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Risk factors for mortality in smear-negative tuberculosis suspects: a cohort study in Harare, Zimbabwe  

PubMed Central

SUMMARY OBJECTIVE To investigate mortality rates and risk factors for death among smear-negative tuberculosis (TB) suspects. DESIGN Cohort study nested within a cluster-randomised trial of community-based active case finding. Smear-negative TB suspects were followed for 12 months, with home tracing where necessary. We calculated mortality rates and used regression analysis to investigate the relationship between clinical characteristics and death. RESULTS Between February 2006 and June 2007, 1195 smear-negative TB suspects were followed for 1136.8 person-years. Human immunodeficiency virus (HIV) prevalence was 63.3%. During follow-up, 139 participants died (11.6%) and mortality rates remained high throughout; 119 (16.5%) HIV-positive individuals and 13 (3.1%) HIV-negative individuals died (HR = 5.8, 95%CI 3.3–10.4, P < 0.001). Advanced immunosuppression was the main risk factor for death among HIV-positive participants, with CD4 count < 50 cells/?l associated with a 13-fold increased risk of death. Anti-retroviral treatment (ART) was initiated by only 106 (14.7%), with long delays in accessing care. CONCLUSION HIV-positive smear-negative TB suspects are at high and sustained risk of death. Current guidelines for the management of HIV-infected TB suspects are limited, and this study adds to evidence that specific policies are required to promote earlier HIV and TB diagnosis and reduce delays in ART initiation.

MacPherson, P.; Dimairo, M.; Bandason, T.; Zezai, A.; Munyati, S. S.; Butterworth, A. E.; Mungofa, S.; Rusakaniko, S.; Fielding, K.; Mason, P. R.; Corbett, E. L.



Investigation Outcomes of Tuberculosis Suspects in the Health Centers of Addis Ababa, Ethiopia  

Microsoft Academic Search

BackgroundLittle is known about the prevalence of tuberculosis (TB) and HIV among TB suspects in primary health care units in Ethiopia.MethodsIn the period of February to March, 2009, a cross sectional survey was done in 27 health centers of Addis Ababa to assess the prevalence of TB and HIV among TB suspects who have > = 2 weeks symptoms of

Amare Deribew; Nebiyu Negussu; Zenebe Melaku; Kebede Deribe; Cesar V. Munayco



[Esophageal tuberculosis].  


Primary esophageal tuberculosis is virtually non-existent and there are few cases described of secondary esophageal tuberculosis. Esophageal tuberculosis should be suspected in patients with dysphagia, positive test results for tuberculin, active pulmonary disease or mediastinal adenopathies. Endoscopic or x-ray images could be indistinguishable from esophageal carcinomas, hence a diagnosis can prevent wrong treatments. Confirming the diagnosis requires isolation of tuberculosis bacillus. Treatment for a patient with esophageal tuberculosis is standard therapy. Key words: Tuberculosis, esophagus. PMID:16865167

Baños, Ramón; Serrano, Andrés; Alberca, Fernando; Alajarín, María; Albaladejo, Aquilino; Vargas, Angel; Molina, Joaquín


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

PubMed Central

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

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



Mycobacterium tuberculosis Prevents Inflammasome Activation  

PubMed Central

SUMMARY Mycobacterium tuberculosis parasitizes host macrophages and subverts host innate and adaptive immunity. A number of cytokines elicited by the tubercle bacilli have been recognized as mediators of mycobacterial clearance or pathology in tuberculosis. Surprisingly, interleukin-1? (IL-1?), a major pro-inflammatory cytokine activated by processing upon assembly of a specialized protein complex termed the inflammasome, has not been implicated in host-pathogen interactions in tuberculosis. Here, we show that M. tuberculosis prevents inflammasome activation and IL-1? processing, and that a functional M. tuberculosis zmp1 gene is required for this process. Infection of macrophages with the zmp1 null M. tuberculosis triggered activation of caspase-1/IL-1? inflammasome, resulting in increased secretion of IL-1?, enhanced mycobacterial phagosome maturation into phagolysosomes, improved mycobacterial clearance by macrophages, and lower bacterial burden in the lungs of aerosol-infected mice. Thus, we uncovered the previously masked role for IL-1? in control of M. tuberculosis, and the existence of a mycobacterial system that prevents IL-1?/inflammasome activation.

Master, Sharon S.; Davis, Alexander. S.; Rampini, Silvana K.; Keller, Christine; Ehlers, Stefan; Springer, Burkhardt; Sander, Peter; Deretic, Vojo



Sex disparities in tuberculosis suspect evaluation: a cross-sectional analysis in rural Uganda  

PubMed Central

SUMMARY SETTING Six primary health care centers in rural Uganda. OBJECTIVE To compare the quality of tuberculosis (TB) evaluation for men and women presenting to primary health care facilities in high-burden settings. DESIGN Cross-sectional study using indicators derived from the International Standards of Tuberculosis Care (ISTC) to compare the quality of TB evaluation services provided to men and women. RESULTS Of 161 230 patient visits between January 2009 and December 2010, 112 329 (69.7%) were women. We considered 3308 (2.1%) patients with cough ? 2 weeks as TB suspects, of whom 1871 (56.6%) were women. Female TB suspects were less likely to be referred for sputum smear examination (45.9% vs. 61.6%, P < 0.001), to complete sputum smear examination if referred (73.7% vs. 78.3%, P = 0.024) and to receive comprehensive evaluation and care as defined by the ISTC (33.0% vs. 45.6%, P < 0.001). After adjusting for age, clinic site and visit date, women remained less likely to be referred for sputum smear examination (risk ratio [RR] 0.81, 95%CI 0.74–0.89, P < 0.001) and to receive ISTC-recommended care (RR 0.79, 95%CI 0.72–0.86, P < 0.001). CONCLUSION Strategies to ensure that women receive appropriate TB evaluation could provide a valuable opportunity for increasing case detection while also promoting equitable and universal access to care.

Miller, C. R.; Davis, J. L.; Katamba, A.; Sserwanga, A.; Kakeeto, S.; Kizito, F.; Cattamanchi, A.



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

PubMed Central

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

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



Test Characteristics of Urinary Lipoarabinomannan and Predictors of Mortality among Hospitalized HIV-Infected Tuberculosis Suspects in Tanzania  

PubMed Central

Background Tuberculosis is the most common cause of death among patients with HIV infection living in tuberculosis endemic countries, but many cases are not diagnosed pre-mortem. We assessed the test characteristics of urinary lipoarabinomannan (LAM) and predictors of mortality among HIV-associated tuberculosis suspects in Tanzania. Methods We prospectively enrolled hospitalized HIV-infected patients in Dar es Salaam, with ?2 weeks of cough or fever, or weight loss. Subjects gave 2 mLs of urine to test for LAM using a commercially available ELISA, ?2 sputum specimens for concentrated AFB smear and solid media culture, and 40 mLs of blood for culture. Results Among 212 evaluable subjects, 143 (68%) were female; mean age was 36 years; and the median CD4 count 86 cells/mm3. 69 subjects (33%) had culture confirmation of tuberculosis and 65 (31%) were LAM positive. For 69 cases of sputum or blood culture-confirmed tuberculosis, LAM sensitivity was 65% and specificity 86% compared to 36% and 98% for sputum smear. LAM test characteristics were not different in patients with bacteremia but showed higher sensitivity and lower specificity with decreasing CD4 cell count. Two month mortality was 64 (53%) of 121 with outcomes available. In multivariate analysis there was significant association of mortality with absence of anti-retroviral therapy (p?=?0.004) and a trend toward association with a positive urine LAM (p?=?0.16). Among culture-negative patients mortality was 9 (75%) of 12 in LAM positive patients and 27 (38%) of 71 in LAM negative patients (p?=?0.02). Conclusions Urine LAM is more sensitive than sputum smear and has utility for the rapid diagnosis of culture-confirmed tuberculosis in this high-risk population. Mortality data raise the possibility that urine LAM may also be a marker for culture-negative tuberculosis.

Teixeira, Pedro; Matee, Mecky; Bakari, Muhammad; Lahey, Timothy; von Reyn, Fordham



Patients in whom active tuberculosis was diagnosed after admission to a Japanese university hospital from 2005 through 2007.  


To identify problems in early diagnosis of tuberculosis and to design countermeasures against the disease, we examined the status of active tuberculosis among patients admitted to a university hospital that did not have an isolation ward for tuberculosis. Between 2005 and 2007, we analyzed demographic characteristics, disease type, chest radiologic findings, and the process leading to diagnosis. Active tuberculosis was diagnosed after admission in 55 patients (34 males and 21 females): pulmonary tuberculosis, 26; tuberculous pleuritis, 13; tuberculous meningitis, 6; miliary tuberculosis, 4; tuberculous pericarditis, 3; lymph-node tuberculosis, 2; and tracheal and bronchial tuberculosis, 1. Although radiographic examinations provided abundant information, chest radiography showed normal findings in 7 patients (12.7%). Computed tomographic scanning was useful for detailed evaluation of abnormalities. Twenty patients (36.4%) were given diagnoses at departments other than ours (Department of Pulmonary Medicine). Numbers of days between hospital admission and diagnosis of tuberculosis (50th percentile/80th percentile) were 8.0/37.8 for miliary tuberculosis, 8.0/8.0 for tracheal and bronchial tuberculosis, 7.5/17.8 for tuberculous pleuritis, 7.0/8.8 for tuberculous pericarditis, 6.0/15.6 for pulmonary tuberculosis, 3.5/4.4 for lymph-node tuberculosis, and 1/1 for tuberculous meningitis. Early diagnosis of tuberculosis requires adherence to the following precautions. Tuberculosis should be suspected in any patient with respiratory symptoms. Sputum tests for acid-fast bacteria should be performed at least three times initially. If findings on chest X-ray films are equivocal, high-resolution computed tomography should be performed to confirm details of shadows and to detect minimal pulmonary shadows or cavitary lesions. Physicians from all specialties should be repeatedly informed about the risk of tuberculosis and should include tuberculosis in the differential diagnosis in patients suspected to have pulmonary diseases. PMID:21476129

Fukushima, Yasutsugu; Shiobara, Kanae; Shiobara, Taichi; Tatewaki, Masamitsu; Anzai, Makiko; Fukushima, Fumiya; Yamada, Issei; Hirata, Hirokuni; Sugiyama, Kumiya; Fukuda, Takeshi



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

PubMed Central

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.

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



Application of cetylpyridinium chloride and sodium chloride decontamination method for recovery of Mycobacterium tuberculosis from clinically suspected cases of pulmonary tuberculosis.  


The study was designed to compare the efficacy of cetylpyridinium chloride (CPC) and sodium chloride (NaCl) decontamination method with N-acetyl L-Cystine (NALC) and sodium hydroxide (NaOH) decontamination (the reference method) method for the recovery of Mycobacterium tuberculosis (MTB) from clinically suspected cases of pulmonary tuberculosis. To evaluate CPC-NaCl and NALC-NaOH decontamination methods, sputum specimens (n = 796) were studied (culturing on Löwenstein-Jensen medium), and the performances were compared. The CPC-NaCl decontamination method demonstrated a sensitivity, specificity, negative predictive value, and positive predictive value of 97.99%, 87.53%, 70.19%, and 99.32%, respectively, when compared to NALC-NaOH decontamination method. In summary, CPC-NaCl decontamination method effectively detected significantly higher number of MTB cases (n = 208) than NALC-NaOH decontamination method (n = 149) particularly in sputum with scanty bacilli and smear-negative cases, indicating the potential of CPC-NaCl decontamination method to preserve paucibacillary cases more efficient than NALC-NaOH decontamination method. PMID:23928270

Shinu, Pottathil; Singh, Varsha; Nair, Anroop; Mehrishi, Priya; Mehta, Sonia; Joshi, Ekta



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

PubMed Central

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

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





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


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


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

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



Preliminary investigation of bovine tuberculosis in suspected beef from a metropolitan abattoir in Ghana with Ziehl-Neelsen microscopy.  


Bovine tuberculosis is an important zoonotic disease transmissible through aerosols inhalation and the ingestion of contaminated milk and meat from cattle. Abattoirs in Ghana mainly depend on post-mortem examinations as means of diagnosing the presence of mycobacterium in meat (beef). A Ziehl-Neelsen microscopy was used to investigate the presence of Mycobacterium bovis as Acid-Fast Bacilli (AFBs) in beef samples from the Kumasi Metropolitan abattoir; thereby vetting post-mortem examinations at the abattoir. Lesioned lung tissues and calcified or puss-filled thoracic lymph nodes were collected at post-mortem as directed by an expert veterinarian. A total of 159 samples from 130 cattle (bulls and cows) were used in this study from April to July 2006. Ninety-five (i.e., 73.1%) of the 130 cattle sampled were positive for AFBs, whilst the remaining thirty-five (26.9%) were negative. Out of the total 159 individual samples specimen collected, 114 (71.7%) were found with AFBs. A total of 64 lung tissues and 95 lymph nodes were collected, respectively. Interestingly, 70.3% of the lung tissues were AFB-positive with 69 (72.6%) out of the 95 lymph nodes, also being positive. The ZN microscopy was effective in detecting the presence of mycobacteria, as 73.1% of the suspected samples were AFB-positive. It presupposes that, abattoir post-mortem examinations were also efficient however; the lapses of non-detection of asymptomatic carcasses could also pose a serious health risk to consumers. Also, lack of a functional on-site laboratory and a practical monitoring system was found to be unfavourable to the maintenance of meat quality. Detailed laboratory examinations (such as culture, PCR and other biochemical tests) to augment ZN microscopy is recommended for thorough detection of bovine tuberculosis. PMID:19943459

Adu-Bobi, N A K; Mak-Mensah, E E; Achel, D G; Gyamfi, O K; Bedzra, K D



Changing patterns in pulmonary tuberculosis  

SciTech Connect

The authors reviewed the initial chest roentgenograms of 182 consecutive adult patients with proven active tuberculosis. Less than 50% of all cases were known or suspected at the time of initial presentation. There is a low degree of correlation between radiologically discernible active pulmonary tuberculosis and extrapulmonary tuberculosis. A high percentage of cases represent uncommon pulmonary locations. The frequency of occurrence of four common pulmonary patterns is presented. 21 references, 4 figures, 5 tables.

Tytle, T.L.; Johnson, T.H.



38 CFR 3.374 - Effect of diagnosis of active tuberculosis.  

Code of Federal Regulations, 2013 CFR

...Service department diagnosis of active pulmonary tuberculosis will be accepted unless...Affairs diagnosis. Diagnosis of active pulmonary tuberculosis by the medical authorities...physician's diagnosis. Diagnosis of active pulmonary tuberculosis by private...



Burden of tuberculosis in Kampala, Uganda  

Microsoft Academic Search

Objective To determine the prevalence and incidence of tuberculosis in one of Uganda's poor peri-urban areas. Methods Multi-stage sampling was used to select a sample of households whose members were evaluated for presence of signs and\\/or symptoms of active tuberculosis; history of tuberculosis treatment; and relevant demographic, socioeconomic, and household environment characteristics. Patients with suspected tuberculosis underwent standardized evaluation for

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



Evaluation of a directly observed six months fully intermittent treatment regimen for tuberculosis in patients suspected of poor compliance.  

PubMed Central

BACKGROUND: Although a priority for tuberculosis control is to achieve the maximum cure rate, compliance with chemotherapy in specific high risk groups (homeless, intravenous drug abusers, chronic alcoholics) is usually poor. METHODS: From January 1990 to December 1994 102 patients with tuberculosis (96 pulmonary, six extrapulmonary) who were poorly compliant with treatment were treated with a six month fully intermittent (twice weekly) directly observed regimen. They comprised 71 homeless subjects, 50 chronic alcoholics, 23 intravenous drug abusers, nine infected with HIV, and 11 who had previously abandoned a daily antituberculosis regimen; 53 had more than one of these risk factors. Treatment included isoniazid and rifampicin for six months and pyrazinamide during the first two months. Patients who failed to take their medication on two consecutive occasions were actively sought by telephone or by personal search. RESULTS: After two months of treatment 95 of the 102 patients had taken their medication regularly and 90 of them had negative cultures. Four of the remaining patients had negative cultures after three months. At the end of the six months 87 patients had completed treatment and were considered cured. Only 15 patients abandoned the treatment (13 of whom had more than one risk factor). Only three relapses occurred in the 102 patients at one year follow up and in the 88 patients followed for two years. Two patients required a change of treatment due to major side effects. Although intravenous drug abuse was the only predictor of non-compliance in the multivariate analysis, if the available variables in the second month of treatment were analysed, current poor compliance and abandonment of treatment in the past were found to be significantly associated with non-compliance. CONCLUSIONS: This study shows the efficacy of this intermittent regimen and the effectiveness of a directly observed treatment programme.

Caminero, J A; Pavon, J M; Rodriguez de Castro, F; Diaz, F; Julia, G; Cayla, J A; Cabrera, P



Total hip arthroplasty for active tuberculosis of the hip  

Microsoft Academic Search

Total hip arthroplasty (THA) has been used as a successful form of treatment in patients with long-standing tuberculosis,\\u000a but it is unclear whether THA should be performed in patients with current infection. We performed THA in six patients with\\u000a advanced active tuberculosis of the hip from 2002 to 2006. Tuberculosis was confirmed in all cases by histological examination.\\u000a All patients

Yongqing Wang; Jingsheng Wang; Zhanmin Xu; Yuan Li; Huimin Wang



Proteomic analysis of sputum in patients with active pulmonary tuberculosis.  


The protein composition of sputum most faithfully reflects the state of the lungs. The aim of this study was to determine whether relative qualitative and quantitative differences in protein expression of sputum could be related to active pulmonary tuberculosis. Sputum samples were collected from 65 patients with active pulmonary tuberculosis and 38 healthy controls. Comprehensive proteomic approaches were used to profile the proteome changes of host sputum in response to Mycobacterium tuberculosis infection using two-dimensional electrophoresis in combination with matrix-assisted laser desorption ionization time-of-flight/time-of-flight mass spectrometry. Mascot software was used to identify proteins from protein databases. Enzyme-linked immunosorbent assay was used to confirm the proteomic results. A total of 62 differentially expressed proteins were identified, among which, 15 proteins were up-regulated and 47 proteins were down-regulated in the tuberculosis sputum compared with the controls. Bacterial protein UqhC was the most increased protein, whereas serum albumin was the most decreased protein in the tuberculosis sputum compared with the controls. The enzyme-linked immunosorbent assay analysis was consistent with proteomic data. Bioinformatics analysis suggested that multiple host cell pathways were involved in the tuberculosis infection processes, including acute phase response, signal transduction, cytoskeleton structure, immune response and so on. In all, for the first time, our results revealed that a number of proteins were differentially expressed during active pulmonary tuberculosis infection. These data will provide valuable clues for further investigation of tuberculosis pathogenesis and biomarkers for detection of active pulmonary tuberculosis infection. PMID:22486982

Fu, Y R; Yi, Z J; Guan, S Z; Zhang, S Y; Li, M



Association between Tobacco Smoking and Active Tuberculosis in Taiwan  

Microsoft Academic Search

Rationale: Previous case-control studies and a small number of cohort studies in high-risk populations have found an association between tobacco and active tuberculosis, but no cohort studies have been conducted in the general population on this association to date. Objectives: To investigate the association between tobacco smoking and active tuberculosis in a cohort of a general population. Methods: 17,699 participants

Hsien-Ho Lin; Majid Ezzati; Hsing-Yi Chang; Megan Murray



Activation of NKT Cells Protects Mice from Tuberculosis  

Microsoft Academic Search

non-MHC-restricted T cells is still not clearly delineated. We have previously reported that CD1d\\/ mice do not differ from CD1d\\/ mice in their survival following infection with M. tuberculosis. We now show that, although CD1d-restricted NKT cells are not required for optimum immunity to M. tuberculosis, specific activation of NKT cells by the CD1d ligand -galactosylceramide protects susceptible mice from

Alissa Chackerian; Jen Alt; Vaji Perera; Samuel M. Behar



Comparison of Sensitivity of QuantiFERON-TB Gold Test and Tuberculin Skin Test in Active Pulmonary Tuberculosis.  


