTB activity, the role of IL-10 in the activation of anti-MTB activity of human macrophages, and the role of Th17/IL-17, Th22/ IL-22 and TNF in the protective immunity against human tuberculosis. In this review, these recent advances in tuberculosis immunity will be described. PMID:22514942

Akagawa, Kiyoko S

2012-02-01

305

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

306

Evaluation of adenosine deaminase activity and antibody to Mycobacterium tuberculosis antigen 5 in cerebrospinal fluid and the radioactive bromide partition test for the early diagnosis of tuberculosis meningitis  

Microsoft Academic Search

A number of different biochemical and serological tests have been described recently for the early and accurate diagnosis of tuberculous meningitis. None of these tests has yet gained widespread acceptance in clinical medicine or in microbiology laboratories. To investigate this problem we evaluated adenosine deaminase activity (ADA), an enzyme linked immunosorbent assay (ELISA) that detects antibody to antigen 5 of

Y M Coovadia; A Dawood; M E Ellis; H M Coovadia; T M Daniel

1986-01-01

307

Crystal structures of Mycobacterium tuberculosis RecA and its complex with ADP–AlF4: implications for decreased ATPase activity and molecular aggregation  

PubMed Central

Sequencing of the complete genome of Mycobacterium tuberculosis, combined with the rapidly increasing need to improve tuberculosis management through better drugs and vaccines, has initiated extensive research on several key proteins from the pathogen. RecA, a ubiquitous multifunctional protein, is a key component of the processes of homologous genetic recombination and DNA repair. Structural knowledge of MtRecA is imperative for a full understanding of both these activities and any ensuing application. The crystal structure of MtRecA, presented here, has six molecules in the unit cell forming a 61 helical filament with a deep groove capable of binding DNA. The observed weakening in the higher order aggregation of filaments into bundles may have implications for recombination in mycobacteria. The structure of the complex reveals the atomic interactions of ADP–AlF4, an ATP analogue, with the P-loop-containing binding pocket. The structures explain reduced levels of interactions of MtRecA with ATP, despite sharing the same fold, topology and high sequence similarity with EcRecA. The formation of a helical filament with a deep groove appears to be an inherent property of MtRecA. The histidine in loop L1 appears to be positioned appropriately for DNA interaction. PMID:11121488

Datta, S.; Prabu, M. M.; Vaze, M. B.; Ganesh, N.; Chandra, Nagasuma R.; Muniyappa, K.; Vijayan, M.

2000-01-01

308

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

309

Mycobacterium tuberculosis Serine/Threonine Protein Kinases.  

PubMed

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

Prisic, Sladjana; Husson, Robert N

2014-10-01

310

Organotin meclofenamic complexes: Synthesis, crystal structures and antiproliferative activity of the first complexes of meclofenamic acid - novel anti-tuberculosis agents.  

PubMed

The complexes [Me(2)(Meclo)SnOSn(Meclo)Me(2)](2) (2) and [Ph(3)Sn(Meclo)] (3) where HMeclo is meclofenamic acid, N-(2,6-dichloro-m-tolylanthranilic acid)], have been prepared and structurally characterized by means of vibrational, (1)H and (13)C NMR spectroscopies. The crystal structure of complexes (2) and (3) have been determined by X-ray crystallography. Three distannoxane rings are present to the dimeric tetraorganodistannoxane of planar ladder arrangement of (2). The structure is centro symmetric and features a central rhombus Sn(2)O(2) unit two additional tin atoms linked at the oxygen atoms. Five- and six-coordinated tin centers are present in the dimer distannoxane. X-ray analysis of (3) revealed a penta-coordinated structure containing Ph(3)Sn coordinated to the chelated carboxylato group. The polar imino hydrogen atom participates in intra-molecular hydrogen bonds. Complexes (2) and (3) are self-assembled via pi-->pi, C-H-pi, stacking interactions and intra-molecular hydrogen bonds. Meclofenamic acid and [Ph(3)Sn(Meclo)] have been evaluated for antiproliferative activity in vitro against three human cancer cell lines: MCF-7 (human breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-small cell lung carcinoma) and a mouse L-929 (a fibroblast-like cell line cloned from strain L). The [Ph(3)Sn(Meclo)] complex exhibited high cytotoxic activity against all the cancer cell lines. Meclofenamic and [Ph(3)Sn(Meclo)] were tested for anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv. The [Ph(3)Sn(Meclo)] complex was found to be a promising anti-mycobacterial lead compound, displaying high activity against M. tuberculosis H37Rv. PMID:19237201

Kovala-Demertzi, Dimitra; Dokorou, Vaso; Primikiri, Alexandra; Vargas, Richy; Silvestru, Cristian; Russo, Umberto; Demertzis, Mavroudis A

2009-05-01

311

Cost-effectiveness of tuberculosis evaluation and treatment of newly-arrived immigrants  

PubMed Central

Background Immigrants to the U.S. are required to undergo overseas screening for tuberculosis (TB), but the value of evaluation and treatment following entry to the U.S. is not well understood. We determined the cost-effectiveness of domestic follow-up of immigrants identified as tuberculosis suspects through overseas screening. Methods Using a stochastic simulation for tuberculosis reactivation, transmission, and follow-up for a hypothetical cohort of 1000 individuals, we calculated the incremental cost-effectiveness of follow-up and evaluation interventions. We utilized published literature, California Reports of Verified Cases of Tuberculosis (RVCTs), demographic estimates from the California Department of Finance, Medicare reimbursement, and Medi-Cal reimbursement rates. Our target population was legal immigrants to the United States, our time horizon is twenty years, and our perspective was that of all domestic health-care payers. We examined the intervention to offer latent tuberculosis therapy to infected individuals, to increase the yield of domestic evaluation, and to increase the starting and completion rates of LTBI therapy with INH (isoniazid). Our outcome measures were the number of cases averted, the number of deaths averted, the incremental dollar cost (year 2004), and the number of quality-adjusted life-years saved. Results Domestic follow-up of B-notification patients, including LTBI treatment for latently infected individuals, is highly cost-effective, and at times, cost-saving. B-notification follow-up in California would reduce the number of new tuberculosis cases by about 6–26 per year (out of a total of approximately 3000). Sensitivity analysis revealed that domestic follow-up remains cost-effective when the hepatitis rates due to INH therapy are over fifteen times our best estimates, when at least 0.4 percent of patients have active disease and when hospitalization of cases detected through domestic follow-up is no less likely than hospitalization of passively detected cases. Conclusion While the current immigration screening program is unlikely to result in a large change in case rates, domestic follow-up of B-notification patients, including LTBI treatment, is highly cost-effective. If as many as three percent of screened individuals have active TB, and early detection reduces the rate of hospitalization, net savings may be expected. PMID:16784541