Objective: To compare the sensitivity of tuberculin skin test (TST) and quantiFERON-TB gold test (QFT-G) in active pulmonary tuberculosis. Study Design: Analytical study. Place and Duration of Study: Department of Pulmonology, Fauji Foundation Hospital, Rawalpindi, from July 2011 to January 2012. Methodology: QuantiFERON-TB gold test (QFT-G) was evaluated and compared it with tuberculin skin test (TST) in 50 cases of active pulmonary tuberculosis, in whom tuberculous infection was suspected on clinical, radiological and microbiological grounds. Sensitivity was determined against postive growth for Mycobacterium tuberculosis. Results: Out of 50 cases, 43 were females and 7 were males. The mean age was 41.84 ± 19.03 years. Sensitivity of QFT-G was 80% while that of TST was 28%. Conclusion: QFT-G has much higher sensitivity than TST for active pulmonary tuberculosis. It is unaffected by prior BCG administration and prior exposure to atypical mycobacteria. A positive QFT-G result can be an adjunct to diagnosis in patients having clinical and radiological data compatible with pulmonary tuberculosis. PMID:24034187

Khalil, Kanwal Fatima; Ambreen, Asma; Butt, Tariq



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



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



Immunostimulatory Activity of Major Membrane Protein II from Mycobacterium tuberculosis? ‡  

PubMed Central

Previously, we observed that both major membrane protein II of Mycobacterium leprae (MMP-ML) and its fusion with M. bovis BCG (BCG)-derived heat shock protein 70 (HSP70) (Fusion-ML) are immunogenic and that recombinant BCG secreting either of these proteins effectively inhibits the multiplication of M. leprae in mice. Here, we purified M. tuberculosis-derived major membrane protein II (MMP-MTB) and its fusion with HSP70 (Fusion-MTB) in a lipopolysaccharide-free condition and evaluated their immunostimulatory abilities. Both MMP-MTB and Fusion-MTB activated monocyte-derived dendritic cells (DC) in terms of phenotype and interleukin-12 (IL-12) production, but Fusion-MTB more efficiently activated them than MMP-MTB did. The IL-12 production was a consequence of the ligation of those recombinant proteins with Toll-like receptor 2. The M. tuberculosis-derived and M. leprae-derived recombinant proteins activated naïve T cells of both CD4 and CD8 subsets, but M. tuberculosis-derived proteins were superior to M. leprae-derived proteins and fusion proteins were superior to MMP, regardless of the origin of the protein. Memory-type CD4+ T cells obtained from BCG-vaccinated healthy individuals seem to be primed with MMP-MTB by the vaccination, and both M. tuberculosis-derived recombinant proteins produced perforin-producing CD8+ T cells from memory-type CD8+ T cells. Further, infection of DC and macrophages with M. tuberculosis H37Ra and H37Rv induced the expression of MMP on their surface. These results indicate that M. tuberculosis-derived MMP, as a sole protein or as part of a fusion protein, may be useful for developing new vaccinating agents against tuberculosis.

Tsukamoto, Yumiko; Endoh, Masumi; Mukai, Tetsu; Maeda, Yumi; Tamura, Toshiki; Kai, Masanori; Makino, Masahiko



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

Code of Federal Regulations, 2010 CFR

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



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

Code of Federal Regulations, 2010 CFR

...2009-07-01 2009-07-01 false Pulmonary tuberculosis shown by X-ray in active...Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active...grant of direct service connection for pulmonary tuberculosis. When under...



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

Code of Federal Regulations, 2013 CFR

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



Risk Factors for Tuberculosis After Highly Active Antiretroviral Therapy Initiation in the United States and Canada: Implications for Tuberculosis Screening  

PubMed Central

Background.?Screening for tuberculosis prior to highly active antiretroviral therapy (HAART) initiation is not routinely performed in low-incidence settings. Identifying factors associated with developing tuberculosis after HAART initiation could focus screening efforts. Methods.?Sixteen cohorts in the United States and Canada contributed data on persons infected with human immunodeficiency virus (HIV) who initiated HAART December 1995–August 2009. Parametric survival models identified factors associated with tuberculosis occurrence. Results.?Of 37845 persons in the study, 145 were diagnosed with tuberculosis after HAART initiation. Tuberculosis risk was highest in the first 3 months of HAART (20 cases; 215 cases per 100000 person-years; 95% confidence interval [CI]: 131–333 per 100000 person-years). In a multivariate Weibull proportional hazards model, baseline CD4+ lymphocyte count <200, black race, other nonwhite race, Hispanic ethnicity, and history of injection drug use were independently associated with tuberculosis risk. In addition, in a piece-wise Weibull model, increased baseline HIV-1 RNA was associated with increased tuberculosis risk in the first 3 months; male sex tended to be associated with increased risk. Conclusions.?Screening for active tuberculosis prior to HAART initiation should be targeted to persons with baseline CD4 <200 lymphocytes/mm3 or increased HIV-1 RNA, persons of nonwhite race or Hispanic ethnicity, history of injection drug use, and possibly male sex.

Lau, Bryan; Zhang, Jinbing; Freeman, Aimee; Bosch, Ronald J.; Brooks, John T.; Deeks, Steven G.; French, Audrey; Gange, Stephen; Gebo, Kelly A.; John Gill, M.; Horberg, Michael A.; Jacobson, Lisa P.; Kirk, Gregory D.; Kitahata, Mari M.; Klein, Marina B.; Martin, Jeffrey N.; Rodriguez, Benigno; Silverberg, Michael J.; Willig, James H.; Eron, Joseph J.; Goedert, James J.; Hogg, Robert S.; Justice, Amy C.; McKaig, Rosemary G.; Napravnik, Sonia; Thorne, Jennifer; Moore, Richard D.



Soluble immunological markers of disease activity in tuberculosis  

Microsoft Academic Search

The obtention of a microbiologically confirmed diag- nosis of tuberculosis (TB), assessment of the extent and intensity of disease activity, and follow-up of the patient response to treatment are all encumbered by our still lim- ited ability to quantify the infectious load using the micro- biological tools available in current practice. In this context, a number of attempts have been

C. Saltini; V. Colizzi



Factors influencing quality of life in patients with active tuberculosis  

Microsoft Academic Search

BACKGROUND: With effective treatment strategies, the focus of tuberculosis (TB) management has shifted from the prevention of mortality to the avoidance of morbidity. As such, there should be an increased focus on quality of life (QoL) experienced by individuals being treated for TB. The objective of our study was to identify areas of QoL that are affected by active TB

Carlo A Marra; Fawziah Marra; Victoria C Cox; Anita Palepu; J Mark Fitzgerald



Tuberculosis (TB): Treatment  


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


Progression to active tuberculosis, but not transmission, varies by M. tuberculosis lineage in The Gambia  

PubMed Central

Considerable variability exists in the outcome of M. tuberculosis infection. We hypothesized that M. africanum was less likely than M. tuberculosis to transmit and progress to tuberculosis disease. In a cohort study of tuberculosis patients and their household contacts in the Gambia, we categorized 1,808 HIV negative tuberculosis contacts according to exposure to M. tuberculosis or to M. africanum. A positive skin test indicated transmission and development of tuberculosis during 2 years of follow-up indicated progression to disease. Transmission was similar, but progression to disease was significantly lower in contacts exposed to M. africanum than to M. tuberculosis (1.0% vs 2.9%; Hazard Ratio (HR) 3.1, 95% CI 1.1–8.7). Within M. tuberculosis sensu stricto, contacts exposed to a Beijing family strain were most likely to progress to disease (5.6%; HR 6.7 (2.0–22) relative to M. africanum). M. africanum and M. tuberculosis transmit equally well to household contacts, but contacts exposed to M. africanum are less likely to progress to tuberculosis disease than those exposed to M. tuberculosis. The variable rate of progression by lineage suggests that TB variability matters in clinical settings and should be taken into account in studies evaluating tuberculosis vaccines and treatment regimens for latent tuberculosis infection.

de Jong, Bouke C.; Hill, Philip C.; Aiken, Alex; Awine, Timothy; Antonio, Martin; Adetifa, Ifedayo M.; Jackson-Sillah, Dolly J.; Fox, Annette; DeRiemer, Kathryn; Gagneux, Sebastien; Borgdorff, Martien W.; McAdam, Keith P.W.J.; Corrah, Tumani; Small, Peter M.; Adegbola, Richard A.



[Interleukin-2 (IL-2) in active pulmonary tuberculosis].  


To clarify the precise of cellular immunity mechanism in pulmonary tuberculosis, we investigated the amount of IL-2 in patients with untreated active pulmonary tuberculosis. When serum adenosine deaminase (ADA) activity was examined using enzyme assay, an abnormally high level was observed in all patients (29.0 + 11.6 IU/ml, mean + SD; 4.5-17.8, normal range). Likewise, the level of serum-soluble interleukin-2 receptor (IL-2R) measured by ELISA showed abnormal high level in all patients (844.3 + 584.8 IU/ml; 80-300, normal range). When stimulated using PHA, the peripheral lymphocyte's ability to produce IL-2 revealed no difference between control subjects and patients. It was, however, noted that the lymphocytes of the patients significantly suppressed IL-2 responsiveness when compared to the control subjects (P less than 0.05). The serum IL-2 concentration measured using RIA could not be detected in any of the patients as was the same for control subject. All of the above mentioned results suggest that T-cell activation which caused increment in serum ADA activity and soluble IL-2R occurred in active pulmonary tuberculosis. The suppressed IL-2 responsiveness in the peripheral lymphocytes of patients proposes the possibility of soluble IL-2R reduction by the negative feedback mechanism in IL-2-sensitive lymphocytes. PMID:1766152

Ida, T; Taniai, S; Makiguchi, K; Otomo, N; Taniguchi, K; Miyazato, I; Chida, M; Ichioka, M; Marumo, F



Changes in Serum Cytokine Levels in Active Tuberculosis With Treatment  

PubMed Central

It has been reported that IFN-?, TNF-?, and IL-12 stimulate, and that IL-10, TGF-?, and IL-4 suppress the protective immune response against tuberculosis. We aim to evaluate changes in the serum levels of pro and antiinflammatory cytokines in active pulmonary tuberculosis (APTB) and the possible effects of treatment on these changes. Serum IL-12p40, IL-4, IL-10, TNF-?, IFN-?, and TGF-?1 levels were determined in 20 APTB cases (group 1) before and 2, 4, and 6 months after therapy. The same parameters were also determined in 9 inactive pulmonary tuberculosis (IPTB) cases (group 2) and 9 healthy controls (HC, group 3). Before treatment, the mean serum IFN-?, TNF-?, and IL-10 levels in group 1 were statistically higher than those in group 2 (P = .001, P = .024, P = .016, resp) or group 3 (P = .003, P = .002, P = .011, resp). The levels in group 1 decreased significantly after treatment (P = .001 for IFN-?, P = .004 for TNF-?, P = .000 for IL-10). The serum levels of IL-12p40 were significantly higher in group 1 than in group 3 (P = .012) and decreased insignificantly after treatment. There was no difference in serum IL-4 and TGF-?1 levels among the groups (P > .05). Because the serum IL-12p40, IL-10, TNF-?, and IFN-? levels were high in APTB, we believe that these cytokines have important roles in the immune response to Mycobacterium tuberculosis (M tuberculosis). These parameters could be used in follow-up as indicators of the success of APTB therapy.

Deveci, Figen; Akbulut, H. Handan; Turgut, Teyfik; Muz, M. Hamdi



Anti-Mycobacterium tuberculosis activity of fungus Phomopsis stipata  

PubMed Central

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

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



In Vitro and In Vivo Activities of Gatifloxacin against Mycobacterium tuberculosis  

PubMed Central

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

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



Peripheral T Cell Cytokine Responses for Diagnosis of Active Tuberculosis  

PubMed Central

Background A test for diagnosis of active Tuberculosis (TB) from peripheral blood could tremendously improve clinical management of patients. Methods Of 178 prospectively enrolled patients with possible TB, 60 patients were diagnosed with pulmonary and 27 patients with extrapulmonary TB. The frequencies of Mycobacterium tuberculosis (MTB) specific CD4+ T cells and CD8+ T cells producing cytokines were assessed using overnight stimulation with purified protein derivate (PPD) or early secretory antigenic target (ESAT)-6, respectively. Results Among patients with active TB, an increased type 1 cytokine profile consisting of mainly CD4+ T cell derived interferon (IFN)-? was detectable. Despite contributing to the cytokine profile as a whole, the independent diagnostic performance of one cytokine producing T cells as well as polyfunctional T cells was poor. IFN-?/Interleukin(IL)-2 cytokine ratios discriminated best between active TB and other diseases. Conclusion T cells producing one cytokine and polyfunctional T cells have a limited role in diagnosis of active TB. The significant shift from a “memory type” to an “effector type” cytokine profile may be useful for further development of a rapid immune-diagnostic tool for active TB.

Nemeth, Johannes; Winkler, Heide-Maria; Zwick, Ralph H.; Muller, Catharina; Rumetshofer, Rudolf; Boeck, Lucas; Burghuber, Otto C.; Winkler, Stefan



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

PubMed Central

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

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



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

PubMed Central

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

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



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

Microsoft Academic Search

Seventeen clinical isolates of Mycobacterium tuberculosis were selected in order to study the bactericidal activities against drug-resistant M. tuberculosis. The effects of different antiseptics against multidrug-resistant M. tuberculosis (MDR-TB) were examined. Each of the test strains was cultured on the surface of an agar slant containing Löwenstein-Jensen medium. 0.05 ml of the bacillary suspension was poured into a test tube,

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



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



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

Code of Federal Regulations, 2013 CFR

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



Multifunctional CD4 T Cell Responses in Patients with Active Tuberculosis  

PubMed Central

The roles of multifunctional CD4 T cells in human tuberculosis are not well defined. In this study, we found that patients with tuberculosis had decreased PMA/ionomycin stimulated multifunctional CD4 T cells, and increased Mycobacterium tuberculosis antigen-specific multifunctional CD4 T cells, when compared to individuals with latent tuberculosis infection and healthy controls. PMA/ionomycin stimulated IFN-?+IL-2+TNF-?+ CD4 T cell responses were decreased in patients with smear-positive tuberculosis compared to those with smear-negative tuberculosis. The percentage of IFN-?+IL-2+TNF-?+ CD4 T cells in smear positive tuberculosis patients negatively correlated with the grade of sputum smear Acid-Fast Bacilli and high-resolution computed tomography score. Therefore, our findings argue against the notion that Mycobacterium tuberculosis antigen-specific multifunctional Th1 responses in peripheral blood can serve as correlates of protective immunity against tuberculosis; they suggest that the decrease in PMA/ionomycin stimulated IFN-?+IL-2+TNF-?+ CD4 T cells may be applied for clinical diagnosis of active tuberculosis.

Qiu, Zhengang; Zhang, Mingxia; Zhu, Yuzhen; Zheng, Feiqun; Lu, Puxuan; Liu, Haiying; Graner, Michael W.; Zhou, Boping; Chen, Xinchun



Use of Multiepitope Polyproteins in Serodiagnosis of Active Tuberculosis  

Microsoft Academic Search

Screening of genomic expression libraries from Mycobacterium tuberculosis with sera from tuberculosis (TB) patients or rabbit antiserum to M. tuberculosis led to the identification of novel antigens capable of detecting specific antibodies to M. tuberculosis. Three antigens, Mtb11 (also known as CFP-10), Mtb8, and Mtb48, were tested together with the previously reported 38-kDa protein, in an enzyme-linked immunosorbent assay (ELISA)

Raymond L. Houghton; Michael J. Lodes; Davin C. Dillon; Lisa D. Reynolds; Craig H. Day; Patricia D. McNeill; Ronald C. Hendrickson; Yasir A. W. Skeiky; Diana P. Sampaio; Roberto Badaro; Konstantin P. Lyashchenko; Steven G. Reed



Plasma Drug Activity Assay for Treatment Optimization in Tuberculosis Patients ? †  

PubMed Central

Low antituberculosis (TB) drug levels are common, but their clinical significance remains unclear, and methods of measurement are resource intensive. Subjects initiating treatment for sputum smear-positive pulmonary TB were enrolled from Kibong'oto National TB Hospital, Tanzania, and levels of isoniazid, rifampin, ethambutol, and pyrazinamide were measured at the time of typical peak plasma concentration (C2 h). To evaluate the significance of the effect of observed drug levels on Mycobacterium tuberculosis growth, a plasma TB drug activity (TDA) assay was developed using the Bactec MGIT system. Time to detection of plasma-cocultured M. tuberculosis versus time to detection of control growth was defined as a TDA ratio. TDA assays were later performed using the subject's own M. tuberculosis isolate and C2 h plasma from the Tanzanian cohort and compared to drug levels and clinical outcomes. Sixteen subjects with a mean age of 37.8 years ± 10.7 were enrolled. Fourteen (88%) had C2 h rifampin levels and 11 (69%) had isoniazid levels below 90% of the lower limit of the expected range. Plasma spiked with various concentrations of antituberculosis medications found TDA assay results to be unaffected by ethambutol or pyrazinamide. Yet with a range of isoniazid and rifampin concentrations, TDA exhibited a statistically significant correlation with drug level and drug MIC, and a TDA of ?1.0 indicated the presence of multidrug-resistant TB. In Tanzania, low (?2.0) TDA was significantly associated with both lower isoniazid and rifampin C2 h levels, and very low (?1.5) TDA corresponded to a trend toward lack of cure. Study of TDA compared to additional clinical outcomes and as a therapeutic management tool is warranted.

Heysell, Scott K.; Mtabho, Charles; Mpagama, Stellah; Mwaigwisya, Solomon; Pholwat, Suporn; Ndusilo, Norah; Gratz, Jean; Aarnoutse, Rob E.; Kibiki, Gibson S.; Houpt, Eric R.



[Serum adenosine deaminase (ADA) activity in patients with active pulmonary tuberculosis].  


To clarify the immunological aspect of tuberculosis, we investigated serum adenosine deaminase (ADA) activity, T and B cell percentile in total peripheral mononuclear cells, peripheral T cell subpopulation and their relationship with other inflammatory parameters in 20 patients with active pulmonary tuberculosis. Serum ADA activity showed abnormal high level in all patients in nontreated phase with significant regression after three months treatment by anti-tuberculous drugs (P less than 0.05). In addition, significant positive correlation was observed between serum ADA activity and erythrocyte sedimentation rate at 1 hour (r = 0.56). Concerning about peripheral T cell subpopulation studied by two colour flow cytometry with FITC-conjugated anti-CD4 and phycoerythrin-conjugated anti-HLA-DR antibody, there was positive correlation between CD4(-) HLA-DR(+) T cell and serum ADA activity (r = 0.59) without any abnormal frequency of each T cell subpopulation. Additionally, after the treatment of pulmonary tuberculosis, significant increase of T cell percentile in total peripheral mononuclear cells were observed (P less than 0.005). In conclusion, these results may suggest serum ADA activity could be a parameter of activity of pulmonary tuberculosis and reflect the function of activated suppressor/cytotoxic T cell. PMID:2214510

Ida, T; Taniai, S; Nitta, M; Shimase, J; Makiguchi, K; Miyasato, I; Chida, M; Shinada, H; Shinohara, Y; Tachi, H



Factors influencing quality of life in patients with active tuberculosis in Pakistan  

Microsoft Academic Search

Evidently Tuberculosis remains a major threat to public health globally. Latterly academia with exertion dedication has tried to extract the health related quality of life of the people with active tuberculosis. Meager studies in Pakistan have tried to explore the factors that influences patient’s health related quality of life besides the disease. The intentions of this study were to scrutinize

Sarwar Awan Masood; Waqas Muhammad; Amir Aslam Muhammad



Regulatory T Cells Depress Immune Responses to Protective Antigens in Active Tuberculosis  

Microsoft Academic Search

Rationale: Tuberculosis (TB) remains a leading cause of death, and the role of T-cell responses to control Mycobacterium tuberculosis infections is well recognized. Patients with latent TB infection de- velop strong IFN- responses to the protective antigen heparin- binding hemagglutinin (HBHA), whereas patients with active TB do not. Objectives: We investigated the mechanism of this difference and evaluated the possible

Jean-Michel Hougardy; Marc Hildebrand; Annie Drowart; Anne-Sophie Debrie; Camille Locht; Francoise Mascart



Analysis of immune responses against a wide range of Mycobacterium tuberculosis antigens in patients with active pulmonary tuberculosis.  


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

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



Activated B cells in the granulomas of nonhuman primates infected with Mycobacterium tuberculosis.  


In an attempt to contain Mycobacterium tuberculosis, host immune cells form a granuloma as a physical and immunological barrier. To date, the contribution of humoral immunity, including antibodies and specific functions of B cells, to M. tuberculosis infection in humans remains largely unknown. Recent studies in mice show that humoral immunity can alter M. tuberculosis infection outcomes. M. tuberculosis infection in cynomolgus macaques recapitulates essentially all aspects of human tuberculosis. As a first step toward understanding the importance of humoral immunity to control of M. tuberculosis infection in primates, we characterized the B-cell and plasma-cell populations in infected animals and found that B cells are present primarily in clusters within the granuloma. The B-cell clusters are in close proximity to peripheral node addressin-positive cells and contain cells positive for Ki-67, a proliferation marker. Granuloma B cells also express CXCR5 and have elevated HLA-DR expression. Tissues containing M. tuberculosis bacilli had higher levels of M. tuberculosis-specific IgG, compared with uninvolved tissue from the same monkeys. Plasma cells detected within the granuloma produced mycobacteria-specific antibodies. Together, these data demonstrate that B cells are present and actively secreting antibodies specific for M. tuberculosis antigens at the site of infection, including lung granulomas and thoracic lymph nodes. These antibodies likely have the capacity to modulate local control of infection in tissues. PMID:22721647

Phuah, Jia Yao; Mattila, Joshua T; Lin, Philana L; Flynn, JoAnne L




PubMed Central

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

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



Mycobacterium tuberculosis Hip1 Dampens Macrophage Proinflammatory Responses by Limiting Toll-Like Receptor 2 Activation?  

PubMed Central

Mycobacterium tuberculosis is a highly successful human pathogen that evades host innate immunity by interfering with macrophage functions. In addition to avoiding macrophage microbicidal activities, M. tuberculosis triggers secretion of proinflammatory cytokines and chemokines in macrophages. The levels of proinflammatory cytokines induced by clinical M. tuberculosis isolates are thought to play an important role in determining tuberculosis disease progression and severity, but the mechanisms by which M. tuberculosis modulates the magnitude of inflammatory responses remain unclear. Here we show that M. tuberculosis restricts robust macrophage activation and dampens proinflammatory responses through the cell envelope-associated serine hydrolase Hip1 (hydrolase important for pathogenesis 1). By transcriptionally profiling macrophages infected with either wild-type or hip1 mutant bacteria, we found that the hip1 mutant induced earlier and significantly higher levels of several proinflammatory cytokines and chemokines. We show that increased activation of Toll-like receptor 2 (TLR2)- and MyD88-dependent signaling pathways mediates the enhanced cytokine secretion induced by the hip1 mutant. Thus, Hip1 restricts the onset and magnitude of proinflammatory cytokines by limiting TLR2-dependent activation. We also show that Hip1 dampens TLR2-independent activation of the inflammasome and limits secretion of interleukin-18 (IL-18). Dampening of TLR2 signaling does not require viable M. tuberculosis or phagocytosis but does require Hip1 catalytic activity. We propose that M. tuberculosis restricts proinflammatory responses by masking cell surface interactions between TLR2 agonists on M. tuberculosis and TLR2 on macrophages. This strategy may allow M. tuberculosis to evade early detection by host immunity, delay the onset of adaptive immune responses, and accelerate disease progression.

Madan-Lala, Ranjna; Peixoto, Katia Vitorello; Re, Fabio; Rengarajan, Jyothi



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


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

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



The ACTIVE Cognitive Training Interventions and the Onset of and Recovery from Suspected Clinical Depression  

PubMed Central

We evaluated the effects of the 3 cognitive interventions fielded in the Advanced Cognitive Training for Independent and Vital Elderly study on 2 subsets of participants—1,606 without and 424 with suspected clinical depression at baseline. In the former group, only the speed of processing (vs. no-contact control) intervention had a significant effect, with its participants being 38% less likely to develop suspected clinical depression at 1 year (adjusted odds ratio = 0.62; p < .01). None of the interventions had a significant effect on recovery from suspected clinical depression in the latter group. Although the etiological mechanism of the speed of processing’s protective effect was not isolated, it may result from successful adaptation to age-related changes through selective optimization with compensation.

Mahncke, Henry W.; Weg, Mark W. Vander; Martin, Rene; Unverzagt, Frederick W.; Ball, Karlene K.; Jones, Richard N.; Tennstedt, Sharon L.



Diagnosis of Active Tuberculosis in China Using an In-House Gamma Interferon Enzyme-Linked Immunospot Assay  

Microsoft Academic Search

Gamma interferon (IFN-) release assays have been proven to be useful in the diagnosis of Mycobacterium tuberculosis infection. Nevertheless, their specificity and sensitivity vary among the different populations studied. Here, we evaluate the value of an in-house IFN- enzyme-linked immunospot (ELISPOT) assay in the diagnosis of active tuberculosis (TB) in Shenzhen, China, where the prevalence of tuberculosis is severe and

Xinchun Chen; Qianting Yang; Mingxia Zhang; Michael Graner; Xiuyun Zhu; Nicolas Larmonier; Mingfeng Liao; Weiye Yu; Qunyi Deng; Boping Zhou



Design, synthesis and inhibition activity of novel cyclic peptides against protein tyrosine phosphatase A from Mycobacterium tuberculosis  

Microsoft Academic Search

Mycobacterium tuberculosis, the causative agent for tuberculosis has employed several signalling molecules to sense the host cellular environment and act accordingly. For example, protein tyrosine phosphatase A (MPtpA) of M. tuberculosis, a signalling protein belonging to the tyrosine phosphatase superfamily, is involved in phagocytosis and is active in virulent mycobacterial form. Starting from a ?-lactam framework a new class of

Koushik Chandra; Debajyoti Dutta; Amit K. Das; Amit Basak



Suspected Brucellosis Case Prompts Investigation of Possible Bioterrorism-Related Activity - New Hampshire and Massachusetts, 1999.  

National Technical Information Service (NTIS)

Brucella species, particularly B. melitensis and B. suis, are potential agents of biological terrorism (1,2). This report describes the public health and law enforcement assessment of a suspected case of brucellosis in a woman, in which the atypical clini...




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...


Host Targeted Activity of Pyrazinamide in Mycobacterium tuberculosis Infection.  


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



An Early Morning Sputum Sample Is Necessary for the Diagnosis of Pulmonary Tuberculosis, Even with More Sensitive Techniques: A Prospective Cohort Study among Adolescent TB-Suspects in Uganda  

PubMed Central

The World Health Organization (WHO) recommends collection of two sputum samples for tuberculosis (TB) diagnosis, with at least one being an early morning (EM) using smear microscopy. It remains unclear whether this is necessary even when sputum culture is employed. Here, we determined the diagnostic yield from spot and the incremental yield from the EM sputum sample cultures among TB-suspected adolescents from rural Uganda. Sputum samples (both spot and early-morning) from 1862 adolescents were cultured by the Lowenstein-Jensen (LJ) and Mycobacterium Growth Indicator Tube (MGIT) methods. For spot samples, the diagnostic yields for TB were 19.0% and 57.1% with LJ and MGIT, respectively, whereas the incremental yields (not totals) of the early-morning sample were 9.5% and 42.9% (P < 0.001) with LJ and MGIT, respectively. Among TB-suspected adolescents in rural Uganda, the EM sputum culture has a high incremental diagnostic yield. Therefore, EM sputum in addition to spot sample culture is necessary for improved TB case detection.

Kateete, David P.; Wajja, Anne; Bugumirwa, Eric; Mboowa, Gerald; Namaganda, Carolyn; Nakayita, Germine; Nassolo, Maria; Mumbowa, Francis; Asiimwe, Benon B.; Waako, James; Verver, Suzanne; Musoke, Philippa; Mayanja-Kizza, Harriet; Joloba, Moses L.



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

PubMed Central

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

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



Vitamin D status and antimicrobial peptide cathelicidin (LL-37) concentrations in patients with active pulmonary tuberculosis  

PubMed Central

Background: Vitamin D insufficiency is common in industrialized and developing nations. Recent studies have shown that vitamin D insufficiency is associated with a higher risk of active tuberculosis. Laboratory studies provided a mechanism for this link on the basis of findings that vitamin D metabolites regulate the expression of cathelicidin (LL-37), which is an endogenous antimicrobial peptide with activity against Mycobacterium tuberculosis. Little information is available on the clinical relation between vitamin D, LL-37 concentrations, and disease severity in patients with tuberculosis. Objective: The primary objective of the study was to evaluate the relation between vitamin D nutriture, serum LL-37 concentrations, and tuberculosis by using samples stored in the Tuberculosis Trials Consortium serum repository. Design: We measured 25-hydroxyvitamin D [25(OH)D] and LL-37 concentrations in 95 serum specimens from patients with culture-confirmed pulmonary tuberculosis and correlated these concentrations to clinical and demographic variables. Results: The prevalence of vitamin D insufficiency [serum 25(OH)D concentration lt 30 ng/mL] in patients with active tuberculosis was 86% (n = 95) with a mean baseline serum 25(OH)D concentration of 20.4 ng/mL. Factors associated with vitamin D insufficiency were black race and indoor lifestyle. The mean ( plusmn SD) baseline LL-37 concentration was 49.5 plusmn 23.8 ng/mL. Higher LL-37 concentrations correlated with acid fast bacilli sputum smear positivity and weight gt 10% below ideal body weight. Serum vitamin D status of the study subjects did not correlate with serum LL-37 concentrations. Conclusion: More prospectively designed studies are needed to evaluate the clinical implications of vitamin D insufficiency in patients with tuberculosis and the utility of circulating LL-37 as a potential biomarker in patients with active tuberculosis disease. The parent trial was registered at as NCT00023335.

Yamshchikov, Alexandra V; Kurbatova, Ekaterina V; Kumari, Meena; Blumberg, Henry M; Ziegler, Thomas R; Ray, Susan M; Tangpricha, Vin



Discovery, Synthesis, and Biological Evaluation of Piperidinol analogs With Anti-tuberculosis Activity  

PubMed Central

Direct anti-tuberculosis screening of commercially available compound libraries identified a novel piperidinol with interesting anti-tuberculosis activity and drug like characteristics. To generate a structure activity relationship about this hit a 22 member optimization library was generated using parallel synthesis. Products of this library 1-((R)-3-(4-chlorophenoxy)-2-hydroxypropyl)-4-(4-chloro-3-(trifluoromethyl) phenyl)piperidin-4-ol and 1-((S)-3-(4-(trifluoromethyl) phenoxy)-2-hydroxypropyl)-4-(4-chloro-3-(trifluoromethyl) phenyl) piperidin-4-ol demonstrated good anti-tuberculosis activity. Unfortunately, side effects were observed upon in vivo anti-tuberculosis testing of these compounds precluding their further advancement, which may be in part due to the secondary pharmacology associated with the aryl piperidinol core.

Sun, Dianqing; Scherman, Michael S.; Jones, Victoria; Hurdle, Julian G.; Woolhiser, Lisa K.; Knudson, Susan E.; Lenaerts, Anne J.; Slayden, Richard A.; McNeil, Michael R.; Lee, Richard E.



Thrombolytic Therapy with Streptokinase and Tissue Plasminogen Activator in a Patient with Suspected Acute Myocardial Infarction: A Decision Analysis  

Microsoft Academic Search

Two commonly used thrombolytic agents are streptokinase (SK) and tissue plasminogen activator (t-PA), which have different impacts on the incidence of mortality and thrombolysis-related acute intracranial hemorrhage. A decision-analytic model was developed to compare the use of SK and t-PA in the treatment of a patient with suspected acute myocardial infarction (AMI). The outcome was health-related quality of life as

Mark D. Hiatt



Prospective Evaluation of a Whole-Blood Test Using Mycobacterium tuberculosis-Specific Antigens ESAT-6 and CFP10 for Diagnosis of Active Tuberculosis  

Microsoft Academic Search

A new immunodiagnostic test based on the Mycobacterium tuberculosis-specific antigens CFP-10\\/ESAT- 6(QFT-RD1) has been launched as an aid in the diagnosis of latent tuberculosis (TB) infection (LTBI). The aim of this study was to evaluate this test for the diagnosis of active TB. Eighty-two patients with suspicion of TB and 39 healthy BCG-vaccinated persons were enrolled. Forty-eight had active TB,

Pernille Ravn; Martin E. Munk; A. B. Andersen; Bettina Lundgren; Jens D. Lundgren; Lars N. Nielsen; Axel Kok-Jensen; Peter Andersen; Karin Weldingh



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

PubMed Central

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

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



Pulmonary immune-compartment-specific interferon gamma responses in HIV-infected individuals with active tuberculosis (TB) in an area of high TB prevalence.  


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

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



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

PubMed Central

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

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



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.

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



Measurement of SF6D utility among patients with active tuberculosis  

Microsoft Academic Search

Inspite of so much development in medical technology, Tuberculosis (TB) is still the problem for humans. Few studies, in Pakistan highlighted the factors that affect patients health related quality of life (HRQOL) with active TB. The aim of this study is to measure short form six dimension (Sf-6D) utility scores of patients with active TB of Sargodha district. 120 active

Masood Sarwar Awan; Muhammad Waqas; Muhammad Amir Aslam; Muhammad Sarwar



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


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

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


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

PubMed Central

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

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



Health State Utilities in Latent and Active Tuberculosis  

Microsoft Academic Search

BackgroundTuberculosis (TB) remains a major public health threat worldwide. Numerous cost-effectiveness analyses of TB screening and treatment strategies have been recently published, but none have utilized quality-adjusted life-years as recommended because of the lack of utilities for TB health states.

Na Guo; Carlo A. Marra; Fawziah Marra; Susanne Moadebi; R. Kevin Elwood; J. Mark FitzGerald



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

PubMed Central

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

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



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

Microsoft Academic Search

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

J. Christian J. Ray; Jian Wang; John Chan; Denise E. Kirschner



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.

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



Mycobacterium tuberculosis DNA gyrase: interaction with quinolones and correlation with antimycobacterial drug activity.  


Genome studies suggest that DNA gyrase is the sole type II topoisomerase and likely the unique target of quinolones in Mycobacterium tuberculosis. Despite the emerging importance of quinolones in the treatment of mycobacterial disease, the slow growth and high pathogenicity of M. tuberculosis have precluded direct purification of its gyrase and detailed analysis of quinolone action. To address these issues, we separately overexpressed the M. tuberculosis DNA gyrase GyrA and GyrB subunits as His-tagged proteins in Escherichia coli from pET plasmids carrying gyrA and gyrB genes. The soluble 97-kDa GyrA and 72-kDa GyrB subunits were purified by nickel chelate chromatography and shown to reconstitute an ATP-dependent DNA supercoiling activity. The drug concentration that inhibited DNA supercoiling by 50% (IC(50)) was measured for 22 different quinolones, and values ranged from 2 to 3 microg/ml (sparfloxacin, sitafloxacin, clinafloxacin, and gatifloxacin) to >1,000 microg/ml (pipemidic acid and nalidixic acid). By comparison, MICs measured against M. tuberculosis ranged from 0.12 microg/ml (for gatifloxacin) to 128 microg/ml (both pipemidic acid and nalidixic acid) and correlated well with the gyrase IC(50)s (R(2) = 0.9). Quinolones promoted gyrase-mediated cleavage of plasmid pBR322 DNA due to stabilization of the cleavage complex, which is thought to be the lethal lesion. Surprisingly, the measured concentrations of drug inducing 50% plasmid linearization correlated less well with the MICs (R(2) = 0.7). These findings suggest that the DNA supercoiling inhibition assay may be a useful screening test in identifying quinolones with promising activity against M. tuberculosis. The quinolone structure-activity relationship demonstrated here shows that C-8, the C-7 ring, the C-6 fluorine, and the N-1 cyclopropyl substituents are desirable structural features in targeting M. tuberculosis gyrase. PMID:15047530

Aubry, Alexandra; Pan, Xiao-Su; Fisher, L Mark; Jarlier, Vincent; Cambau, Emmanuelle



Mycobacterium tuberculosis DNA Gyrase: Interaction with Quinolones and Correlation with Antimycobacterial Drug Activity  

PubMed Central

Genome studies suggest that DNA gyrase is the sole type II topoisomerase and likely the unique target of quinolones in Mycobacterium tuberculosis. Despite the emerging importance of quinolones in the treatment of mycobacterial disease, the slow growth and high pathogenicity of M. tuberculosis have precluded direct purification of its gyrase and detailed analysis of quinolone action. To address these issues, we separately overexpressed the M. tuberculosis DNA gyrase GyrA and GyrB subunits as His-tagged proteins in Escherichia coli from pET plasmids carrying gyrA and gyrB genes. The soluble 97-kDa GyrA and 72-kDa GyrB subunits were purified by nickel chelate chromatography and shown to reconstitute an ATP-dependent DNA supercoiling activity. The drug concentration that inhibited DNA supercoiling by 50% (IC50) was measured for 22 different quinolones, and values ranged from 2 to 3 ?g/ml (sparfloxacin, sitafloxacin, clinafloxacin, and gatifloxacin) to >1,000 ?g/ml (pipemidic acid and nalidixic acid). By comparison, MICs measured against M. tuberculosis ranged from 0.12 ?g/ml (for gatifloxacin) to 128 ?g/ml (both pipemidic acid and nalidixic acid) and correlated well with the gyrase IC50s (R2 = 0.9). Quinolones promoted gyrase-mediated cleavage of plasmid pBR322 DNA due to stabilization of the cleavage complex, which is thought to be the lethal lesion. Surprisingly, the measured concentrations of drug inducing 50% plasmid linearization correlated less well with the MICs (R2 = 0.7). These findings suggest that the DNA supercoiling inhibition assay may be a useful screening test in identifying quinolones with promising activity against M. tuberculosis. The quinolone structure-activity relationship demonstrated here shows that C-8, the C-7 ring, the C-6 fluorine, and the N-1 cyclopropyl substituents are desirable structural features in targeting M. tuberculosis gyrase.