Porco, Travis C; Lewis, Bryan; Marseille, Elliot; Grinsdale, Jennifer; Flood, Jennifer M; Royce, Sarah E

2006-01-01

312

Play the Tuberculosis Game  

MedlinePLUS

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

313

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

314

Integration of tuberculosis screening at an HIV voluntary counselling and testing centre in Haiti  

Microsoft Academic Search

Objective: To describe the integration of tuberculosis screening into the activities of an HIV voluntary counselling and testing (VCT) centre in a country with endemic tuberculosis. Setting: An HIV VCT centre in Port au Prince, Haiti. Design: All patients presenting for HIV VCT who reported cough received same-day evaluation for active tuberculosis. Of the 1327 adults presenting to the centre

Amelia L. Burgess; Daniel W. Fitzgerald; Patrice Severe; Patrice Joseph; Ernst Noel; Nalin Rastogi; Warren D. Johnson; Jean W. Pape

315

Sterilizing Activity of Novel TMC207- and PA-824-Containing Regimens in a Murine Model of Tuberculosis?†  

PubMed Central

To truly transform the landscape of tuberculosis treatment, novel regimens containing at least 2 new drugs are needed to simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. As part of an ongoing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, TMC207 plus pyrazinamide, alone or in combination with any third drug, proved superior to the first-line regimen including rifampin, pyrazinamide, and isoniazid. On the basis of CFU counts at 1 month, clofazimine proved to be the best third drug combined with TMC207 and pyrazinamide, whereas the addition of PA-824 was modestly antagonistic. Relapse results were inconclusive due to the low rate of relapse in all test groups. In the second experiment evaluating 3-drug combinations composed of TMC207, pyrazinamide, PA-824, moxifloxacin, and rifapentine, TMC207 plus pyrazinamide plus either rifapentine or moxifloxacin was the most effective, curing 100% and 67% of the mice treated, respectively, in 2 months of treatment. Four months of the first-line regimen did not cure any mice, whereas the combination of TMC207, PA-824, and moxifloxacin cured 50% of the mice treated. The results reveal new building blocks for novel regimens with the potential to shorten the duration of treatment for both drug-susceptible and drug-resistant tuberculosis, including the combination of TMC207, pyrazinamide, PA-824, and a potent fluoroquinolone. PMID:21930883

Tasneen, Rokeya; Li, Si-Yang; Peloquin, Charles A.; Taylor, Dinesh; Williams, Kathy N.; Andries, Koen; Mdluli, Khisimuzi E.; Nuermberger, Eric L.

2011-01-01

316

Activation of ATP Binding for the Autophosphorylation of DosS, a Mycobacterium tuberculosis Histidine Kinase Lacking an ATP Lid Motif*  

PubMed Central

The sensor histidine kinases of Mycobacterium tuberculosis, DosS and DosT, are responsible for sensing hypoxic conditions and consist of sensor and kinase cores responsible for accepting signals and phosphorylation activity, respectively. The kinase core contains a dimerization and histidine phosphate-accepting (DHp) domain and an ATP binding domain (ABD). The 13 histidine kinase genes of M. tuberculosis can be grouped based on the presence or absence of the ATP lid motif and F box (elements known to play roles in ATP binding) in their ABDs; DosS and DosT have ABDs lacking both these elements, and the crystal structures of their ABDs indicated that they were unsuitable for ATP binding, as a short loop covers the putative ATP binding site. Although the ABD alone cannot bind ATP, the kinase core is functional in autophosphorylation. Appropriate spatial arrangement of the ABD and DHp domain within the kinase core is required for both autophosphorylation and ATP binding. An ionic interaction between Arg440 in the DHp domain and Glu537 in the short loop of the ABD is available and may open the ATP binding site, by repositioning the short loop away from the site. Mutations at Arg440 and Glu537 reduce autophosphorylation activity. Unlike other histidine kinases containing an ATP lid, which protects bound ATP, DosS is unable to accept ATP until the ABD is properly positioned relative to the histidine; this may prevent unexpected ATP reactions. ATP binding can, therefore, function as a control mechanism for histidine kinase activity. PMID:23486471

Cho, Ha Yeon; Lee, Young-Hoon; Bae, Young-Seuk; Kim, Eungbin; Kang, Beom Sik

2013-01-01

317

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

318

Male breast tuberculosis.  

PubMed Central

Tuberculosis of the breast is rare and tuberculosis of the male breast is not a recognised entity. We describe a man with tuberculosis of the breast which was clinically thought to be a malignancy. Images Figure 1 Figure 2 PMID:9338032

Jaideep, C.; Kumar, M.; Khanna, A. K.

1997-01-01

319

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

PubMed

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

Choi, Eun Kyung

2013-12-01

320

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

321

Value of third sputum smear for detection of pulmonary tuberculosis in HIV infected patients  

PubMed Central

We evaluated diagnostic yield of third sputum smear in patients co infected with HIV for detection of pulmonary tuberculosis (TB). Among 139 pulmonary tuberculosis cases confirmed with positive sputum culture, diagnostic yield of first smear of sputum with acid fast staining was 81.9%. Incremental yield of 2nd and 3rd samples was 11.7% and 6.3% respectively. So two sputum smears may be enough for primary evaluation of HIV infected patients suspected to TB. PMID:24470949

Marjani, Majid; Tabarsi, Payam; Baghaei, Parvaneh; Mansouri, Davoud; Masjedi, Mohammad Reza; Velayati, Ali Akbar

2012-01-01

322

Value of third sputum smear for detection of pulmonary tuberculosis in HIV infected patients.  

PubMed

We evaluated diagnostic yield of third sputum smear in patients co infected with HIV for detection of pulmonary tuberculosis (TB). Among 139 pulmonary tuberculosis cases confirmed with positive sputum culture, diagnostic yield of first smear of sputum with acid fast staining was 81.9%. Incremental yield of 2(nd) and 3(rd) samples was 11.7% and 6.3% respectively. So two sputum smears may be enough for primary evaluation of HIV infected patients suspected to TB. PMID:24470949

Marjani, Majid; Tabarsi, Payam; Baghaei, Parvaneh; Mansouri, Davoud; Masjedi, Mohammad Reza; Velayati, Ali Akbar

2012-04-27

323

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

Microsoft Academic Search

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

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

324

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

PubMed Central

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

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

2014-01-01

325

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

Microsoft Academic Search

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

Dermot Maher

2010-01-01

326

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

327

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

SciTech Connect

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

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

2014-10-02

328

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

PubMed Central

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

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

2014-01-01

329

Peritoneal carcinomatosis mimicking a peritoneal tuberculosis  

PubMed Central

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

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

2015-01-01

330

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.

331

The RD1 Locus in the Mycobacterium tuberculosis Genome Contributes to Activation of Caspase-1 via Induction of Potassium Ion Efflux in Infected Macrophages ?  

PubMed Central

A genomic locus called “region of difference 1” (RD1) in Mycobacterium tuberculosis has been shown to contribute to the generation of host protective immunity as well as to the virulence of the bacterium. To gain insight into the molecular mechanism, we investigated the difference in the cytokine-inducing ability between H37Rv and a mutant strain deficient for RD1 (?RD1). We found that RD1 is implicated in the production of caspase-1-dependent cytokines, interleukin-18 (IL-18) and IL-1?, from infected macrophages. The expression of these cytokines was similarly induced after infection with H37Rv and ?RD1. However, the activation of caspase-1 was observed only in H37Rv-infected macrophages. The cytokine production and caspase-1 activation were induced independently of type I interferon receptor signaling events. We also found that the activation of caspase-1 was markedly inhibited with increasing concentrations of extracellular KCl. Furthermore, the production of IL-18 and IL-1? and caspase-1 activation were induced independently of a P2X7 purinergic receptor, and the inability of ?RD1 in caspase-1 activation was compensated for by nigericin, an agent inducing the potassium ion efflux. Based on these results, we concluded that RD1 participates in caspase-1-dependent cytokine production via induction of the potassium ion efflux in infected macrophages. PMID:19596775

Kurenuma, Takeshi; Kawamura, Ikuo; Hara, Hideki; Uchiyama, Ryosuke; Daim, Sylvia; Dewamitta, Sita Ramyamali; Sakai, Shunsuke; Tsuchiya, Kohsuke; Nomura, Takamasa; Mitsuyama, Masao

2009-01-01

332

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

333

Tuberculosis and MDR-TB in the northern emirates of United Arab Emirates: a 5-year study.  

PubMed

In this study, we describe the prevalence of TB and occurrence of multi-drug-resistance tuberculosis (MDR-TB) in a major referral hospital belonging to the Ministry of Health in Sharjah, United Arab Emirates (UAE). A retrospective re-view of the clinical and laboratory records of 1,810 suspected cases of TB was carried out between January 2004 and September 2008. The antimicrobial susceptibility patterns of each Mycobacterium tuberculosis isolate were analyzed. During the study period, 312 M. tuberculosis culture confirmed cases were recorded; 230 were males and 82 were females. The majority of TB cases (36%) were seen among expatriates from South and Southeast Asian countries. Fifty-one active TB cases (16%) were reported in native people (Emaratis) of the country. The peak age group was between 16 and 45 years. Among first-line antituberculosis drugs, resistance to isoniazid was the most common (21%), followed by streptomycin (14%). MDR-TB was found in 15 cases (4.8%). Although the prevalence of TB in UAE is fairly low, an increasing number of cultures confirmed TB and MDR-TB among native and expatriate patients, necessitating improved vigilance in case detection, effec-tive management and prevention of MDR and XDR-TB emergence in the country. PMID:20578495

Al-Zarouni, Mansour; Dash, Nihar; Al Ali, Mahar; Al-Shehhi, Fatma; Panigrahi, Debadatta

2010-01-01

334

Impaired Degranulation and Proliferative Capacity of Mycobacterium tuberculosis-Specific CD8+ T Cells in HIV-Infected Individuals With Latent Tuberculosis.  

PubMed

Human immunodeficiency virus (HIV)-infected individuals with latent Mycobacterium tuberculosis infection have substantially higher rates of progression to active tuberculosis than HIV-uninfected individuals with latent tuberculosis. To explore HIV-induced deficits in M. tuberculosis-specific CD8(+) T-cell functions, we compared interferon ? production, degranulation, and proliferation of CD8(+) T cells in response to M. tuberculosis peptides (ESAT-6/CFP-10) between HIV-infected (median CD4(+) T-cell count, 522 cells/µL; interquartile range, 318-585 cells/µL) and HIV-uninfected individuals with latent tuberculosis from South Africa. We found that M. tuberculosis-specific degranulation and proliferative capacities were impaired in the HIV-infected group. Thus, our results suggest that HIV coinfection compromises CD8(+) T-cell functions in latent tuberculosis. PMID:25205634

Kalokhe, Ameeta S; Adekambi, Toidi; Ibegbu, Chris C; Ray, Susan M; Day, Cheryl L; Rengarajan, Jyothi

2015-02-15

335

[An unusual presentation of tuberculosis].  