Aubry, Alexandra; Pan, Xiao-Su; Fisher, L. Mark; Jarlier, Vincent; Cambau, Emmanuelle



Validating New Tuberculosis Computational Models with Public Whole Cell Screening Aerobic Activity Datasets  

Microsoft Academic Search

Purpose  The search for small molecules with activity against Mycobacterium tuberculosis (Mtb) increasingly uses high throughput screening and computational methods. Several public datasets from the Collaborative\\u000a Drug Discovery Tuberculosis (CDD TB) database have been evaluated with cheminformatics approaches to validate their utility\\u000a and suggest compounds for testing.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Previously reported Bayesian classification models were used to predict a set of 283 Novartis

Sean Ekins; Joel S. Freundlich


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

PubMed Central

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

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



Immediate Cementless Total Hip Arthroplasty for the Treatment of Active Tuberculosis  

Microsoft Academic Search

We report the results of a primary total hip arthroplasty (THA) in 7 patients with advanced active tuberculous arthritis of the hip and had lost the chance of preserving the hip without replacement surgery. Tuberculosis was confirmed in all cases by the culture or histological examination. All patients were treated with primary THA followed by antituberculous medications for 1 year.

Taek Rim Yoon; Sung Man Rowe; Setyagung Budi Santosa; Sung Taek Jung; Jong Keun Seon



Ventricular arrhythmias during treatment with alteplase (recombinant tissue plasminogen activator) in suspected acute myocardial infarction  

Microsoft Academic Search

Continuous electrocardiography during the first 24 hours of a stay in a coronary care unit was used to record ventricular arrhythmias during treatment with alteplase (recombinant tissue plasminogen activator) or placebo. Recordings were made on 378 of the 436 patients admitted to a double blind trial of alteplase or placebo in one participating centre of the Anglo-Scandinavian study of early

R G Wilcox; J Eastgate; E Harrison; A M Skene



Primary health care staff's perceptions of childhood tuberculosis: a qualitative study from Tanzania  

PubMed Central

Background Diagnosing tuberculosis in children remains a great challenge in developing countries. Health staff working in the front line of the health service delivery system has a major responsibility for timely identification and referral of suspected cases of childhood tuberculosis. This study explored primary health care staff's perception, challenges and needs pertaining to the identification of children with tuberculosis in Muheza district in Tanzania. Methods We conducted a qualitative study that included 13 semi-structured interviews and 3 focus group discussions with a total of 29 health staff purposively sampled from primary health care facilities. Analysis was performed in accordance with the principles of a phenomenological analysis. Results Primary health care staff perceived childhood tuberculosis to be uncommon in the society and tuberculosis was rarely considered as a likely differential diagnosis. Long duration and severe signs of disease together with known exposure to tuberculosis were decisive for the staff to suspect tuberculosis in children and refer them to hospital. None of the staff felt equipped to identify cases of childhood tuberculosis and they experienced lack of knowledge, applicable tools and guidelines as the main challenges. They expressed the need for more training, supervision and referral feedback to improving case identification. Conclusions Inadequate awareness of the burden of childhood tuberculosis, limited knowledge of the wide spectrum of clinical presentation and lack of clinical decision support strategies is detrimental to the health staff's central responsibility of suspecting and referring children with tuberculosis especially in the early disease stages. Activities to improve case identification should focus on skills required by primary health care staff to fulfil their responsibility and reflect primary health care level capacities and challenges.



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

Microsoft Academic Search

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

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



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.

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



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


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

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


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


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

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


Identification of Early Secretory Antigen Target-6 Epitopes for the Immunodiagnosis of Active Tuberculosis  

PubMed Central

The early secretory antigenic target (ESAT)-6 purified protein and peptides from Mycobacterium tuberculosis were evaluated as antigens for the immunodiagnosis of tuberculosis (TB). Because the control of TB requires improved diagnostic procedures, efforts have increased to identify Mycobacterium tuberculosis–specific epitopes for the immunodiagnosis of active TB and to discriminate between active and latent states of infection. Two multiepitopic peptides from ESAT-6 protein were selected by computational analysis. Patients with active TB (7 HIV+ and 20 HIV?) and control patients (17 HIV+ and 28 HIV?) were enrolled. Enzyme-linked immunospot assay analysis for interferon-? expression by peripheral blood mononuclear cells was quantified after stimulation with selected ESAT-6 peptides, purified protein derivative, or the intact ESAT-6 protein. During active TB, 20 of 27 patients responded in vitro to ESAT-6 peptides and 23 of 27 patients to purified protein derivative. None of the controls without active TB, including individuals with latent TB infection, recognized ESAT-6 peptides. By contrast, latently infected individuals did respond in vitro to both intact ESAT-6 protein and purified protein derivative. Thus, high T-cell response frequencies to ESAT-6 peptides are present only during active TB and can be used to discriminate between active and latent forms of infection.

Vincenti, Donatella; Carrara, Stefania; De Mori, Patrizia; Pucillo, Leopoldo P; Petrosillo, Nicola; Palmieri, Fabrizio; Armignacco, Orlando; Ippolito, Giuseppe; Girardi, Enrico; Amicosante, Massimo; Goletti, Delia



Anti Mycobacterium tuberculosis Activities of New Fluoroquinolones in Combination with Other Antituberculous Drugs  

Microsoft Academic Search

Objectives: Studies were undertaken in order to assess the anti- Mycobacterium tuberculosis (MTB) activities of newly developed fluoroquinolones in combination with other antituberculous drugs.Methods: A new C-8-methoxyl fluoroquinolone, gatifloxacin (GFLX), and a new C-8-chloro fluoroquinolone, sitafloxacin (STFX), in combination with other drugs were examined for their activities against extracellular growing MTB organisms and those replicating in RAW264.7 macrophages (RAW-M?s).Results: STFX

H. Tomioka; K. Sato; T. Shimizu; C. Sano



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.

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



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


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



Risk factors for tuberculosis  

Microsoft Academic Search

Risk factors for tuberculosis. P.D.O. Davies. The risk of developing tuberculosis is dependent on both the risk of being infected and the risk of infection lead- ing on to active disease. The former will depend on the inci- dence of tuberculosis in the community where the individual lives or works. The latter will depend on many factors im- pinging on

P. D. O. Davies



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


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



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


Resistance to isoniazid (INH), one of the main drugs used in tuberculosis (TB) therapy, is mostly due to chromosomal mutations in target genes. However, approximately 20-30% of INH resistant Mycobacterium tuberculosis isolates do not have mutations in any of the genes associated with INH resistance. This suggests that other mechanism(s) may be involved, namely efflux pump systems capable of extruding the drug to the exterior of the cell. In a previous work, we have induced clinical INH susceptible M. tuberculosis isolates and the H37Rv reference strain to high-level resistance to INH, by gradual exposure to increasing concentrations of this drug. In the present study, we have characterized these strains and Mycobacterium bovis BCG induced to INH resistance with respect to their efflux activity and its contribution to INH resistance using the following approach: determination of the susceptibility to INH in the presence and absence of the efflux inhibitors (EIs) chlorpromazine, thioridazine and verapamil; evaluation of efflux activity by a semi-automated fluorometric method; and quantification of the expression level of genes coding for efflux pumps by real-time RT-qPCR. The EIs decreased INH resistance in the INH induced strains, in particular verapamil promoted a reversal of resistance in some of the strains tested. The induced strains presented an increased efflux activity that was inhibited by the EIs and showed overexpression of the efflux pump genes efpA, mmpL7, mmr, p55 and the Tap-like gene Rv1258c. Altogether, these results correlate efflux activity with INH resistance and demonstrate that efflux pumps play an important role in acquired INH resistance in M. tuberculosis complex. The development of EIs that can restore the antimicrobial activity of the antibiotic subject to efflux is an approach that can be useful in order to prevent the emergence of this resistance and guide the development of new effective anti-TB therapeutical approaches. PMID:21871582

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



Perforated tuberculosis lymphadenitis.  


A 26-year-old man (human immunodeficiency virus-positive and not taking highly active antiretroviral treatment [HAART]) presented to the emergency room with 2 months of malaise, 20 kg weight loss, high spiking fevers, generalized lymph nodes, night sweats, dry cough, and chest pain when swallowing. On physical examination, he had multiple cervical lymphadenopathies. Suspecting a systemic opportunistic infection, a contrasted chest computed tomography (CT) was done, showing an esophageal to mediastinum fistulae. Two days after admission, a fluoroscopic contrasted endoscopy was done that showed two esophageal fistulae from scrofula to esophagus and then, to mediastinum. A bronchoalveolar lavage and a cervical lymphadenopathy biopsy were done, both showing multiple acid-fast bacillae, where cultures grew Mycobacterium tuberculosis. PMID:23740190

Cataño, Juan; Cardeño, John



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


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

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



T4 lymphopenia in patients with active pulmonary tuberculosis.  

PubMed Central

The numbers of cells bearing the T3 (pan-T cell), the T4 (putative helper/inducer cells), the T8 (putative suppressor/cytotoxic cells) and B cell phenotypic markers were counted in venous blood samples from 26 newly diagnosed pulmonary tuberculosis patients and 29 healthy controls from East Java. The absolute T cell count was lower in the patients and T4 cells were fewer in patients (mean 748/mm3) than in controls (mean 1,043/mm3), but there were no significant differences in total T8 cell and B cell counts between patients and controls. The T4:T8 ratio was not disturbed in many patients, but it was less than 1.6 in 11 of 26 patients and in only three of 29 controls: this ratio was less than 1.2 (the lower limit of 'normal') in six patients but no controls. The intensity of the T4 lymphopenia was unrelated to the extent of the lesion seen radiologically or the size of the skin test reaction to PPD. Levels of interferon-alpha were not elevated in the serum of any of the patients or controls. It is suggested that the T4 lymphopenia was a reaction to the mycobacterial infection and not a manifestation of underlying secondary (acquired) immune deficiency.

Beck, J S; Potts, R C; Kardjito, T; Grange, J M



Quantitative scoring of an interferon-  assay for differentiating active from latent tuberculosis  

Microsoft Academic Search

The aim of this study was to assess the contribution of an interferon-c release assay (T-SPOT.TB) to the differentiation of active tuberculosis (TB) from latent TB infection by quantifying spot-forming units (sfu). The investigation was a prospective study of contacts exposed to a case of contagious TB and cases of HIV-negative culture-proven TB referred over a 16-month period. Tuberculin skin

J. P. Janssens; P. Roux-Lombard; T. Perneger; M. Metzger; R. Vivien; T. Rochat



Diabetes Mellitus Increases the Risk of Active Tuberculosis: A Systematic Review of 13 Observational Studies  

Microsoft Academic Search

BackgroundSeveral studies have suggested that diabetes mellitus (DM) increases the risk of active tuberculosis (TB). The rising prevalence of DM in TB-endemic areas may adversely affect TB control. We conducted a systematic review and a meta-analysis of observational studies assessing the association of DM and TB in order to summarize the existing evidence and to assess methodological quality of the

Christie Y Jeon; Megan B Murray



Meropenem-Clavulanic Acid Shows Activity against Mycobacterium tuberculosis In Vivo  

PubMed Central

The carbapenems imipenem and meropenem in combination with clavulanic acid reduced the bacterial burden in Mycobacterium tuberculosis-infected macrophages by 2 logs over 6 days. Despite poor stability in solution and a short half-life in rodents, treatment of chronically infected mice revealed significant reductions of bacterial burden in the lungs and spleens. Our results show that meropenem has activity in two in vivo systems, but stability and pharmacokinetics of long-term administration will offer significant challenges to clinical evaluation.

England, Kathleen; Boshoff, Helena I. M.; Arora, Kriti; Weiner, Danielle; Dayao, Emmanuel; Schimel, Daniel; Via, Laura E.



Active tuberculosis among Iraqi schoolchildren with positive skin tests and their household contacts  

Microsoft Academic Search

In a prospective cohort study in Iraq, schoolchildren with a positive tuberculin skin test during the nationwide survey in 2000 were followed up in 2002 to determine prevalence of latent tuberculosis (TB) infection and risk factors among household contacts. Of 205 children, 191 remained skin-test positive in 2002. Based on X-ray and clinical examination, 9 children (4.4%) were active TB

W. Al-Kubaisy; A. Al-Dulaymi; H. D. Selman



Tuberculosis in HIV-infected persons in the context of wide availability of highly active antiretroviral therapy.  


Highly active antiretroviral therapy (HAART) greatly reduces the risk of developing tuberculosis for HIV-infected persons. Nonetheless, HIV-associated tuberculosis continues to occur in countries where HAART is widely used. To identify the characteristics of HIV-infected persons who develop tuberculosis in the context of the availability of HAART, the current authors analysed data taken from 271 patients diagnosed, in Italy, during 1999-2000. These patients represent 0.7% of the 40,413 HIV-infected patients cared for in the clinical units participating in this current study. From the data it was observed that 20 patients (7.4%) had a previous episode of tuberculosis whose treatment was not completed. Eighty-one patients (29.9%) were diagnosed with HIV at tuberculosis diagnosis, 108 (39.8%) were aware of their HIV status but were not on antiretroviral treatment and 82 (30.3%) were on antiretroviral treatment. Patients on antiretroviral treatment were significantly less immunosuppressed than patients with HIV diagnosed concurrently with tuberculosis, or other patients not on antiretrovirals (median CD4 lymphocytes count: 220 cells x mm(-3) versus 100 cells x mm(-3), and 109 cells x mm(-3), respectively). No significant differences in clinical presentation of tuberculosis according to antiretroviral therapy status were recorded. Failure of tuberculosis control interventions (e.g. noncompletion of treatment) and of HIV care (delayed diagnosis of HIV infection and suboptimal uptake of therapy) may contribute to continuing occurrence of HIV-associated tuberculosis in a country where highly active antiretroviral therapy is largely available. However, a significant proportion of cases occur in patients who are on antiretroviral treatment. PMID:15293599

Girardi, E; Antonucci, G; Vanacore, P; Palmieri, F; Matteelli, A; Iemoli, E; Carradori, S; Salassa, B; Pasticci, M Bruna; Raviglione, M C; Ippolito, G



Which aminoglycoside or fluoroquinolone is more active against Mycobacterium tuberculosis in mice?  

PubMed Central

To identify the most active aminoglycoside or fluoroquinolone for the treatment of tuberculosis, the in vivo activities of four different aminoglycosides and three different fluoroquinolones were compared with that of isoniazid (INH) in a murine tuberculosis model. Mice were each inoculated intravenously with 2.3 x 10(7) CFU of Mycobacterium tuberculosis H37Rv. Treatment began the next day (D1) after inoculation and continued for 4 weeks, at the frequency of six times weekly with one of the following regimens: INH, 25 mg/kg; ofloxacin, 200 mg/kg; levofloxacin, 100 or 200 mg/kg; sparfloxacin (SPFX), 50 mg/kg; and streptomycin, kanamycin, amikacin (AMIKA), and isepamicin, all at 200 mg/kg. The dosages of the treatments were presumably equivalent to their clinically tolerated dosages. The severity of infection and effectiveness of the treatment were assessed by the survival rate, spleen weights, gross lung lesions, and the numbers of CFU in the spleens. The results indicate that INH is more bactericidal than any of the aminoglycosides or fluoroquinolones tested, that AMIKA is the most active aminoglycoside, and that SPFX at 50 mg/kg is far more bactericidal than the treatment with other fluoroquinolones.

Lounis, N; Ji, B; Truffot-Pernot, C; Grosset, J



Synthesis of gatifloxacin derivatives and their biological activities against Mycobacterium leprae and Mycobacterium tuberculosis.  


Novel 3'-piperazinyl derivatives of the 8-hydrogeno and 8-methoxy-6-fluoro-1-cyclopropyl-4-quinolone-3-carboxylic acid scaffolds were designed, synthesized and characterized by (1)H, (13)C and (19)F NMR, and HRMS. The activity of these derivatives against pathogenic mycobacteria (M. leprae and M. tuberculosis), wild-type (WT) strains or strains harboring mutations implicated in quinolone resistance, were determined by measuring drug concentrations inhibiting cell growth (MIC) and/or DNA supercoiling by DNA gyrase (IC(50)), or inducing 25% DNA cleavage by DNA gyrase (CC(25)). Compound 4 (with a methoxy in R(8) and a secondary carbamate in R(3)') and compound 5 (with a hydrogen in R(8) and an ethyl ester in R(3)') displayed biological activities close to those of ofloxacin but inferior to those of gatifloxacin and moxifloxacin against M. tuberculosis and M. leprae WT DNA gyrases, whereas all of the compounds were less active in inhibiting M. tuberculosis growth and M. leprae mutant DNA gyrases. Since R(3)' substitutions have been poorly investigated previously, our results may help to design new quinolone derivatives in the future. PMID:23294829

Gomez, Catherine; Ponien, Prishila; Serradji, Nawal; Lamouri, Aazdine; Pantel, Alix; Capton, Estelle; Jarlier, Vincent; Anquetin, Guillaume; Aubry, Alexandra



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.

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



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


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

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



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.

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



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

PubMed Central

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

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



Increased Levels of BAFF and APRIL Related to Human Active Pulmonary Tuberculosis  

PubMed Central

Background Despite great efforts to improve diagnosis and treatment, tuberculosis (TB) remains a major health problem worldwide, especially in developing countries. Lack of concrete immune markers is still the obstacle to properly evaluate active TB. Therefore, identification of more validated biomarkers and phenotypic signatures is imperative. In particular, T cell-related biomarkers are more significant. Methodology To understand the nature of CD4+ T cell-derived signatures involved in infection and disease development, we examined and analyzed whole genome expression profiles of purified CD4+ T cells from healthy individuals (HD), two distinct populations with latent infection (with low or high IFN-? levels, LTBL/LTBH) and untreated TB patients. Following, we validated the expression profiles of genes in the peripheral CD4+ T cells from each group and examined secretion levels of distinct cytokines in serum and pleural effusion. Principal Findings Our bio-informatic analyses indicate that the two latent populations and clinical TB patients possess distinct CD4+ T cell gene expression profiles. Furthermore, The mRNA and protein expression levels of B cell activating factor (BAFF), which belongs to the TNF family, and a proliferation-inducing ligand (APRIL) were markedly up-regulated at the disease stage. In particular, the dramatic enhancement of BAFF and APRIL in the pleural effusion of patients with tuberculosis pleurisy suggests that these proteins may present disease status. In addition, we found that the BAFF/APRIL system was closely related to the Th1 immune response. Our study delineates previously unreported roles of BAFF and APRIL in the development of tuberculosis, and these findings have implications for the diagnosis of the disease. Our study also identifies a number of transcriptional signatures in CD4+ T cells that have the potential to be utilized as diagnostic and prognostic tools to combat the tuberculosis epidemic.