PubMed

A 67-year-old male was hospitalized because of nonspecific symptoms and bilateral pleural effusions. He gave no history of cough, dyspnea or thoracic pain. The blood counts showed moderate anemia and high-grade lymphopenia. The tuberculin test and the anergy-panel were both negative. Testing for HIV was negative. Analysis of pleural fluid showed an exudate with 47% lymphocytes and absence of acid-fast bacilli on Ziehl-Neelsen smear. On histologic examination, the pleural tissue showed no evidence of granuloma. However, cultures for mycobacteria of pleural tissue yielded M. tuberculosis. In this case of pleural tuberculosis, leading symptoms were absent and the tuberculin test was negative in the presence of active tuberculosis. In addition, the cells in the pleural effusion were not predominantly lymphocytic. Patients presenting with unclear effusion should undergo extensive investigations, including a tuberculin test, and anergy panel, pleural fluid cultures, and pleural biopsy with cultures for microorganisms, with the object of establishing or ruling out pleural tuberculosis. PMID:9011935

Lefkovits, M; Reusser, P

1996-12-28

336

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

337

Tuberculosis: evidence review for newly arriving immigrants and refugees  

PubMed Central

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

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

2011-01-01

338

Tuberculosis diagnosis: primary health care or emergency medical services?  

PubMed Central

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

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

2013-01-01

339

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

PubMed

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

2014-05-01

340

Cationic amphipathic D-enantiomeric antimicrobial peptides with in vitro and ex vivo activity against drug-resistant Mycobacterium tuberculosis.  

PubMed

Tuberculosis (TB) is the leading cause of bacterial death worldwide. Due to the emergence of multi-drug resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), and the persistence of latent infections, a safe and effective TB therapy is highly sought after. Antimicrobial peptides (AMPs) have therapeutic potential against infectious diseases and have the ability to target microbial pathogens within eukaryotic cells. In the present study, we investigated the activity of a family of six AMPs containing all-D amino acids (D-LAK peptides) against MDR and XDR clinical strains of Mycobacterium tuberculosis (Mtb) both in vitro and, using THP-1 cells as a macrophage model, cultured ex vivo. All the D-LAK peptides successfully inhibited the growth of Mtb in vitro and were similarly effective against MDR and XDR strains. D-LAK peptides effectively broke down the heavy clumping of mycobacteria in broth culture, consistent with a 'detergent-like effect' that could reduce the hydrophobic interactions between the highly lipidic cell walls of the mycobacteria, preventing bacteria cell aggregation. Furthermore, though not able to eradicate the intracellular mycobacteria, D-LAK peptides substantially inhibited the intracellular growth of drug-resistant Mtb clinical isolates at concentrations that were well tolerated by THP-1 cells. Finally, combining D-LAK peptide with isoniazid could enhance the anti-TB efficacy. D-LAK peptide, particularly D-LAK120-A, was effective as an adjunct agent at non-toxic concentration to potentiate the efficacy of isoniazid against drug-resistant Mtb in vitro, possibly by facilitating the access of isoniazid into the mycobacteria by increasing the surface permeability of the pathogen. PMID:25154927

Lan, Yun; Lam, Jason T; Siu, Gilman K H; Yam, Wing Cheong; Mason, A James; Lam, Jenny K W

2014-12-01

341

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

Microsoft Academic Search

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

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

1999-01-01

342

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

Microsoft Academic Search

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

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

2009-01-01

343

Randomized Dose-Ranging Study of the 14-Day Early Bactericidal Activity of Bedaquiline (TMC207) in Patients with Sputum Microscopy Smear-Positive Pulmonary Tuberculosis  

PubMed Central

Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log10 CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant (P = 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group (P = 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14-day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies. PMID:23459487

Dawson, Rodney; Von Groote-Bidlingmaier, Florian; Symons, Gregory; Venter, Amour; Donald, Peter R.; Conradie, Almari; Erondu, Ngozi; Ginsberg, Ann M.; Egizi, Erica; Winter, Helen; Becker, Piet; Mendel, Carl M.

2013-01-01

344

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 ...

345

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, ...

346

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 ...

347

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

348

Women and tuberculosis.  

PubMed

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

Connolly, M; Nunn, P

1996-01-01

349

Research on the occurrence of Mycobacterium tuberculosis antigens in the circulating immune complexes, isolated from serum of patients with tuberculosis  

PubMed Central

Background Tuberculosis is one of the most dangerous infectious diseases and has among the highest mortality rates of all infectious diseases. There are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world’s population is infected with Mycobacterium tuberculosis and remains asymptomatic. Despite the great progress in its diagnosis and treatment, tuberculosis is still a serious health and social problem. The contact between the immune system and Mycobacterium tuberculosis initiates cell-specific (Th1) and humoral-specific (Th2) responses. Many studies about the presence of antituberculotic antibodies in the serum have produced inconsistent results because of a high proportion of false-positive or false-negative results. The purpose of this study was to confirm whether circulating immune complexes (CIC) isolated from the serum of patients with tuberculosis are accompanied by antigenic proteins typical of Mycobacterium tuberculosis. Material/Methods We assayed serum samples from 42 patients with tuberculosis. The control group consisted of the sera samples taken from 45 healthy subjects. The immunochemical analysis of dissociated immune complexes using the dot blot method demonstrated positive reaction on the presence of Mycobacterium tuberculosis antigens in all patients with tuberculosis. Results All patients with tuberculosis demonstrated a high serum concentration of CIC protein. The mean serum concentration of CIC protein was significantly higher in patients than in controls: 0.081 g/l in the control group and 0.211 g/l in the tuberculosis patients. Conclusions The analysis of CIC suggests that it may be a helpful test for patients with tuberculosis because of its quickness, simplicity of the idea, and limited invasiveness. PMID:24384554