Liu, Kai; Zhang, Yan; Hu, Shizong; Yu, Yang; Yang, Qianting; Jin, Dongdong; Chen, Xinchun; Jin, Qi; Liu, Haiying



Reduced Frequency of Memory T Cells and Increased Th17 Responses in Patients with Active Tuberculosis  

PubMed Central

Phenotypic and functional alterations in Mycobacterium tuberculosis T cell subsets have been reported in patients with active tuberculosis. A better understanding of these alterations will increase the knowledge about immunopathogenesis and also may contribute to the development of new diagnostics and prophylactic strategies. Here, the ex vivo phenotype of CD4+ and CD8+ T cells and the frequency and phenotype of gamma interferon (IFN-?)- and interleukin 17 (IL-17)-producing cells elicited in short-term and long-term cultures following CFP-10 and purified protein derivative (PPD) stimulation were determined in noninfected persons (non-TBi), latently infected persons (LTBi), and patients with active tuberculosis (ATB). Phenotypic characterization of T cells was done based on the expression of CD45RO and CD27. Results show that ATB had a reduced frequency of circulating CD4+ CD45RO+ CD27+ T cells and an increased frequency of CD4+ CD45RO? CD27+ T cells. ATB also had a higher frequency of circulating IL-17-producing CD4+ T cells than did LTBi after PPD stimulation, whereas LTBi had more IFN-?-producing CD4+ T cells than did non-TBi. The phenotype of IFN-?-producing cells at 24 h differs from the phenotype of IL-17-producing cells with no differences between LTBi and ATB. At 144 h, IFN-?- and IL-17-producing cells were mainly CD45RO+ CD27+ T cells and they were more frequent in ATB. These results suggest that M. tuberculosis infection induces alterations in T cells which interfere with an adequate specific immune response.

Marin, Nancy D.; Paris, Sara C.; Rojas, Mauricio



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


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



Activities of Drug Combinations against Mycobacterium tuberculosis Grown in Aerobic and Hypoxic Acidic Conditions  

PubMed Central

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

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



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


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

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



Role of Metal Ions on the Activity of Mycobacterium tuberculosis Pyrazinamidase  

PubMed Central

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

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



Tuberculosis (TB)  


... email. » Register for ENews Home > Lung Disease > Tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease that usually infects ... can attack almost any part of the body. Tuberculosis is spread from person to person through the ...


Evaluating of Oleoresin Capsicum (OC) Use by Law Enforcement Agencies: Impact on Injuries to Officers and Suspects. Final Activity Report.  

National Technical Information Service (NTIS)

This report describes a two-year study to collect and analyze data on injuries to suspects resulting from police use of force and to officers from assaults occurring in the line of duty. Information from multiple sources was abstracted from hard copy and ...

J. M. Bowling M. Gaines



Higher Frequency of T-Cell Response to M. tuberculosis Latency Antigen Rv2628 at the Site of Active Tuberculosis Disease than in Peripheral Blood  

Microsoft Academic Search

RationaleDue to the invasive nature of the procedures involved, most studies of Mycobacterium tuberculosis (Mtb)-specific immunity in humans have focused on the periphery rather than the site of active infection, the lung. Recently, antigens associated with Mtb-latency and -dormancy have been described using peripheral blood (PB) cells; however their response in the lung is unknown. The objective of this report

Teresa Chiacchio; Elisa Petruccioli; Valentina Vanini; Ornella Butera; Gilda Cuzzi; Linda Petrone; Giuseppe Matteucci; Francesco Nicola Lauria; Kees L. M. C. Franken; Enrico Girardi; Tom H. M. Ottenhoff; Delia Goletti



[A study on relation between active pulmonary tuberculosis and underlying diseases].  


A study was made on the relation between active pulmonary tuberculosis and underlying diseases in 119 tuberculosis patients. Out of total 119 patients, 87 patients (73.1%) had underlying diseases. The most common underlying disease was diabetes mellitus in 34 patients (39.1%), followed by HCV (+) chronic hepatitis, sequela of cerebral infarction, hypertension and gastric ulcer. In patients who had underlying diseases, the mean age was higher, proportion of sputum smear positive cases was higher, albumin was lower, and period until sputum culture negative conversion was longer. In patients who had diabetes mellitus, proportion of cases with cavity on chest X-P was higher, and in patients who had sequela of cerebral infarction or hypertension, mean age was higher. In patients who had diabetes mellitus and whose HbA1C was > or = 9%, proportion of smear positive cases was higher, albumin was lower and period until culture negative conversion was longer than in patients who had diabetes mellitus and whose HbA1c was < 9%, suggesting that control of blood sugar in diabetes mellitus related to severity of pulmonary tuberculosis. In patients who had diabetes mellitus and whose albumin was < 3 g/dl, period until culture negative conversion was longer than in patients who had diabetes mellitus and whose albumin was > or = 3 g/dl. In patients who had underlying diseases, these diseases caused decline of tuberculous immunity and nutritional disturbance represented by lower albumin also promoted decline of tuberculous immunity. It is suggested that the underlying diseases affected the onset and progression of pulmonary tuberculosis. PMID:11676119

Tamura, M; Shirayama, R; Kasahara, R; Miyazaki, R; Yoshikawa, M; Tsukaguchi, K; Yoneda, T; Narita, N



C4-Alkylthiols with activity against Moraxella catarrhalis and Mycobacterium tuberculosis  

PubMed Central

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

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



[Managment of tuberculosis in an University of Campania].  


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


Field Evaluation of a Rapid Immunochromatographic Test for Tuberculosis  

PubMed Central

Rapid diagnostic tests for tuberculosis (TB) are needed to facilitate early treatment of TB and prevention of Mycobacterium tuberculosis transmission. The ICT Tuberculosis test is a rapid, card-based immunochromatographic test for detection of antibodies directed against M. tuberculosis antigens. The objective of the study was to evaluate the performance of the ICT Tuberculosis test for the diagnosis of active pulmonary TB (PTB) with whole blood, plasma, and serum from patients suspected of having PTB and from asymptomatic controls in a setting with a high prevalence of PTB. Seventy patients suspected of having PTB (and who were later confirmed to have or not to have PTB by use of M. tuberculosis culture as the “gold standard”) and 42 controls were studied. Twenty-one controls were neither vaccinated with Mycobacterium bovis bacillus Calmette-Guérin (BCG) nor tuberculin skin test (TST) positive (group A controls), and 21 controls were TST positive and/or had previously been vaccinated with BCG (group B controls). Study subjects were drawn from one hospital and one primary health care unit in Rio de Janeiro City, Brazil. One version of the test (ICT-1) was evaluated by using whole blood, plasma, and serum samples. Sera obtained for this study were frozen and later tested with a manufacturer-modified version of the test (ICT-2). Among the patients suspected of having PTB, the sensitivities of the ICT-1 with whole blood, serum, and plasma were 83, 65, and 70%, respectively, and the specificities were 46, 67, and 56%, respectively. Among the group A controls, the specificities of ICT-1 with the three specimen types were 95, 100, and 95%, respectively. Among the group B controls, the specificities of ICT-1 with the three specimen types were 71, 86, and 86%, respectively. Among the patients suspected of having PTB, the sensitivity of ICT-2 was 70% and the specificity was 65%. Among the group A controls, the specificity of ICT-2 was 95%, and among the group B controls, the specificity of ICT-2 was 81%. With a 29% observed prevalence of PTB among patients suspected of having PTB, the positive predictive values of the ICT tests ranged from 39 to 50% and the negative predictive values ranged from 82 to 87%. The ICT Tuberculosis tests were not sufficiently predictive to warrant their widespread use as routine diagnostic tests for PTB in this setting. However, further evaluation of these tests in specific epidemiologic settings may be warranted.

Gounder, Celine; de Queiroz Mello, Fernanda Carvalho; Conde, Marcus B.; Bishai, William R.; Kritski, Afranio L.; Chaisson, Richard E.; Dorman, Susan E.



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.

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



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

PubMed Central

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

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



Tuberculosis and nutrition  

PubMed Central

Malnutrition and tuberculosis are both problems of considerable magnitude in most of the underdeveloped regions of the world. These two problems tend to interact with each other. Tuberculosis mortality rates in different economic groups in a community tend to vary inversely with their economic levels. Similarly, nutritional status is significantly lower in patients with active tuberculosis compared with healthy controls. Malnutrition can lead to secondary immunodeficiency that increases the host's susceptibility to infection. In patients with tuberculosis, it leads to reduction in appetite, nutrient malabsorption, micronutrient malabsorption, and altered metabolism leading to wasting. Both, protein-energy malnutrition and micronutrients deficiencies increase the risk of tuberculosis. It has been found that malnourished tuberculosis patients have delayed recovery and higher mortality rates than well-nourished patients. Nutritional status of patients improves during tuberculosis chemotherapy. High prevalence of human immunodeficiency (HIV) infection in the underdeveloped countries further aggravates the problem of malnutrition and tuberculosis. Effect of malnutrition on childhood tuberculosis and tuberculin skin test are other important considerations. Nutritional supplementation may represent a novel approach for fast recovery in tuberculosis patients. In addition, raising nutritional status of population may prove to be an effective measure to control tuberculosis in underdeveloped areas of world.

Gupta, Krishna Bihari; Gupta, Rajesh; Atreja, Atulya; Verma, Manish; Vishvkarma, Suman



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


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

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



Antimycobacterial activity of bisbenzylisoquinoline alkaloids from Tiliacora triandra against multidrug-resistant isolates of Mycobacterium tuberculosis.  


Bisbenzylisoquinoline alkaloids, tiliacorinine (1), 2'-nortiliacorinine (2), and tiliacorine (3), isolated from the edible plant, Tiliacora triandra, as well as a synthetic derivative, 13'-bromo-tiliacorinine (4), were tested against 59 clinical isolates of multidrug-resistant Mycobacterium tuberculosis (MDR-MTB). The alkaloids 1-4 showed MIC values ranging from 0.7 to 6.2 ?g/ml, but they exhibited the MIC value at 3.1 ?g/ml against most MDR-MTB isolates. The present work suggests that bisbenzylisoquinoline alkaloids are potential new chemical scaffolds for antimycobacterial activity. PMID:22418278

Sureram, Sanya; Senadeera, Sarath P D; Hongmanee, Poonpilas; Mahidol, Chulabhorn; Ruchirawat, Somsak; Kittakoop, Prasat



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


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



Assessment of clofazimine activity in a second-line regimen for tuberculosis in mice.  


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

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



Suspected Motor Problems and Low Preference for Active Play in Childhood Are Associated with Physical Inactivity and Low Fitness in Adolescence  

PubMed Central

Background This prospective longitudinal study investigates whether suspected motor problems and low preference for active play in childhood are associated with physical inactivity and low cardiorespiratory fitness in adolescence. Methodology/Principal Findings The study sample consisted of the Northern Finland Birth Cohort 1986 (NFBC 1986) composed of 5,767 children whose parents responded to a postal inquiry concerning their children's motor skills at age 8 years and who themselves reported their physical activity at age 16 years. Cardiorespiratory fitness was measured with a cycle ergometer test at age 16 years. Odds ratios (OR) and their 95% confidence intervals (95% CI) for the level of physical activity and fitness were obtained from multinomial logistic regression and adjusted for socio-economic position and body mass index. Low preference for active play in childhood was associated with physical inactivity (boys: OR 3.31, 95% CI 2.42–4.53; girls: OR 1.79, 95% CI 1.36–2.36) and low cardiorespiratory fitness (boys: OR 1.87, 95% CI 1.27–2.74; girls: OR 1.52, 95% CI 1.09–2.11) in adolescence. Suspected gross (OR 2.16, 95% CI 1.33–3.49) and fine (OR 1.88, 95% CI 1.35–2.60) motor problems were associated with physical inactivity among boys. Children with suspected motor problems and low preference for active play tended to have an even higher risk of physical inactivity in adolescence. Conclusions/Significance Low preference for active play in childhood was associated with physical inactivity and low cardiorespiratory fitness in adolescence. Furthermore, children with suspected motor problems and low preference for active play tended to have an even higher risk of physical inactivity in adolescence. Identification of children who do not prefer active play and who have motor problems may allow targeted interventions to support their motor learning and participation in active play and thereby promote their physical activity and fitness in later life.

Kantomaa, Marko T.; Purtsi, Jarno; Taanila, Anja M.; Remes, Jouko; Viholainen, Helena; Rintala, Pauli; Ahonen, Timo; Tammelin, Tuija H.



Effects of weak acids, UV and proton motive force inhibitors on pyrazinamide activity against Mycobacterium tuberculosis in vitro  

Microsoft Academic Search

Background: Pyrazinamide is a paradoxical frontline tuberculosis drug characterized by high sterilizing in vivo activity but poor in vitro activity. Pyrazinamide is thought to act by the entrapment of pyrazinoic acid in the bacterial cell, leading to acidification and membrane damage. Consequently, the effects of weak acids and molecules affecting membranes added to pyrazinamide were studied. Objectives: To examine the

Mary Margaret Wade; Ying Zhang



Novel Biomarkers Distinguishing Active Tuberculosis from Latent Infection Identified by Gene Expression Profile of Peripheral Blood Mononuclear Cells  

Microsoft Academic Search

BackgroundHumans infected with Mycobacterium tuberculosis (MTB) can delete the pathogen or otherwise become latent infection or active disease. However, the factors influencing the pathogen clearance and disease progression from latent infection are poorly understood. This study attempted to use a genome-wide transcriptome approach to identify immune factors associated with MTB infection and novel biomarkers that can distinguish active disease from

Chanyi Lu; Jing Wu; Honghai Wang; Sen Wang; Ni Diao; Feifei Wang; Yan Gao; Jiazhen Chen; Lingyun Shao; Xinhua Weng; Ying Zhang; Wenhong Zhang



The Tim3-Galectin 9 Pathway Induces Antibacterial Activity in Human Macrophages Infected with Mycobacterium tuberculosis  

PubMed Central

T cell Ig and mucin domain 3 (Tim3) is an inhibitory molecule involved in immune tolerance, autoimmune responses, and antiviral immune evasion. However, we recently demonstrated that Tim3 and Galectin-9 (Gal9) interaction induces a program of macrophage activation that results in killing of Mycobacterium tuberculosis in the mouse model of infection. In this study, we sought to determine whether the Tim3–Gal9 pathway plays a similar role in human pulmonary TB. We identified that pulmonary TB patients have reduced expression of Tim3 on CD14+ monocytes in vivo. By blocking Tim3 and Gal9 interaction in vitro, we show that these molecules contribute to the control of intracellular bacterial replication in human macrophages. The antimicrobial effect was partially dependent on the production of IL-1?. Our results establish that Tim3–Gal9 interaction activates human M. tuberculosis –infected macrophages and leads to the control of bacterial growth through the production of the proinflammatory cytokine IL-1?. Data presented in this study suggest that one of the potential pathways activated by Tim3/Gal9 is the secretion of IL-1?, which plays a crucial role in antimicrobial immunity by modulating innate inflammatory networks.

Chavez-Galan, Leslie; Torre-Bouscoulet, Luis; Nava-Gamino, Lourdes; Barrera, Lourdes; Jayaraman, Pushpa; Torres-Rojas, Martha; Salazar-Lezama, Miguel Angel; Behar, Samuel M.



QuantiFERON(R)-TB Gold In-Tube Performance for Diagnosing Active Tuberculosis in Children and Adults in a High Burden Setting  

PubMed Central

Aim To determine whether QuantiFERON®-TB Gold In-Tube (QFT) can contribute to the diagnosis of active tuberculosis (TB) in children in a high-burden setting and to assess the performance of QFT and tuberculin skin test (TST) in a prospective cohort of TB suspect children compared to adults with confirmed TB in Tanzania. Methods Sensitivity and specificity of QFT and TST for diagnosing active TB as well as indeterminate QFT rates and IFN-? levels were assessed in 211 TB suspect children in a Tanzanian district hospital and contrasted in 90 adults with confirmed pulmonary TB. Results Sensitivity of QFT and TST in children with confirmed TB was 19% (5/27) and 6% (2/31) respectively. In adults sensitivity of QFT and TST was 84% (73/87) and 85% (63/74). The QFT indeterminate rate in children and adults was 27% and 3%. Median levels of IFN-? were lower in children than adults, particularly children <2 years and HIV infected. An indeterminate result was associated with age <2 years but not malnutrition or HIV status. Overall childhood mortality was 19% and associated with an indeterminate QFT result at baseline. Conclusion QFT and TST showed poor performance and a surprisingly low sensitivity in children. In contrast the performance in Tanzanian adults was good and comparable to performance in high-income countries. Indeterminate results in children were associated with young age and increased mortality. Neither test can be recommended for diagnosing active TB in children with immature or impaired immunity in a high-burden setting.

Rose, Michala V.; Kimaro, Godfather; Nissen, Thomas N.; Kroidl, Inge; Hoelscher, Michael; Bygbjerg, Ib C.; Mfinanga, Sayoki G.; Ravn, Pernille



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

Microsoft Academic Search

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

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



Detection of interleukin-2 in addition to interferon-gamma discriminates active tuberculosis patients, latently infected individuals, and controls.  


Effective control of tuberculosis (TB) includes discrimination of subjects with active TB from individuals with latent TB infection (LTBI). As distinct interferon (IFN)-gamma and interleukin (IL)-2 profiles of antigen-specific T-cells have been associated with different clinical stages and antigen loads in several viral and bacterial diseases, we analysed these cytokines in TB using a modified QuantiFERON-TB Gold In Tube test. Detection of IL-2 in addition to IFN-gamma distinguishes not only Mycobacterium tuberculosis-infected subjects from healthy controls, but also individuals with LTBI from active TB patients. This may help to improve diagnostic tests for TB. PMID:19886902

Biselli, R; Mariotti, S; Sargentini, V; Sauzullo, I; Lastilla, M; Mengoni, F; Vanini, V; Girardi, E; Goletti, D; D' Amelio, R; Nisini, R



Comparison of Three Methods for the Identification of Mycobacterium tuberculosis  

Microsoft Academic Search

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



Transcriptional profile of the immune response in the lungs of patients with active tuberculosis.  


Despite advances in diagnosis and treatment, Mycobacterium tuberculosis causes active disease in about 8 million people worldwide annually. The study of the interplay between the host and the pathogen at the site of infection in human TB may contribute to elucidate the pathogenesis of the disease. In this work, using macroarray technology and real-time PCR, we analyzed the modulation of 847 genes encoding immune-inflammatory mediators in BALF samples of patients affected by active pulmonary TB (PTB) and control patients affected by non-TB diseases. The data show that the PTB milieu contains a complex network of gene activation. Different genes with adhesive properties and involved in tissue repair and fibrosis were modulated. In TB patients, we observed the up-regulation of cytokines, including IFN-gamma and IFN-gamma pathway genes, of several apoptotic genes, and of potent transcriptional activators. These findings can contribute to elucidate the mechanisms of MTB pathogenicity in humans. PMID:16905363

Grassi, Manuela; Bocchino, Marialuisa; Marruchella, Almerico; Volpe, Elisabetta; Saltini, Cesare; Colizzi, Vittorio; Mariani, Francesca



Health Care Workers and Tuberculosis  


... Active tuberculosis is much less common than a tuberculosis infection, which your immune system can suppress on its own. If I had bacille Calmette-Guérin (BCG) vaccine, do I need to have a skin test? ...


Suspected adverse reactions, 2008  

Microsoft Academic Search

Reports to the UK Suspected Adverse Reaction Surveillance Scheme (SARSS) in 2008 increase by around 11 per cent compared with 2007Low incidence of suspected adverse reactions following bluetongue virus vaccinationIncrease in reports of suspected lack of efficacy to canine parvovirus vaccinationRabbit deaths reported after off-label use of dexmedetomidineThese are some of the results from the SARSS in 2008, as discussed

F. Dyer; E. Brown; S. Cooles; A. Tait



Loss of kinase activity in Mycobacterium tuberculosis multidomain protein Rv1364c.  