Przybylski, Grzegorz; Go?da, Ryszard

2014-01-01

350

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

351

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

352

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

Microsoft Academic Search

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

Jirarut Jonmalung; Therdsak Prammananan; Manoon Leechawengwongs; Angkana Chaiprasert

2010-01-01

353

Tuberculosis: Medico-Legal Aspects  

PubMed Central

Tuberculosis is a diffusive infectious disease whose typical behaviour differentiates it from other infectious diseases spread by human-to-human transmission (flu, chicken pox, cholera, etc.) that follow a classic epidemic pattern. Indeed, in the presence of a known source of Koch bacilli that is capable of spreading the bacteria by air, not all exposed individuals inhale the bacteria, not all those who inhale them absorb them, not all those who absorb the bacteria are unable to eliminate them, not all who are able to eliminate them do so using delayed hypersensitivity, not all those who react with delayed hypersensitivity suffer lasting tissue damage (among other things, minor), not all who suffer tissue damage have anatomical sequelae, and not all those who have anatomical sequelae, however minimal, become carriers of bacilli in the latent period. The vast majority (90–95%) of the latter – which are in any case a portion, not the totality of those exposed – remain asymptomatic throughout their lives and never develop active tuberculosis. Based on these biological characteristics and the legal concepts of “epidemic” and “disease,” it becomes highly problematic, if not impossible, to assert both that tuberculosis can cause events of sufficient magnitude to be associated with the crime of “epidemic,” and that the mere diagnosis of a latent tuberculosis infection is sufficient to assume the presence of an illness legally prosecutable in criminal proceedings or a disability prosecutable in civil proceedings. Furthermore, clinically apparent tuberculosis is a temporarily—and in some cases permanently—disabling condition, and in certain work environments, even with the difficulties caused by the lack of available effective diagnostic tools and the insidious behaviour of the disease in the early stages, targeted monitoring to identify other persons who may become ill is appropriate. PMID:24804006

Vetrugno, G.; De-Giorgio, F.; D’Alessandro, F.; Scafetta, I.; Berloco, F.; Buonsenso, D.; Abbate, F.; Scalise, G.; Pascali, V.L.; Valentini, P

2014-01-01

354

HTLV-1 infection is associated with a history of active tuberculosis among family members of HTLV-1-infected patients in Peru  

PubMed Central

SUMMARY The purpose of this study was to assess the association between human T-lymphotropic virus 1 (HTLV-1) and a lifetime history of active tuberculosis (TB) among relatives of HTLV-1-infected patients. We reviewed clinical charts of all relatives of HTLV-1-infected index cases who attended our institute in Lima from 1990–2004. The data of 1233 relatives was analysed; 394 (32·0%) were HTLV-1 positive. Eighty-one subjects (6·6%) had a history of active TB, including 45/394 (11·4%) HTLV-1-positive and 36/839 (4·3%) HTLV-1-negative relatives (P<0·001). On multivariate analysis, three factors were associated with TB history: HTLV-1 infection (adjusted OR 2·5, 95% CI 1·6–3·9), age (adjusted OR 1·3, 95% CI 1·1–1·5 per 10-year age increase) and relation to the index case (adjusted OR 2·6, 95% CI 1·3–5·1, for siblings vs. spouses of index cases). In conclusion, HTLV-1 infection may increase the susceptibility to active TB. In populations where both infections are frequent, such an association could affect the dynamics of TB. PMID:17892632

VERDONCK, K.; GONZÁLEZ, E.; SCHROOTEN, W.; VANHAM, G.; GOTUZZO, E.

2008-01-01

355

Natural Killer cell activation distinguishes M. tuberculosis-mediated Immune reconstitution syndrome (IRIS) from chronic HIV and HIV-MTB co-infection  

PubMed Central

Background With increased access to antiretroviral treatment (ART), Immune Reconstitution Inflammatory Syndrome (IRIS) in Mycobacterium tuberculosis (MTB)-infected populations remains a clinical challenge. We studied a cross-sectional cohort of HIV-infected subjects in Johannesburg (South Africa) to help define the immune correlates that best distinguish IRIS from ongoing MTB cases. Methods We studied HIV+ subjects developing MTB-related unmasking IRIS (u-TB-IRIS) after ART initiation; control groups were HIV subjects and HIV-TB co-infected subjects with comparable ART treatment. Testing was conducted with whole blood-based 4-color flow cytometry and plasma-based Luminex cytokine assessment. Results NK cell activation, C-reactive protein and IL-8 serum concentration were significantly higher in u-TB-IRIS subjects as compared to both control groups. In addition, all MTB co-infected subjects, independent of clinical presentation, had higher neutrophils and T cell activation, together with lower lymphocytes, CD4+ T cell and myeloid DC counts. Using conditional inference tree analysis we show that elevated NK cell activation in combination with lymphocyte count characterizes the immunological profile of u-TB-IRIS. Conclusions Our results support a role for innate immune effectors in the immunopathogenesis of unmasking MTB-related IRIS, and identify new immune parameters defining this pathology. PMID:21826013

Conradie, F.; Foulkes, A.S.; Ive, P.; Yin, X.; Roussos, K.; Glencross, D.K.; Lawrie, D.; Stevens, W.; Montaner, L.J.; Sanne; Azzoni, L.