The alternative sigma factors are regulated by a phosphorylation-mediated signal transduction cascade involving anti-sigma factors and anti-anti-sigma factors. The proteins regulating Mycobacterium tuberculosis sigma factor F (SigF), anti-SigF and anti-anti-SigF have been identified, but the factors catalyzing phosphorylation-dephosphorylation have not been well established. We identified a distinct pathogenic species-specific multidomain protein, Rv1364c, in which the components of the entire signal transduction cascade for SigF regulation appear to be encoded in a single polypeptide. Sequence analysis of M. tuberculosis Rv1364c resulted in the prediction of various domains, namely a phosphatase (RsbU) domain, an anti-SigF (RsbW) domain, and an anti-anti-SigF (RsbV) domain. We report that the RsbU domain of Rv1364c bears all the conserved features of the PP2C-type serine/threonine phosphatase family, whereas its RsbW domain has certain substitutions and deletions in regions important for ATP binding. Another anti-SigF protein in M. tuberculosis, UsfX (Rv3287c), shows even more unfavorable substitutions in the kinase domain. Biochemical assay with the purified RsbW domain of Rv1364c and UsfX showed the loss of ability of autophosphorylation and phosphotransfer to cognate anti-anti-SigF proteins or artificial substrates. Both the Rv1364c RsbW domain and UsfX protein display very weak binding with fluorescent ATP analogs, despite showing functional interactions characteristic of anti-SigF proteins. In view of conservation of specific interactions with cognate sigma and anti-anti-sigma factor, the loss of kinase activity of Rv1364c and UsfX appears to form a missing link in the phosphorylation-dependent interaction involved in SigF regulation in Mycobacterium. PMID:19016841

Sachdeva, Preeti; Narayan, Azeet; Misra, Richa; Brahmachari, Vani; Singh, Yogendra



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

PubMed Central

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

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



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.



Active case finding for tuberculosis among high-risk groups in low-incidence countries.  


In low-incidence countries, tuberculosis (TB) is now largely concentrated in high-risk groups such as migrants, homeless people, illicit drug users, alcoholics and prisoners. This has led to increased efforts to implement targeted active case finding for TB among specific populations. This review examines the evidence supporting active case finding in migrants and social risk groups, as well as the cost-effectiveness of interventions. While data from observational studies support active case finding in defined high-risk groups, further research to determine the effectiveness of specific tools and the cost-effectiveness of screening strategies is needed to inform evidence-based control methods in low-incidence countries. Inevitably, addressing TB in low-incidence countries will depend on effective disease control in high-burden countries. PMID:23575321

Zenner, D; Southern, J; van Hest, R; DeVries, G; Stagg, H R; Antoine, D; Abubakar, I



Pulmonary Tuberculoma and Miliary Tuberculosis in Silicosis  

PubMed Central

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

Verma, Sanjeev Kumar; Karmakar, Saurabh



Discovery of new 1,3,5-triazine scaffolds with potent activity against Mycobacterium tuberculosis H37Rv.  


A series of eighty one 2,4,6-trisubstituted-1,3,5-triazines were synthesized and evaluated in vitro for the growth inhibition of Mycobacterium tuberculosis H37Rv. Fifteen compounds from this series exhibited good to moderate activity with an MIC in the range 1.56-3.12 microg/mL and most of them were found to be nontoxic against VERO cells and MBMDMQs (mouse bone marrow derived macrophages). This is for the first time that 2,4,6-trisubstituted-1,3,5-triazines were identified as a potent inhibitors of M. tuberculosis H37Rv. PMID:20452706

Sunduru, Naresh; Gupta, Leena; Chaturvedi, Vinita; Dwivedi, Richa; Sinha, Sudhir; Chauhan, Prem M S



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


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

Magombedze, Gesham; Mulder, Nicola



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


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

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



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

Microsoft Academic Search

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

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



Catalytic synthesis of enantiopure mixed diacylglycerols - synthesis of a major M. tuberculosis phospholipid and platelet activating factor.  


An efficient catalytic one-pot synthesis of TBDMS-protected diacylglycerols has been developed, starting from enantiopure glycidol. Subsequent migration-free deprotection leads to stereo- and regiochemically pure diacylglycerols. This novel strategy has been applied to the synthesis of a major Mycobacterium tuberculosis phospholipid, its desmethyl analogue, and platelet activating factor. PMID:24057355

Fodran, Peter; Minnaard, Adriaan J



Chlorinated Coumarins from the Polypore Mushroom Fomitopsis officinalis and Their Activity against Mycobacterium tuberculosis.  


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

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



Immune Complexes Isolated from Patients with Pulmonary Tuberculosis Modulate the Activation and Function of Normal Granulocytes  

PubMed Central

Circulating immune complexes (ICs) are associated with the pathogenesis of several diseases. Very little is known about the effect of ICs on the host immune response in patients with tuberculosis (TB). The effects of ICs isolated from patients with TB in modulating the release of calcium, cytokines, and granular proteins were studied in normal granulocytes, as were their chemotactic, phagocytic, and oxidative burst processes. ICs from TB patients induced decreased production of cytokines and platelet-activating factor (PAF) from normal granulocytes. ICs from TB patients also induced enhanced chemotaxis and phagocytosis but caused diminished oxidative burst. This was accompanied by an increased release in intracellular calcium. On the other hand, ICs from TB patients induced increased release of the granular proteins human neutrophil peptides 1 to 3 (HNP1–3). Thus, ICs from patients with TB exhibit a profound effect on granulocyte function with activation of certain effector mechanisms and dampening of others.

Senbagavalli, P.; Hilda, J. Nancy; Ramanathan, V. D.; Kumaraswami, V.; Nutman, Thomas B.



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.



Design, Synthesis and Study of a Mycobactin-artemisinin Conjugate that has Selective and Potent Activity Against Tuberculosis and Malaria  

PubMed Central

Although the antimalarial agent, artemisinin itself is not active against tuberculosis, conjugation to a mycobacterial specific siderophore (microbial iron chelator) analog induces significant and selective anti-tuberculosis activity, including activity against MDR and XDR strains of Mtb. The conjugate also retains potent antimalarial activity. Physicochemical and whole cell studies indicate that ferric to ferrous reduction of the iron complex of the conjugate initiates the expected bactericidal Fenton-type radical chemistry on the artemisinin component. Thus, this “Trojan Horse” approach demonstrates that new pathogen selective therapeutic agents can be generated in which the iron component of the delivery vehicle also participates in triggering the antibiotic activity. The result is that one appropriate conjugate has potent and selective activity against two of the most deadly diseases in the world.

Miller, Marvin J.; Walz, Andrew J.; Zhu, Helen; Wu, Chunrui; Moraski, Garrett; Mollmann, Ute; Tristani, Esther M.; Crumbliss, Alvin L.; Ferdig, Michael T.; Checkley, Lisa; Edwards, Rachel L.; Boshoff, Helena I.



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.  

PubMed Central

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 Mycobacterium tuberculosis, and the radioactive bromide partition test (BPT) in the cerebrospinal fluid (CSF). Cerebrospinal fluid specimens from children with tuberculous, pyogenic, and viral meningitis as well as from patients with pulmonary tuberculosis without meningitis and from controls with normal CSFs were included inn the study. In addition, we estimated ADAs in serum samples from selected children in these groups. The sensitivity and specificity of the three tests evaluated in the CSF were: ADA assay 73% and 71%; BPT 92% and 92%; and ELISA for antibody to antigen 5, 53% and 90%, 40% and 94%, and 27% and 100%, respectively, at tires of more than or equal to 1:20, 1:40, and 1:80. The serum ADA was lower (11.0 +/- 6.15 IU/l) in children with tuberculous meningitis when compared with those with pulmonary tuberculosis alone (25.8 +/- 20.9 IU/l). The BPT was found to be the most reliable test in the early differentiation of tuberculous from other causes of meningitis and remained abnormal for a period of up to five months after the beginning of treatment. Accordingly, we believe that the BPT should be used in conjunction with bacterial and fungal antigen detection systems for the initial differentiation of clinically suspicious tuberculous meningitis from Gram or culture negative cases, or both, of bacterial and fungal meningitis.

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



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

Microsoft Academic Search

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

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


Mannose-capped Lipoarabinomannan from Mycobacterium tuberculosis induces soluble tumor necrosis factor receptor production through tumor necrosis factor alpha-converting enzyme activation.  


Primary Mycobacterium tuberculosis infection results in granuloma formation in lung tissue. A granuloma encapsulates mycobacterium-containing cells, thereby preventing dissemination and further infection. Tumor necrosis factor alpha (TNF-?) is a host-protective cytokine during M. tuberculosis infection due to its role in promoting and sustaining granuloma formation. TNF activity is regulated through the production of soluble TNF receptors (sTNFRI and sTNFRII). Therefore, we examined the potential production of endogenous sTNFRs during M. tuberculosis infection. Using the murine model of aerosol M. tuberculosis infection, we determined that levels of sTNFR production were elevated in bronchoalveolar lavage fluid 1 month following infection. An investigation of M. tuberculosis cell wall components identified that the known virulence factor mannose-capped lipoarabinomannan (ManLAM) was sufficient to induce sTNFR production, with sTNFRII being produced preferentially compared with sTNFRI. ManLAM stimulated the release of sTNFRs without TNF production, which corresponded to an increase in TNF-?-converting enzyme (TACE) activity. To determine the relevance of these findings, serum samples from M. tuberculosis-infected patients were tested and found to have an increase in the sTNFRII/sTNFRI ratio. These data identify a mechanism by which M. tuberculosis infection can promote the neutralization of TNF and furthermore suggest the potential use of the sTNFRII/sTNFRI ratio as an indicator of tuberculosis disease. PMID:22927046

Richmond, Jillian M; Duffy, Elizabeth R; Lee, Jinhee; Kaboli, Kavon; Kim, Yun Seong; Remick, Daniel G; Kornfeld, Hardy; Cruikshank, William W



Mannose-Capped Lipoarabinomannan from Mycobacterium tuberculosis Induces Soluble Tumor Necrosis Factor Receptor Production through Tumor Necrosis Factor Alpha-Converting Enzyme Activation  

PubMed Central

Primary Mycobacterium tuberculosis infection results in granuloma formation in lung tissue. A granuloma encapsulates mycobacterium-containing cells, thereby preventing dissemination and further infection. Tumor necrosis factor alpha (TNF-?) is a host-protective cytokine during M. tuberculosis infection due to its role in promoting and sustaining granuloma formation. TNF activity is regulated through the production of soluble TNF receptors (sTNFRI and sTNFRII). Therefore, we examined the potential production of endogenous sTNFRs during M. tuberculosis infection. Using the murine model of aerosol M. tuberculosis infection, we determined that levels of sTNFR production were elevated in bronchoalveolar lavage fluid 1 month following infection. An investigation of M. tuberculosis cell wall components identified that the known virulence factor mannose-capped lipoarabinomannan (ManLAM) was sufficient to induce sTNFR production, with sTNFRII being produced preferentially compared with sTNFRI. ManLAM stimulated the release of sTNFRs without TNF production, which corresponded to an increase in TNF-?-converting enzyme (TACE) activity. To determine the relevance of these findings, serum samples from M. tuberculosis-infected patients were tested and found to have an increase in the sTNFRII/sTNFRI ratio. These data identify a mechanism by which M. tuberculosis infection can promote the neutralization of TNF and furthermore suggest the potential use of the sTNFRII/sTNFRI ratio as an indicator of tuberculosis disease.

Richmond, Jillian M.; Duffy, Elizabeth R.; Lee, Jinhee; Kaboli, Kavon; Remick, Daniel G.; Kornfeld, Hardy



Immediate cementless total hip arthroplasty for the treatment of active tuberculosis.  


We report the results of a primary total hip arthroplasty (THA) in 7 patients with advanced active tuberculous arthritis of the hip and had lost the chance of preserving the hip without replacement surgery. Tuberculosis was confirmed in all cases by the culture or histological examination. All patients were treated with primary THA followed by antituberculous medications for 1 year. Cementless stems and sockets were used in all patients. The average follow-up period was 4.8 years. The reactivation of the infection was not detected in all cases. The result was excellent in all patients according to the Harris Hip Score. Total hip arthroplasty in the tuberculous hip is a safe procedure and produces superior functional results compared with resection arthroplasty or arthrodesis. The results of primary THA in the selected patients was satisfactory as they rapidly recover from the disease. PMID:16230246

Yoon, Taek Rim; Rowe, Sung Man; Santosa, Setyagung Budi; Jung, Sung Taek; Seon, Jong Keun



Screening a library of 1,600 adamantyl ureas for anti-Mycobacterium tuberculosis activity in vitro and for better physical chemical properties for bioavailability  

PubMed Central

Adamantyl ureas were previously identified as a group of compounds active against Mycobacterium tuberculosis in culture with minimum inhibitor concentrations (MICs) below 0.1 ?g/ml. These compounds have been shown to target MmpL3, a protein involved in secretion of trehalose mono-mycolate. They also inhibit both human soluble epoxide hydrolase (hsEH) and M. tuberculosis epoxide hydrolases. However, active compounds to date have high cLogP’s and are poorly soluble, leading to low bioavailability and thus limiting any therapeutic application. In this study, a library of 1,600 ureas (mostly adamantyl ureas), which were synthesized for the purpose of increasing the bioavailability of inhibitors of hsEH, was screened for activity against M. tuberculosis. 1-Adamantyl-3-phenyl ureas with a polar para substituent were found to retain moderate activity against M. tuberculosis and one of these compounds was shown to be present in serum after oral administration to mice. However, neither it, nor a closely related analog, reduced M. tuberculosis infection in mice. No correlation between in vitro potency against M. tuberculosis and the hsEH inhibition were found supporting the concept that activity against hsEH and M. tuberculosis can be separated. Also there was a lack of correlation with cLogP and inhibition of the growth of M. tuberculosis. Finally, members of two classes of adamantyl ureas that contained polar components to increase their bioavailability, but lacked efficacy against growing M. tuberculosis, were found to taken up by the bacterium as effectively as a highly active apolar urea suggesting that these modifications to increase bioavailability affected the interaction of the urea against its target rather than making them unable to enter the bacterium.

Scherman, Michael S.; North, Elton J.; Jones, Victoria; Hess, Tammara N.; Grzegorzewicz, Anna E.; Kasagami, Takeo; Kim, In-Hae; Merzlikin, Oleg; Lenaerts, Anne J.; Lee, Richard E.; Jackson, Mary; Morisseau, Christophe; McNeil, Michael R.



Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site.  


Mycobacterium tuberculosis salicylate synthase (MbtI) catalyses the first committed step in the biosynthesis of mycobactin T, an iron-chelating siderophore essential for the virulence and survival of M. tuberculosis. Co-crystal structures of MbtI with members of a first generation inhibitor library revealed large inhibitor-induced rearrangements within the active site of the enzyme. This plasticity of the MbtI active site was probed via the preparation of a library of inhibitors based on a 2,3-dihydroxybenzoate scaffold with a range of substituted phenylacrylate side chains appended to the C3 position. Most compounds exhibited moderate inhibitory activity against the enzyme, with inhibition constants in the micromolar range, while several dimethyl ester variants possessed promising anti-tubercular activity in vitro. PMID:23108268

Manos-Turvey, Alexandra; Cergol, Katie M; Salam, Noeris K; Bulloch, Esther M M; Chi, Gamma; Pang, Angel; Britton, Warwick J; West, Nicholas P; Baker, Edward N; Lott, J Shaun; Payne, Richard J



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



BCG Vaccination and Active Tuberculosis Prevention: A Three-Year Study  

Microsoft Academic Search

Background: Six to eight million people are infected with tuberculosis (TB) annually throughout the world, out of which 2 to 3 million die. BCG vaccination and its efficacy are always used in tuberculosis control planning. There are different rates of BCG vaccination efficacy in the world from 0 to 80%. BCG vaccine has different efficacy in endemic and non-endemic areas.

Masoomeh Alimagham; Saeid Aminiafshar; Siamak Farahmand; Parviz Vahdani; Mostafa Alavi; Kamran Sharafi


Sterilizing Activity of Second-Line Regimens Containing TMC207 in a Murine Model of Tuberculosis  

PubMed Central

Rationale The sterilizing activity of the regimen used to treat multidrug resistant tuberculosis (MDR TB) has not been studied in a mouse model. Objective and Methods Swiss mice were intravenously inoculated with 6 log10 of Mycobacterium tuberculosis (TB) strain H37Rv, treated with second-line drug combinations with or without the diarylquinoline TMC207, and then followed without treatment for 3 more months to determine relapse rates (modified Cornell model). Measurements Bactericidal efficacy was assessed by quantitative lung colony-forming unit (CFU) counts. Sterilizing efficacy was assessed by measuring bacteriological relapse rates 3 months after the end of treatment. Main Results The relapse rate observed after 12 months treatment with the WHO recommended MDR TB regimen (amikacin, ethionamide, pyrazinamide and moxifloxacin) was equivalent to the relapse rate observed after 6 months treatment with the recommended drug susceptible TB regimen (rifampin, isoniazid and pyrazinamide). When TMC207 was added to this MDR TB regimen, the treatment duration needed to reach the same relapse rate dropped to 6 months. A similar relapse rate was also obtained with a 6-month completely oral regimen including TMC207, moxifloxacin and pyrazinamide but excluding both amikacin and ethionamide. Conclusions In this murine model the duration of the WHO MDR TB treatment could be reduced to 12 months instead of the recommended 18–24 months. The inclusion of TMC207 in the WHO MDR TB treatment regimen has the potential to further shorten the treatment duration and at the same time to simplify treatment by eliminating the need to include an injectable aminoglycoside.

Lounis, Nacer; Andries, Koen; Jarlier, Vincent



Differential serum cytokine levels are associated with cytokine gene polymorphisms in north Indians with active pulmonary tuberculosis.  


Globally only 5-10% of people encountering Mycobacterium tuberculosis have a lifetime risk of active disease indicating a strong host genetic bias towards development of tuberculosis. In the current study we investigated genotype variants pertaining to five cytokine genes namely IFNG, TNFA, IL4, IL10 and IL12 in the north Indian population with active pulmonary tuberculosis (APTB) and correlated the serum cytokine levels with the corresponding genotypes. Twenty five single nucleotide polymorphisms (SNPs) including six loci examined for the first time in tuberculosis were selected for genotyping in 108 patients with APTB from north India and 48 healthy regional controls (HC). Applying exclusion criteria 12 SNPs passed all the filters and were analysed further. The serum cytokine concentrations were measured by ELISA. Compared to HC mean serum IFN-?, IL-12, IL-4, and IL-10 levels were higher in APTB (p = 0.3661, p = 0.0186, p = 0.003, p = 0.7, respectively). In contrast the mean serum TNF-? level was higher in HC (p = 0.007). Comparison of genotypes and serum levels of the corresponding cytokine genes reveal that though IFN-? and IL-4 levels were higher in APTB the genotype variants showed no difference between HC and APTB. In contrast the genotypes of the selected rsIDs in the TNFA, IL12 and IL10 genes showed significant association with the varying serum levels of corresponding cytokines. The variant of the TNFA gene at rs3093662, the IL12 gene at rs3213094 and rs3212220 and the IL10 gene at rs3024498 did show a strong indication to be of relevance to the immunity to tuberculosis. To our knowledge this is the first report from this region relating genotypes and serum cytokine levels in north Indian population. PMID:21463712

Abhimanyu; Mangangcha, Irengbam Rocky; Jha, Pankaj; Arora, Komal; Mukerji, Mitali; Banavaliker, Jayant Nagesh; Brahmachari, Vani; Bose, Mridula



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


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

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



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


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

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



The clinical utility of tuberculin skin test and interferon-? release assay in the diagnosis of active tuberculosis among young adults: a prospective observational study  

PubMed Central

Background The roles of the tuberculin skin test (TST) and QuantiFERON®-TB Gold In-Tube assay (QFT-IT) in the diagnosis of active tuberculosis (TB) are not clear in young adults. We evaluated the diagnostic accuracy of the TST and QFT-IT in smear-negative TB among young adults with no underlying disease. Methods We prospectively enrolled 166 young participants 20-29 years of age with suspected active TB in a military hospital of South Korea. The TST and QFT-IT were performed for all participants. Results Of the 143 patients included in the analysis, active TB was diagnosed in 100 (69.9%). There were 141 male patients, none of whom had immunosuppressive disease. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of TST were 94% (95% CI, 87-98%), 88% (95% CI, 74-96%), 95% (95% CI, 88-98%), and 86% (95% CI, 72-94%), respectively. The sensitivity, specificity, PPV, and NPV of the QFT-IT were 93% (95% CI, 86-97%), 95% (95% CI, 81-99%), 98% (95% CI, 92-99%), and 84% (95% CI, 69-93%), respectively. No significant differences were found between the TST and QFT-IT in any statistic. Conclusions Both the TST and QFT-IT showed high sensitivity and specificity in differentiating active TB from other diseases. The diagnostic accuracy of these two tests did not differ significantly when applied to this clinical population of young, immunocompetent adults in whom neonatal BCG vaccination was common, there was no history of previous TB and in whom suspicion of TB was high. Trial registration NCT00982969



IL23R(Arg381Gln) Functional Polymorphism Is Associated with Active Pulmonary Tuberculosis Severity  

PubMed Central

The purpose of our study was to investigate the association between a functional single nucleotide polymorphism (SNP) in the interleukin-23 receptor gene (IL23R; rs11209026, 1142 Gwild type ? Areduced function, Arg381Gln) and disease severity outcome in pulmonary tuberculosis (TB) in the Tunisian population. SNP was investigated in a population of 168 patients with active pulmonary TB (cases were stratified into patients with minimal/moderate lung involvement, i.e., patients with minimal/moderate disease [Pmd], and patients with extensive lung involvement, i.e., patients with active disease [Pad]) and 150 healthy subjects. Genotype analyses were carried out using the PCR-restriction fragment length polymorphism method. We have found that the IL23R reduced-function allele 1142A and genotypes AA and AG were overrepresented, especially in the Pad subgroup compared with the control group (51% versus 18% [P = 10?8], 33% versus 5% [P = 10?8], and 36% versus 26% [P = 5 × 10?3], respectively). Additionally, comparison of the Pad and the Pmd groups showed that the A allele and AA genotype seemed to be associated with 2.79-fold (P = 4 × 10?5) and 7.74-fold (P = 10?5) increased risks of TB with minimal/moderate lung involvement, respectively. Our results demonstrate that the reduced-function polymorphism 1142G ? A encoded by IL23R influences the outcome of disease severity of active pulmonary TB in Tunisian patients.

Boukadida, Jalel



Increased Frequency of Myeloid-derived Suppressor Cells during Active Tuberculosis and after Recent Mycobacterium tuberculosis Infection Suppresses T-Cell Function.  


Rationale: Inadequacy of T-cell responses may result in the development of tuberculosis (TB). Myeloid-derived suppressor cells (MDSCs) have been described as suppressors of T-cell function in cancer biology and recently in several infectious diseases. Objectives: To explore the presence and role of MDSCs in TB. Methods: We analyzed surface markers of MDSCs in peripheral blood and at the site of disease in TB cases and in patients with lung cancer, and in peripheral blood of asymptomatic tuberculin skin test-positive individuals with recent (household) or remote exposure to Mycobacterium tuberculosis (M.tb) and in uninfected healthy control subjects. To evaluate the suppressive capacity of MDSCs, cells of household contacts infected with M.tb and TB cases were isolated and cocultured with CD3(+) T cells. Measurements and Main Results: Our results demonstrate an increased presence of MDSCs after recent M.tb infection and disease. We confirm their suppression of CD4(+) T-cell function, including reduced cytokine responses and inhibition of CD4(+) T-cell proliferation. Only MDSCs from TB cases reduced T-cell activation, altered T-cell trafficking, and suppressed CD8(+) T-cell functions. M.tb-expanded MDSCs were associated with significantly higher IL-1?, IL-6, IL-8, granulocyte colony-stimulating factor, and monocyte chemotactic protein-1, and reduced granulocyte-macrophage colony-stimulating factor and macrophage inflammatory protein-1 beta levels in coculture. Conclusions: These data reveal that innate MDSCs are induced not only during active TB at similar levels as found in cancer, but also in healthy individuals after recent exposure to M.tb. These cells diminish protective T-cell responses and may contribute to the inability of hosts to eradicate the infection and add to the subsequent development of TB disease. PMID:23885784

du Plessis, Nelita; Loebenberg, Laurianne; Kriel, Magdalena; von Groote-Bidlingmaier, Florian; Ribechini, Eliana; Loxton, Andre G; van Helden, Paul D; Lutz, Manfred B; Walzl, Gerhard



The diagnosis of tuberculosis.  


Childhood tuberculosis accounts for a significant proportion of the global tuberculosis disease burden. However, tuberculosis in children is difficult to diagnose, because disease tends to be paucibacillary and sputum samples are often not easy to obtain. The diagnosis of tuberculosis in children is traditionally based on chest radiography, tuberculin skin testing, and mycobacterial staining/culture from appropriate samples. Newer diagnostic strategies have included improved bacteriologic and molecular methods, as well as new methods for sample collection from children. Recently, immune-based diagnostics, such as the interferon-gamma release assays, have been introduced for clinical use. These tests do not offer substantial improvements in sensitivity over tuberculin skin testing for the diagnosis of active disease but may be useful in excluding false-positive tuberculin skin tests. Further research is needed to develop better diagnostic tests for tuberculosis in children. PMID:22330167

Shingadia, Delane



Seasonality of Tuberculosis  

PubMed Central

Objectives: This study was designed to review previous studies and analyse the current knowledge and controversies related to seasonal variability of tuberculosis (TB) to examine whether TB has an annual seasonal pattern. Study Design and Methods: Systematic review of peer reviewed studies identified through literature searches using online databases belonging to PubMed and the Cochrane library with key words “Tuberculosis, Seasonal influence” and “Tuberculosis, Seasonal variation”. The search was restricted to articles published in English. The references of the identified papers for further relevant publications were also reviewed. Results: Twelve studies conducted between the period 1971 and 2006 from 11 countries/regions around the world (South Western Cameroon, South Africa, India, Hong Kong, Japan, Kuwait, Spain, UK, Ireland, Russia, and Mongolia) were reviewed. A seasonal pattern of tuberculosis with a mostly predominant peak is seen during the spring and summer seasons in all of the countries (except South Western Cameroon and Russia). Conclusions: The observation of seasonality leads to assume that the risk of transmission of M. tuberculosis does appear to be the greatest during winter months. Vitamin D level variability, indoor activities, seasonal change in immune function, and delays in the diagnosis and treatment of tuberculosis are potential stimuli of seasonal tuberculosis disease. Additionally, seasonal variation in food availability and food intake, age, and sex are important factors which can play a role in the tuberculosis notification variability. Prospective studies regarding this topic and other related subjects are highly recommended.

Fares, Auda



Endobronchial tuberculosis: histopathological subsets and microbiological results  

PubMed Central

Background Endobronchial tuberculosis (EBTB) is defined as a tuberculous infection of the tracheobronchial tree with microbial and histopathological evidence, with or without parenchymal involvement. Bronchoscopic appearances of EBTB have been divided into seven subtypes: actively caseating, edematous-hyperemic, fibrostenotic, tumorous, granular, ulcerative, and nonspecific bronchitic. However, information for establishing a definite microbiological diagnosis in each of these categories is lacking. We aimed to present bronchoscopic appearances and percentages for the EBTB subtypes and to compare bronchoscopic appearances with microbiological positivity in bronchial lavage fluid. Methods From 2003 to 2009, 23 biopsy-proven EBTB patients were enrolled in the study. Diagnosis of EBTB was histopathologically confirmed in all patients. Results The commonest subtype was the edematous-hyperemic type (34.7%); other subtypes in order of occurrence were: tumorous (21.7%), granular (17.3%), actively caseating (17.3%), fibrostenotic (4.3%), and nonspecific bronchitic (4.3%). Although all patients were sputum-smear-negative for acid-fast bacilli (AFB), 26% of patients were smear-positive for AFB in the bronchial lavage fluid. The bronchial lavage fluid grew Mycobacterium tuberculosis in 39.1% of all patients. The bronchial lavage smear positivity for AFB in the bronchial lavage fluid was 75%, 25%, 20%, 12.5%, 0%, and 0% for the granular, actively caseating, tumorous, edematous-hyperemic, fibrostenotic, and nonspecific bronchitic subtypes of EBTB, respectively. Culture positivity for Mycobacterium tuberculosis in bronchial lavage fluid was 75%, 50%, 40%, 25%, 0%, and 0%, respectively. Conclusion The commonest subtype of EBTB was the edematous-hyperemic subtype. The granular type had the highest smear positivity and culture positivity for Mycobacterium tuberculosis in bronchial lavage fluid. Bronchoscopy should be performed in all patients suspected to have EBTB.



Interferon-? release assays in the diagnosis of active tuberculosis disease in a low-incident setting: a 5-year review of data.  


The role of interferon-? release assays in the diagnosis of active tuberculosis disease is uncertain, and recent guidelines do not support their routine use. We reviewed the clinical records of 415 patients who had a QuantiFERON-TB Gold In-Tube assay between 29 June 2005 and 28 October 2010 to determine its performance in the diagnosis of active tuberculosis disease in a low prevalence setting, specifically in human immunodeficiency virus (HIV) -positive and HIV-negative patients, those of UK and non-UK origin, and those with pulmonary and extrapulmonary disease. For the diagnosis of active tuberculosis disease the overall sensitivity of QuantiFERON-TB Gold In-Tube assay was 71.4% (95% CI 59.3-81.1), specificity was 81.0% (95% CI 75.5-85.6) and negative predictive value was 92.6% (95% CI 88.2-95.5). No significant difference in sensitivity was seen in culture-positive and culture-negative tuberculosis, in pulmonary and extrapulmonary disease, or with HIV infection. Specificity and negative predictive value were significantly higher in patients of UK origin compared with those of non-UK origin (89.3% (95% CI 83.3-93.3) and 97.1% (95% CI 92.7-98.9) versus 66.3% (95% CI 55.6-75.5) and 83.3% (95% CI 72.6-90.4)). Our study suggests that there may be a role for interferon-? release assays in excluding active tuberculosis disease, particularly extrapulmonary disease, in patients originating from areas of low tuberculosis incidence, with a negative test highly predictive of a lack of active tuberculosis disease in this group. We cannot support the use of these assays in the diagnosis of active tuberculosis infection in patients from areas of higher incidence. PMID:23398570

Lavender, T W; Barrett, A; Magee, J; Ong, E L C



Tuberculin testing of individuals infected with the human immunodeficiency virus : relationship with peripheral T-cell counts and active tuberculosis  

Microsoft Academic Search

Objective: To evaluate tuberculin test results and relate them to the presence or absence of active tuberculosis, as well as to CD4 + and CD8 + T-lymphocyte counts. Method: The charts of 802 patients with acquired immunodeficiency syndrome treated between August of 1985 and March of 2003 were reviewed. Of the 185 patients submitted to tuberculin tests (23.1%), 107 (57.8%)

Lenice d. R. Souza; Jussara M. Machado; Domingos A. Meira; Karlla Cunha



AB 74. Recurrence of pulmonary tuberculosis in a patient with undiagnosed kidney tuberculosis  

PubMed Central

Background Tuberculosis of the urinary system commonly complicates post-primary tuberculosis. In patients with active kidney tuberculosis, coincident lung disease often prevails in clinical picture, thus the diagnosis of urinary disease often escapes. Presentation of an interesting case of lung and kidney tuberculosis. Patients and Methods A 32 year-old female was referred to our clinic for investigation of possible kidney and lung tuberculosis. The patient reported two years of dysuric symptoms, with recurrent episodes of painless macroscopic haematuria. From recent history the patient reported two hospitalizations over a month due to fever and malaise, with laboratory findings of normochromic normocytic anemia, high ESR and microscopic hematuria and aseptic pyuria with normal renal function. Chest CT revealed scattered infiltrates in the middle and upper lung fields, ground-glass opacities and tree-in-bud pattern. CT scan of the abdomen showed hydronephrosis and hypodense areas in the left and right kidney, findings we also confirmed by kidney ultrasonography. Patient presented in our clinic with low grade fever and satisfactory respiratory function, while findings from the physical examination of the chest were insignificant. Mantoux test showed an infiltration of 15 mm. Direct sputum examination by Ziehl-Nielsen staining and PCR for M.Tuberculosis were negative. Ultimately, the diagnosis of lung disease and urinary tuberculosis were confirmed by positive Gen-probe results of gastric fluid and urine specimens and subsequent positive cultures. Prompt initiation of antituberculous therapy was followed by the patient’s marked clinical improvement within a few days and subsequent negative urine examination by Ziehl-Nielsen staining. Results Due to suspected hematogenous spread, the patient underwent fundoscopy and CT scan of the brain which revealed no pathological findings. To address hydronephrosis, a Pig-tail catheter was inserted in the left kidney. The patient received anti-tuberculous therapy for a year. During the follow-up period she remained in excellent general condition, with negative sputum and urine cultures and improvement of the imaging findings in the lungs and kidneys. Conclusions The initial presentation of urinary tract tuberculosis may be vague and the false interpretation of symptoms can result in great harm to the patient.

Fouka, Evangelia; Stephanopoulou, Pinelopi; Vlaikos, Dimosthenis; Loridas, Nikolaos; Kalaitzidou, Eftychia



Cutaneous Tuberculosis  

PubMed Central

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

Frankel, Amylynne; Penrose, Carolin



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

ERIC Educational Resources Information Center

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

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



Increased mortality associated with treated active tuberculosis in HIV-infected adults in Tanzania.  


Active tuberculosis (TB) among HIV-infected patients, even when successfully treated, may be associated with excess mortality. We conducted a prospective cohort study nested in a randomized TB vaccine trial to compare mortality between HIV-infected patients diagnosed and treated for TB (TB, n = 77) and HIV-infected patients within the same CD4 range, who were not diagnosed with or treated for active TB (non-TB, n = 308) in the period 2001-2008. Only twenty four subjects (6%) were on antiretroviral therapy at the beginning of this study. After accounting for covariate effects including use of antiretroviral therapy, isoniazid preventive therapy, and receipt of vaccine, we found a four-fold increase in mortality in TB patients compared with non-TB patients (adjusted Hazard Ratio 4.61; 95% Confidence Interval (CI): 1.63, 13.05). These findings suggest that treatment for TB alone is not sufficient to avert the excess mortality associated with HIV-related TB and that prevention of TB may provide a mortality benefit. PMID:23523641

Kabali, Conrad; Mtei, Lillian; Brooks, Daniel R; Waddell, Richard; Bakari, Muhammad; Matee, Mecky; Arbeit, Robert D; Pallangyo, Kisali; von Reyn, C Fordham; Horsburgh, C Robert



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

PubMed Central

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

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



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.

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



Tuberculosis (For Parents)  


... 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 ...


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.  


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



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.

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



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


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



Mineralogy and geochemistry of suspected mud volcano fluid migration pathways within the footwall of the active Chishan Fault, southern Taiwan  

NASA Astrophysics Data System (ADS)

During a 2008 investigation in the footwall of the active Chishan thrust fault in southern Taiwan, foliated, dark, planar bands were mapped as cross-cutting Plio-Pleistocene mudstones of the Gutingkeng Formation. It was originally hypothesized that these bands were localized shear zones associated with the Chishan fault, but normal sense-of-shear indicators observed in this thrust fault zone proved problematic. We developed a new hypothesis that the dark bands are inactive fluid migration pathways from now-eroded mud volcanoes in the over-pressurized footwall of the Chishan fault. Dark band and wall rock mudstone samples, along with sediment from several currently active mud volcanoes along the Chishan fault, were gathered in March 2009 and tested for mineralogical and chemical variations. X-Ray diffraction revealed no difference in mineralogy between the dark bands of mudstone and the wall rock around them. You et al. (2004) recorded a high concentration of boron in Chishan fault mud volcano fluids, and preliminary results of our rock and sediment samples using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES) indicate elevated concentrations of boron in the active mud volcano sediments and dark band mudstones versus the unaltered mudstones. Since fluid pathways will often coincide with permeable shear zones, the overprinting of sheared rock fabrics and fluid/mud transport is likely in these localized structures.

Sobolewski, S. M.; Gourley, J. R.



Bactericidal Activity in Whole Blood as a Potential Surrogate Marker of Immunity after Vaccination against Tuberculosis  

Microsoft Academic Search

The development of new tuberculosis (TB) vaccines will require the identification of correlates of human protection. This study examined the balance between immunity and virulence in a whole blood infection model in which intracellular mycobacterial survival was measured using BACTEC. In the blood of tuberculin-negative donors, counts of Mycobacterium tuberculosis H37Ra organisms fell by 0.14 log10 CFU during 96 h

Seon-Hee Cheon; Beate Kampmann; Amy G. Hise; Manijeh Phillips; Ho-Yeon Song; Katherine Landen; Qing Li; Rhonda Larkin; Jerrold J. Ellner; Richard F. Silver; Daniel F. Hoft; Robert S. Wallis



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

Microsoft Academic Search

HIV\\/AIDS (human immunodeficiency virus\\/acquired immunodeficiency syndrome) and TB (tuberculosis) are two of the world's major pandemics, the brunt of which falls on sub-Saharan Africa. Efforts aimed at controlling HIV\\/AIDS have largely focused on prevention, little attention having been paid to care. Work on TB control has concentrated on case detection and treatment. HIV infection has complicated the control of tuberculosis.

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


Mycobacterial Bacilli Are Metabolically Active during Chronic Tuberculosis in Murine Lungs: Insights from Genome-Wide Transcriptional Profiling  

Technology Transfer Automated Retrieval System (TEKTRAN)

Chronic tuberculosis represents a major health problem for one third of the world’s population today. A key question relevant to chronic tuberculosis is the physiological status of Mycobacterium tuberculosis during this important stage of infection. Previous work on chronic tuberculosis revealed t...


Bacteriostatic and bactericidal activities of benzoxazinorifamycin KRM-1648 against Mycobacterium tuberculosis and Mycobacterium avium in human macrophages.  

PubMed Central

Inhibitory and bactericidal activities of KRM-1648 were determined against Mycobacterium tuberculosis and M. avium residing in human monocyte-derived macrophages and extracellular M. tuberculosis and M. avium. MICs and MBCs of KRM-1648 against intracellular and extracellular bacteria were substantially lower than those of rifampin. The MICs and MBCs of either drug against the intracellular bacteria were only twofold lower than or equal to the values found for extracellular bacteria. The prolonged effect of KRM-1648 found in this study is probably associated with high ratios of intracellular accumulation, which were 50- to 100-fold higher than that found for rifampin. Further studies on intracellular distribution of KRM-1648 and on the sites of actual interaction between the drug and bacteria residing in macrophages are necessary, as well as evaluation of combined effects of KRM-1648 with other drugs in long-term macrophage culture experiments.

Mor, N; Simon, B; Heifets, L



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

PubMed Central

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

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



Tuberculosis Fluoroscopy

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).