2011-01-01

356

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

357

Imipenem for Treatment of Tuberculosis in Mice and Humans  

PubMed Central

Chemotherapy of tuberculosis caused by multiple-drug-resistant (MDR) strains is problematic because of choices limited to relatively inefficacious and toxic drugs. Some beta-lactam antibiotics are active against Mycobacterium tuberculosis in vitro. We investigated the efficacy of imipenem in a mouse model of tuberculosis and in humans with MDR tuberculosis. Mice infected with M. tuberculosis strain H37Rv were treated with isoniazid or imipenem. Residual organisms in lung and spleen and survival of imipenem-treated mice were compared to those of untreated or isoniazid-treated mice. Ten patients with MDR tuberculosis also were treated with imipenem in combination with other first- or second-line agents; elimination of M. tuberculosis from sputum samples was measured by quantitative culture. Although it was less effective than isoniazid, imipenem significantly reduced the numbers of M. tuberculosis organisms in lungs and spleens and improved survival of mice. Eight of 10 patients with numerous risk factors for poor outcomes responded to imipenem combination therapy with conversion of cultures to negative. Seven remained culture-negative off of therapy. There were two deaths, one of which was due to active tuberculosis. Organisms were eliminated from the sputa of responders at a rate of 0.35 log10 CFU/ml/week. Relapse upon withdrawal of imipenem and development of resistance to imipenem in a nonresponder suggest that imipenem exerts antimycobacterial activity in humans infected with M. tuberculosis. Imipenem had antimycobacterial activity both in a mouse model and in humans at high risk for failure of treatment for MDR tuberculosis. PMID:15980354

Chambers, Henry F.; Turner, Joan; Schecter, Gisela F.; Kawamura, Masae; Hopewell, Philip C.

2005-01-01

358

Life and death in the granuloma: immunopathology of tuberculosis  

Microsoft Academic Search

During tuberculosis (TB) infection, the granuloma provides the microenvironment in which antigen-specific T cells colocate with and activate infected macrophages to inhibit the growth of Mycobacterium tuberculosis. Although the granuloma is the site for mycobacterial killing, virulent mycobacteria have developed a variety of mechanisms to resist this macrophage-mediated killing. These surviving mycobacteria become dormant, however, if host cellular immunity or

Bernadette M Saunders; Warwick J Britton

2007-01-01

359

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

360

TUBERCULOSIS COMO ENFERMEDAD OCUPACIONAL  

PubMed Central

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

Mendoza-Ticona, Alberto

2014-01-01

361

Role of the Phosphatidylinositol 3Kinase and Mitogen-Activated Protein Kinase Pathways in the Secretion of Tumor Necrosis Factor-? and Interleukin10 by the PPD Antigen of Mycobacterium tuberculosis  

Microsoft Academic Search

Here we investigated the role of the phosphatidylinositol 3-kinase (PI 3-K) and mitogen-activated protein kinase (MAPK) pathways in the secretion of tumor necrosis factor (TNF)-? and interleukin (IL)-10 in human primary monocytes after stimulation with the PPD antigen of Mycobacterium tuberculosis. MAPK [extracellular signal-regulated kinase (ERK) 1\\/2 and p38] and Akt are rapidly phosphorylated in human monocytes stimulated with PPD.

Saet-Byel Jung; Chang-Hwa Song; Chul-Su Yang; Su-Young Kim; Kil-Soo Lee; A-Rum Shin; Ji-Sook Lee; Hae Sung Nam; Hwa-Jung Kim; Jeong-Kyu Park; Tae-Hyun Paik; Eun-Kyeong Jo

2005-01-01

362

Blood cultures for the diagnosis of multidrug-resistant and extensively drug-resistant tuberculosis among HIV-infected patients from rural South Africa: a cross-sectional study  

Microsoft Academic Search

BACKGROUND: The yield of mycobacterial blood cultures for multidrug-resistant (MDR) and extensively drug-resistant tuberculosis (XDR-TB) among drug-resistant TB suspects has not been described. METHODS: We performed a retrospective, cross-sectional analysis to determine the yield of mycobacterial blood cultures for MDR-TB and XDR-TB among patients suspected of drug-resistant TB from rural South Africa. Secondary outcomes included risk factors of Mycobacterium tuberculosis

Scott K Heysell; Tania A Thomas; Neel R Gandhi; Anthony P Moll; François J Eksteen; Yacoob Coovadia; Lynette Roux; Palav Babaria; Umesh Lalloo; Gerald Friedland; Sarita Shah

2010-01-01

363

Diagnostic Accuracy and Clinical Role of Rapid C-Reactive Protein Testing in HIV-infected TB Suspects in South Africa  

PubMed Central

Objective We sought to determine the accuracy and role of rapid C-reactive protein (CRP) testing in HIV-infected tuberculosis suspects. Design We enrolled HIV-infected adults (?18 years) with a cough for ?2 weeks and negative sputum smears for acid-fast bacilli (AFB) in KwaZulu-Natal, South Africa. Participants were evaluated for pulmonary tuberculosis by a nurse with rapid CRP, and independently by a physician with a chest radiograph. Rapid CRP test results were compared to laboratory CRP and sputum sent for confirmation of tuberculosis. Results Among 93 participants, 55 (59%) were female, mean age was 35 years, and median CD4 count was 177/mm3. Forty-five (54%) participants were diagnosed with pulmonary tuberculosis. Diagnostic sensitivity and specificity were 95% (95% CI 74–99%) and 51% (95% CI 35–66%) for rapid CRP > 8 mg/l, 87% (95% CI 73–96%) and 53% (95% CI 38–68%) for nurse assessment, and 69% (95% CI 52–83%) and 76% (95%CI 61–87%) for physician examination. Combining a positive rapid CRP (> 8 mg/l) to nurse and physician assessments decreased post- test probability of pulmonary tuberculosis from 22% to 6% and 32% to 6%, respectively. Conclusion Rapid CRP testing helped exclude pulmonary tuberculosis, and may be a valuable test to assist nurses and physicians in tuberculosis-endemic regions. PMID:24505819

Drain, Paul K.; Mayeza, Lungile; Bartman, Patricia; Hurtado, Rocio; Moodley, Prashini; Varghese, Sunil; Maartens, Gary; Alvarez, Gonzalo G.; Wilson3, Douglas

2014-01-01

364

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

365

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

366

Mycobacterial antigen driven activation of CD14++CD16- monocytes is a predictor of tuberculosis-associated immune reconstitution inflammatory syndrome.  

PubMed

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

2014-10-01

367

TUBERCULOSIS 1 Tuberculosis in Aboriginal Populations in Canada  

E-print Network

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

Peak, Derek

368

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

369

[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

370

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

371

Evaluation of Nested Polymerase Chain Reaction for Rapid Diagnosis of Clinically Suspected Tuberculous Pleurisy  

PubMed Central

Background: Early diagnosis of tuberculosis is important in its control. The conventional techniques like smear microscopy and culture suffer from low sensitivity for diagnosis of extra-pulmonary tuberculosis like Pleural Tuberculosis (PTB) due to paucibacillary nature of the fluid. Polymerase Chain Reaction (PCR) is presently seen as a promising alternative to conventional techniques. In this study we have evaluated IS6110 sequence based nested PCR (nPCR) for the detection of Mycobacterium tuberculosis (MTB) DNA directly from clinical samples. The results of PCR were compared with the results of conventional methods like smear, culture and Adenosine Deaminase (ADA) activity. Material and Methods: A total of 50 pleural fluid samples from the patients with history suggestive of tuberculosis were taken. All the samples were processed for Ziehl-Neelsan (ZN) staining for Acid Fast Bacilli (AFB), culture ADA activity and PCR with primers targeting 123bp fragment of IS6110 of MTB complex. Results: A significant difference was seen in the sensitivities of conventional methods and PCR (p<0.05). Out of these 50 samples 3 were positive by smear, culture was positive in 5 samples, 21 samples showed high ADA activity and 29 were positive by PCR with overall 100% sensitivity of PCR using culture on LJ media as gold standard. Conclusions: The combined analysis of nPCR, ADA activity and other lab investigations can be very useful in the rapid diagnosis in cases of PTB. PMID:24392371

Gill, Manmeet Kaur; Kukreja, Sahiba; Chhabra, Namrata

2013-01-01

372

Quantiferon-TB Gold: Performance for Ruling out Active Tuberculosis in HIV-Infected Adults with High CD4 Count in Côte d'Ivoire, West Africa  

PubMed Central

Objective To assess the performance of QuantiFERON-TB Gold In-Tube (QFT-GIT) test for active tuberculosis (TB) in HIV adults, and its variation over time in patients on antiretroviral therapy (ART) and/or isoniazide preventive therapy (IPT). Methods Transversal study and cohort nested in the Temprano ANRS 12136 randomized controlled trial assessing benefits of initiating ART earlier than currently recommended by World Health Organization, with or without a 6-month IPT. Performance of QFT-GIT for detecting active TB at baseline in the first 50% participants, and 12-month incidence of conversion/reversion in the first 25% participants were assessed. QFT-GIT threshold for positivity was 0.35 IU/ml. Results Among the 975 first participants (median baseline CD4 count 383/mm3, positive QFT-GIT test 35%), 2.7% had active TB at baseline. QFT-GIT sensitivity, specificity, positive and negative predictive value for active TB were 88.0%, 66.6%, 6.5% and 99.5%. For the 444 patients with a second test at 12 months, rates for conversion and reversion were 9.3% and 14%. Reversion was more frequent in patients without ART and younger patients. IPT and early ART were not associated with reversion/conversion. Conclusion A negative QFT-GIT could rule out active TB in HIV-infected adults not severely immunosuppressed, thus avoiding repeated TB testing and accelerating diagnosis and care for other diseases. Trial Registration ClinicalTrials.gov NCT00495651. PMID:25330161

Danel, Christine; Kabran, Mathieu; Inwoley, André; Badje, Anani; Herrmann, Jean Louis; Moh, Raoul; Lecarrou, Jérôme; Gabillard, Delphine; Ntakpe, Jean Baptiste; Deschamps, Nina; Ouattara, Eric; Perronne, Christian; Eholie, Serge; Anglaret, Xavier

2014-01-01

373

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

PubMed

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

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

2015-04-01

374

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

375

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

376

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

PubMed

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

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

2014-10-18

377

Tuberculosis: Latency and Reactivation  

Microsoft Academic Search

Tuberculosis is a major cause of death around the world, with most of the 1.5 million deaths per year attributable to the disease occurring in developing countries. This disease is caused by Mycobacterium tuberculosis, an acid-fast bacillus that is transmitted primarily via the respiratory route. Infection occurs in the lungs, but the organism can seed any organ via hematogenous spread.

JOANNE L. FLYNN; JOHN CHAN

2001-01-01

378

"Tuberculosis Case Management" Training.  

ERIC Educational Resources Information Center

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

Knebel, Elisa; Kolodner, Jennifer

2001-01-01

379

Myths of tuberculosis.  

PubMed

Myths, or misconceptions, of disease and therapy are not confined to patients; they also affect those who practice medicine. Myths are particularly evident in a "dogma" that concerns diagnosis and treatment of tuberculosis. If the elimination of tuberculosis is to be achieved, we must first eliminate the myths, which impede prevention and control of the disease. PMID:1645402

Lanphear, B P; Snider, D E

1991-04-01

380

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

381

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

382

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

383

M. tuberculosis in Lymph Node Biopsy Paraffin-Embedded Sections  

PubMed Central

Background. Tuberculosis lymphadenitis is one of the most common forms of all extrapulmonary tuberculosis. Objective. To evaluate the magnitude of M. tuberculosis from lymph node biopsy paraffin-embedded sections among suspected patients visiting the Jimma University Specialized Hospital. Method. A cross-sectional study design of histological examination among lymph node biopsy paraffin-embedded sections by Ziehl-Neelsen and hematoxylin/eosin staining technique was conducted from December, 2009, to October, 2010, at the Department of Medical Laboratory Science and Pathology. Result. Histopathological examination of the specimens by hematoxylin and eosin staining technique revealed the presence of granulomas. But for the caseation and necrosis they were present in 85% cases of nodal tissue biopsies. From those, 56.7% were from females. The presence of acid-fast bacilli was microscopically confirmed by ZN staining in 37 (61.7%) of the nodal tissue biopsies. Conclusion and Recommendation. Tuberculosis lymphadenitis is significantly more common in females. Hence, attention should be given for control and prevention of extrapulmonary tuberculosis. PMID:22567262

Eshete, Abdurehman; Zeyinudin, Ahmed; Ali, Solomon; Abera, Solomon; Mohammed, Mona

2011-01-01

384

Tuberculosis burden in an urban population: a cross sectional tuberculosis survey from Guinea Bissau  

PubMed Central

Background Little is known about the prevalence of pulmonary tuberculosis (TB) in low income countries. We conducted a cross sectional survey for pulmonary TB and TB symptoms in Bissau, Guinea-Bissau, in an urban cohort with known HIV prevalence. TB surveillance in the area is routinely based on passive case finding. Methods Two cohorts were selected based on a previous HIV survey, but only 52.5% of those enrolled in the adult cohort had participated in the HIV survey. One cohort included all adults living in 384 randomly selected houses; in this cohort 8% (135/1687) were HIV infected. The other included individuals 50 years or older from all other houses in the study area; of these 11% (62/571) were HIV infected. Symptom screening was done through household visits using a standardised questionnaire. TB suspects were investigated with sputum smear microscopy and X-ray. Results In the adult cohort, we found 4 cases among 2989 individuals screened, giving a total TB prevalence of 134/100,000 (95% CI 36-342/100,000). In the >50 years cohort, we found 4 cases among 571 individuals screened, giving a total prevalence of 701/100,000 (191-1784/100.000). Two of the eight detected TB cases were unknown by the TB program. Of the total TB cases five were HIV uninfected while three had unknown HIV status. The prevalence of TB symptoms was 2.1% (63/2989) and 10.3% (59/571) in the two cohorts respectively. Conclusions In conclusion we found a moderately high prevalence of pulmonary TB and TB symptoms in the general population, higher among elderly individuals. By active case finding unknown cases were detected. Better awareness of TB and its symptoms needs to be promoted in low income settings. PMID:20398388

2010-01-01

385

Phytochemical Analyses and Activity of Herbal Medicinal Plants of North- East India for Anti-Diabetic, Anti-Cancer and Anti-Tuberculosis and their Docking Studies.  

PubMed

The traditional knowledge of medicinal plants that are in use by the indigenous Jaintia tribes residing in few isolated pockets of North-East India is documented here. The present study was carried out through the personal discussion with the president of the Jaintia Indigenous Herbal Medicine Association, Dr.H.Carehome Pakyntein from Jowai, Meghalaya. The plants being used generation after generation by his family of herbalists to cure ailments like tuberculosis, cancer and diabetes were selected for the present study. In order to scientifically validate the use of these selected plants for the cure of selected diseases, phytochemical analyses, characterization and molecular docking studies of some of the selected compounds from these plants have been carried out. The compounds 2-hydroxy-4-methoxy- Benzaldehyde from methanolic extract of Strophanthus Wallichii and DL tetrahydropalmatine from Stephania Hernandifolia have been confirmed after determining their molecular structures, justifying the activity of these two plants against TB and cancer, respectively. The present study covers the potentials of some of the medicinal plants of North east India in curing common diseases due to which millions of people suffer and die. The presence of certain compounds in these plants related to the cure of the diseases deserves further studies. PMID:25579573

Suhitha, Sivasubramanian; Devi, Seenivasan Karthiga; Gunasekaran, Krishnasamy; Pakyntein, H Carehome; Bhattacharjee, Atanu; Velmurugan, Devadasan

2015-01-01

386

Characterization of active site structure in CYP121. A cytochrome P450 essential for viability of Mycobacterium tuberculosis H37Rv.  

PubMed

Mycobacterium tuberculosis (Mtb) cytochrome P450 gene CYP121 is shown to be essential for viability of the bacterium in vitro by gene knock-out with complementation. Production of CYP121 protein in Mtb cells is demonstrated. Minimum inhibitory concentration values for azole drugs against Mtb H37Rv were determined, the rank order of which correlated well with Kd values for their binding to CYP121. Solution-state spectroscopic, kinetic, and thermodynamic studies and crystal structure determination for a series of CYP121 active site mutants provide further insights into structure and biophysical features of the enzyme. Pro346 was shown to control heme cofactor conformation, whereas Arg386 is a critical determinant of heme potential, with an unprecedented 280-mV increase in heme iron redox potential in a R386L mutant. A homologous Mtb redox partner system was reconstituted and transported electrons faster to CYP121 R386L than to wild type CYP121. Heme potential was not perturbed in a F338H mutant, suggesting that a proposed P450 superfamily-wide role for the phylogenetically conserved phenylalanine in heme thermodynamic regulation is unlikely. Collectively, data point to an important cellular role for CYP121 and highlight its potential as a novel Mtb drug target. PMID:18818197

McLean, Kirsty J; Carroll, Paul; Lewis, D Geraint; Dunford, Adrian J; Seward, Harriet E; Neeli, Rajasekhar; Cheesman, Myles R; Marsollier, Laurent; Douglas, Philip; Smith, W Ewen; Rosenkrands, Ida; Cole, Stewart T; Leys, David; Parish, Tanya; Munro, Andrew W

2008-11-28

387

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

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

2014-09-01

388

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

389

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

390

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

PubMed Central

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

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

2011-01-01

391

Eicosanoid pathways regulate adaptive immunity to Mycobacterium tuberculosis  

PubMed Central

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

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

2011-01-01

392

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