Enzymatic Activities and DNA Substrate Specificity of Mycobacterium tuberculosis DNA Helicase XPB  

PubMed Central

XPB, also known as ERCC3 and RAD25, is a 3??5? DNA repair helicase belonging to the superfamily 2 of helicases. XPB is an essential core subunit of the eukaryotic basal transcription factor complex TFIIH. It has two well-established functions: in the context of damaged DNA, XPB facilitates nucleotide excision repair by unwinding double stranded DNA (dsDNA) surrounding a DNA lesion; while in the context of actively transcribing genes, XPB facilitates initiation of RNA polymerase II transcription at gene promoters. Human and other eukaryotic XPB homologs are relatively well characterized compared to conserved homologs found in mycobacteria and archaea. However, more insight into the function of bacterial helicases is central to understanding the mechanism of DNA metabolism and pathogenesis in general. Here, we characterized Mycobacterium tuberculosis XPB (Mtb XPB), a 3??5? DNA helicase with DNA-dependent ATPase activity. Mtb XPB efficiently catalyzed DNA unwinding in the presence of significant excess of enzyme. The unwinding activity was fueled by ATP or dATP in the presence of Mg2+/Mn2+. Consistent with the 3??5? polarity of this bacterial XPB helicase, the enzyme required a DNA substrate with a 3? overhang of 15 nucleotides or more. Although Mtb XPB efficiently unwound DNA model substrates with a 3? DNA tail, it was not active on substrates containing a 3? RNA tail. We also found that Mtb XPB efficiently catalyzed ATP-independent annealing of complementary DNA strands. These observations significantly enhance our understanding of the biological roles of Mtb XPB.

Balasingham, Seetha V.; Zegeye, Ephrem Debebe; Homberset, Havard; Rossi, Marie L.; Laerdahl, Jon K.; Bohr, Vilhelm A.; T?njum, Tone



Comparison of activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human macrophages.  

PubMed Central

The activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human monocyte-derived macrophages were determined. The MICs and MBCs of rifapentine for intracellular bacteria were two- to fourfold lower than those of rifampin. For extracellular bacteria, this difference was less noticeable. Nevertheless, the more favorable pharmacokinetics of rifapentine over rifampin was addressed in other experimental models. These models showed substantial differences after short pulsed exposures of the infected macrophages to the drugs and when the infected macrophages were exposed to changing drug concentrations that imitated the pharmacokinetic curves observed in blood. Once-a-week exposures to rifapentine concentrations equivalent to those attained in blood after one 600-mg dose resulted during the first week in a dramatic decline in the number of bacteria, and this decline was maintained at a minimal level for a period of four weeks. The results of this study have shown the suitability of rifapentine for intermittent-treatment regimens. The prolonged effect of rifapentine found in this study may be associated with high ratios of intracellular accumulation, which were four- to fivefold higher than those found for rifampin. Further studies on the intracellular distribution of rifamycins and on the sites of actual interaction between the drugs and bacteria residing in macrophages are necessary.

Mor, N; Simon, B; Mezo, N; Heifets, L



Serological tests for the diagnosis of active tuberculosis: relevance for India  

PubMed Central

Diagnostic tests for active tuberculosis (TB) based on the detection of antibodies (serological tests) have been commercially available for decades, although no international guidelines have recommended their use. An estimated 1.5 million serological TB tests, mainly enzyme-linked immunosorbent assays, are performed in India alone every year, mostly in the private sector. The cost of serological tests in India is conservatively estimated at US $15 million (825 million) per year. Findings from systematic reviews on the diagnostic accuracy of serological tests for both pulmonary and extra-pulmonary TB suggest that these tests are inaccurate and imprecise. A cost-effectiveness modelling study suggests that, if used as a replacement test for sputum microscopy, serology would increase costs to the Indian TB control sector approximately 4-fold and result in fewer disability-adjusted life years averted and more false-positive diagnoses. After considering all available evidence, the World Health Organization issued a strong recommendation against the use of currently available commercial serological tests for the diagnosis of TB disease. The expanding evidence base continues to demonstrate that the harms/risks of serological tests far outweigh the benefits. Greater engagement of the private sector is needed to discontinue the use of serological tests and to replace these tests with WHO-endorsed new diagnostics in India. The recent ban on import or sale of TB serological tests by the Indian health ministry is a welcome step in the right direction.

Steingart, Karen R.; Ramsay, Andrew; Dowdy, David W.; Pai, Madhukar



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


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

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



Spectrum of urogenital tuberculosis.  


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

Kulchavenya, Ekaterina; Zhukova, Irina; Kholtobin, Denis



Two cases of chronic arthritis of the forearm due to Mycobacterium tuberculosis.  


In the absence of coexisting active pulmonary disease, tuberculosis is frequently not considered in the differential diagnosis of chronic inflammation of the joints. The cases of two immigrant patients with tuberculous arthritis involving the forearm are reported. In both cases non-specific arthritis or trauma was suspected, resulting in a delay between the onset of symptoms and institution of specific therapy of 21 and 24 months, respectively. Diagnosis was achieved by histological and microbiological examination of synovial biopsy material. Polymerase chain reaction for Mycobacterium tuberculosis complex was positive in only one patient. Treatment consisted of antituberculosis chemotherapy, surgical synovectomy, and debridement of the affected joints. These cases serve as a reminder that, although rare, tuberculosis can cause chronic arthritis. PMID:9721964

Hunfeld, K P; Rittmeister, M; Wichelhaus, T A; Brade, V; Enzensberger, R



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...


IL-10 Dependent Suppression of Type 1, Type 2 and Type 17 Cytokines in Active Pulmonary Tuberculosis  

PubMed Central

Background Although Type 1 cytokine responses are considered protective in pulmonary tuberculosis (PTB), their role as well as those of Type 2, 17 and immunoregulatory cytokines in tuberculous lymphadenitis (TBL) and latent tuberculosis (LTB) have not been well studied. Aim and Methods To identify cytokine responses associated with pulmonary tuberculosis (TB), TB lymphadenitits and latent TB, we examined mycobacterial antigen-specific immune responses of PTB, TBL and LTB individuals. More specifically, we examined ESAT-6 and CFP-10 induced Type 1, Type 2 and Type 17 cytokine production and their regulation using multiplex ELISA. Results PTB individuals exhibited a significantly lower baseline as well as antigen-specific production of Type 1 (IFN?, TNF? and IL-2); Type 2 (IL-4) and Type 17 (IL-17A and IL-17F) cytokines in comparison to both TBL and LTB individuals. TBL individuals exhibited significantly lower antigen-specific IFN? responses alone in comparison to LTB individuals. Although, IL-10 levels were not significantly higher, neutralization of IL-10 during antigen stimulation resulted in significantly enhanced production of IFN?, IL-4 and IL-17A in PTB individuals, indicating that IL-10 mediates (at least partially) the suppression of cytokine responses in PTB. Conclusion Pulmonary TB is characterized by an IL-10 dependent antigen-specific suppression of Type 1, Type 2 and Type 17 cytokines, reflecting an important association of these cytokines in the pathogenesis of active TB.

Kumar, Nathella Pavan; Gopinath, Venugopal; Sridhar, Rathinam; Hanna, Luke E.; Banurekha, Vaithilingam V.; Jawahar, Mohideen S.; Nutman, Thomas B.; Babu, Subash



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

PubMed Central

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

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



[Endoscopic diagnosis and clinical experience of colonic tuberculosis].  


From February 1979 to May 1994, 18 cases of colonic tuberculosis were detected by colonscopy at Chang Gung Momorial Hospital, Linkou Medical Center. There were 10 males and 8 females, with mean age of 43.6. In ten, the diagnosis was confirmed histologically or bacteriologically in colonic biopsy material and post-operated lymph nodes. The remaining 8 patients was suspected on colonoscopy, and had good response to antituberculous therapy. The major symptoms were abdominal pain (83%), diarrhea (67%), and body weight loss (61%). Average duration from symptoms to diagnosis was 4.1 months. Chest X-ray revealed active pulmonary tuberculosis in 14 of 18 patients (78%), 4 of 14 patients were military type. The colonic tuberculosis involved in ileocecal area in 6, ileocecum and contiguous colonic regions in 7, segmental colonic involvement in 4, and pancolitis in 1 patient. Multiple ulceration and ulcerohypertrophic lesions were the major colonoscopic findings. Typical caseating granuloma were found in 5 cases (36%) from colonoscopic biopsy, the other 5 from surgical resected specimens. Antituberculous therapy produced remarkable symptomatic improvement in all patients except 2 cases complicated with intestinal obstruction necessitating laparotomy. Colonoscopy with biopsy is a useful diagnostic tool in early diagnosis and avoiding unnecessary laparotomy in colonic tuberculosis. PMID:9041758

Lin, C J; Wu, C S; Chen, P C; Kuo, Y C; Chang, K Y; Wu, S S; Tung, S Y



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


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 1-3 min. In vitro antitubercular activity of these triazoles was screened against Mycobacterium tuberculosis H(37)Rv strain. Four of the compounds showed MIC in the range of 1.56-3.13 ?g/mL proving their potential activity. PMID:22061642

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



Detection of gasoline on arson suspects' hands.  


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

Muller, Dan; Levy, Aharon; Shelef, Ran



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


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



Vaccinia expression of Mycobacterium tuberculosis- secreted proteins: tissue plasminogen activator signal sequence enhances expression and immunogenicity of M. tuberculosis Ag85  

Microsoft Academic Search

There is increasing evidence to implicate a role for CD8+ T cells in protective immunity against tuberculosis. Recombinant vaccinia (rVV) expressing Mycobacterium tuberculosis (MTB) proteins can be used both as tools to dissect CD8+ T-cell responses and, in attenuated form, as candidate vaccines capable of inducing a balanced CD4+\\/CD8+ T-cell response. A panel of rVV was constructed to express four

Adam S. Malin; Kris Huygen; Michael Mackett; Lisa Brandt; Peter Andersen; Steven M. Smith; Hazel M. Dockrell



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



Tuberculosis and Pregnancy  

Microsoft Academic Search

Tuberculosis (TB) is a common infectious disease caused by Mycobacterium tuberculosis, which commonly attacks the lungs (as pulmonary TB) but can also affect other organ systems. Over one third of the world’s\\u000a population now carries the TB bacterium. Not everyone infected develops active TB, and latent (asymptomatic) infection is\\u000a common. TB is a problem not only in the developing world

John B. Bass; James N. Byrd


[Clinical forms and treatment of tuberculosis in children].  


In France, the incidence of tuberculosis has been in constant decline over recent decades which has resulted in the lifting of mandatory vaccination as well as a growing lack of awareness of the action to take with a "suspect" child. Treatment should be coordinated between doctors from anti-tuberculosis centres and specialised hospital departments. PMID:22420075

Donato, Leonardo; Mansilla, Marie


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.

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



Chemokines induced by infection of mononuclear phagocytes with mycobacteria and present in lung alveoli during active pulmonary tuberculosis.  


The capacity of Mycobacterium tuberculosis (MTB) to induce production of chemokines with known chemotactic activity for monocytes and lymphocytes, the cellular building blocks of granulomas, was investigated. These chemokines included regulated upon activation, normal T cell expressed and secreted (RANTES), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1alpha (MIP-1alpha). MTB stimulated production of MCP-1 and MIP-1alpha by blood monocytes (MN) and alveolar macrophages (AM). MTB infection of MN and AM stimulated release but not production of RANTES. AM produced or released significantly higher levels than MN of RANTES (by 2.1-fold), MCP-1 (by 6.9-fold), and MIP-1alpha (by 5. 5-fold) (P < 0.05 for each). This study also confirmed that MTB-infected AM produce the chemokine interleukin (IL)-8. MTB infection of AM resulted in increased steady-state expression of messenger RNA (mRNA) for MCP-1 and MIP-1alpha and minimal increased expression of RANTES mRNA. Both an avirulent (H37Ra) and a virulent (H37Rv) strain of MTB and purified protein derivative of H37Rv but not latex beads induced production of chemokines. Supernatants of MTB-infected cells demonstrated chemotactic activity for both monocytes and lymphocytes partially inhibitable by neutralizing antibodies against the chemokines studied. Bronchoalveolar lavage fluid from patients with active pulmonary tuberculosis as compared with healthy control subjects contained increased levels of RANTES (by 8-fold), MCP-1 (by 2.7-fold), and IL-8 (by 8.9-fold) (P < 0.05), but not MIP-1alpha, as compared with healthy control subjects. Thus, multiple chemokines may be involved in recruitment of cells for granuloma formation in tuberculosis. PMID:9730880

Sadek, M I; Sada, E; Toossi, Z; Schwander, S K; Rich, E A



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.

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



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


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



Early detection of tuberculosis through community-based active case finding in Cambodia  

PubMed Central

Background Since 2005, Cambodia’s national tuberculosis programme has been conducting active case finding (ACF) with mobile radiography units, targeting household contacts of TB patients in poor and vulnerable communities in addition to routine passive case finding (PCF). This paper examines the differences in the demographic characteristics, smear grades, and treatment outcomes of pulmonary TB cases detected through both active and passive case finding to determine if ACF could contribute to early case finding, considering associated project costs for ACF. Methods Demographic characteristics, smear grades, and treatment outcomes were compared between actively (n?=?405) and passively (n?=?602) detected patients by reviewing the existing programme records (including TB registers) of 2009 and 2010. Additional analyses were performed for PCF cases detected after the ACF sessions (n?=?91). Results The overall cost per case detected through ACF was US$ 108. The ACF approach detected patients from older populations (median age of 55 years) compared to PCF (median age of 48 years; p?activity that is likely to have additional benefits such as contribution to early case finding and detection of patients from a vulnerable age group, possibly with an extended benefit for reducing secondary cases in the community. Further investigations are required to clarify the primary benefits of ACF in early and increased case detection and to assess its secondary impact on reducing on-going transmission.



Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models  

PubMed Central

This study extends earlier reports regarding the in vitro and in vivo efficacies of the nitroimidazopyran PA-824 against Mycobacterium tuberculosis. PA-824 was tested in vitro against a broad panel of multidrug-resistant clinical isolates and was found to be highly active against all isolates (MIC < 1 ?g/ml). The activity of PA-824 against M. tuberculosis was also assessed grown under conditions of oxygen depletion. PA-824 showed significant activity at 2, 10, and 50 ?g/ml, similar to that of metronidazole, in a dose-dependent manner. In a short-course mouse infection model, the efficacy of PA-824 at 50, 100, and 300 mg/kg of body weight formulated in methylcellulose or cyclodextrin/lecithin after nine oral treatments was compared with those of isoniazid, rifampin, and moxifloxacin. PA-824 at 100 mg/kg in cyclodextrin/lecithin was as active as moxifloxacin at 100 mg/kg and isoniazid at 25 mg/kg and was slightly more active than rifampin at 20 mg/kg. Long-term treatment with PA-824 at 100 mg/kg in cyclodextrin/lecithin reduced the bacterial load below 500 CFU in the lungs and spleen. No significant differences in activity between PA-824 and the other single drug treatments tested (isoniazid at 25 mg/kg, rifampin at 10 mg/kg, gatifloxacin at 100 mg/kg, and moxifloxacin at 100 mg/kg) could be observed. In summary, its good activity in in vivo models, as well as its activity against multidrug-resistant M. tuberculosis and against M. tuberculosis isolates in a potentially latent state, makes PA-824 an attractive drug candidate for the therapy of tuberculosis. These data indicate that there is significant potential for effective oral delivery of PA-824 for the treatment of tuberculosis.

Lenaerts, Anne J.; Gruppo, Veronica; Marietta, Karen S.; Johnson, Christine M.; Driscoll, Diane K.; Tompkins, Nicholas M.; Rose, Jerry D.; Reynolds, Robert C.; Orme, Ian M.



Fiberoptic bronchoscopy for the rapid diagnosis of smear-negative pulmonary tuberculosis  

PubMed Central

Background This study was aimed to investigate the diagnostic value of fiberoptic bronchoscopy (FOB) with chest high-resolution computed tomography (HRCT) for the rapid diagnosis of active pulmonary tuberculosis (PTB) in patients suspected of PTB but found to have a negative sputum acid-fast bacilli (AFB) smear. Methods We evaluated the diagnostic accuracy of results from FOB and HRCT in 126 patients at Gangnam Severance Hospital (Seoul, Korea) who were suspected of having PTB. Results Of 126 patients who had negative sputum AFB smears but were suspected of having PTB, 54 patients were confirmed as having active PTB. Hemoptysis was negatively correlated with active PTB. Tree-in-bud appearance on HRCT was significantly associated with active PTB. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FOB alone was 75.9%, 97.2%, 95.3%, and 84.3%, respectively, for the rapid diagnosis of active PTB. The combination of FOB and HRCT improved the sensitivity to 96.3% and the NPV to 96.2%. Conclusions FOB is a useful tool in the rapid diagnosis of active PTB with a high sensitivity, specificity, PPV and NPV in sputum smear-negative PTB-suspected patients. HRCT improves the sensitivity of FOB when used in combination with FOB in sputum smear-negative patients suspected of having PTB.



Comparative miRNA Expression Profiles in Individuals with Latent and Active Tuberculosis  

Microsoft Academic Search

The mechanism of latent tuberculosis (TB) infection remains elusive. Several host factors that are involved in this complex process were previously identified. Micro RNAs (miRNAs) are endogenous ?22 nt RNAs that play important regulatory roles in a wide range of biological processes. Several studies demonstrated the clinical usefulness of miRNAs as diagnostic or prognostic biomarkers in various malignancies and in

Chuan Wang; Shunyao Yang; Gang Sun; Xuying Tang; Shuihua Lu; Olivier Neyrolles; Qian Gao; Stefan Bereswill



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

Microsoft Academic Search

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

Peter Daley; Ruth McNerney



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

Microsoft Academic Search

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



Cytotoxic Activity of Dendritic Cells as a Possible Mechanism of Negative Regulation of T Lymphocytes in Pulmonary Tuberculosis  

PubMed Central

The PD-1/B7-H1-mediated induction of T cell apoptosis/anergy as a possible mechanism of immune response failure was studied in 76 patients with pulmonary tuberculosis (TB) with normal and low-proliferative response to antigens of M. tuberculosis (purified protein derivative (PPD)). It was revealed that dendritic cells (DCs), generated in vitro from patient blood monocytes with GM-CSF + IFN-?, were characterized by increased B7-H1 expression, upproduction of IL-10, and reducing of allostimulatory activity in mixed lymphocyte culture (MLC). Moreover, DCs of patients with TB were able to enhance T cell apoptosis and to block T-cell division in MLC. It was shown that neutralizing anti-PD1 antibodies significantly decreased the proapoptogenic/tolerogenic effect of DCs. Correlation analysis revealed a direct relationship between IL-10 production and level of B7-H1 expression in the general group of investigated patients. It was demonstrated that generation of healthy donor DCs in the presence of IL-10 led to an increase in the number of DCs-expressed B7-H1 molecule, DC proapoptogenic activity, and a decrease in their allostimulatory activity. Obviously, the revealed phenomenon of the PD-1/B7-H1-mediated pro-apoptogenic activity of DCs is clinically significant since the cytotoxic/tolerogenic potential of DCs is more pronounced in patients with PPD anergy.

Sakhno, Ludmila V.; Tikhonova, Marina A.; Tyrinova, Tamara V.; Leplina, Olga Yu.; Shevela, Ekaterina Ya.; Nikonov, Sergey D.; Zhdanov, Oleg A.; Ostanin, Alexander A.; Chernykh, Elena R.



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


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

Maeda, Hideo; Shirai, Chika



Tuberculosis in asylum seekers in Belgium  

Microsoft Academic Search

Countries with a low incidence of tuberculosis have recently been faced with the problem of tuberculosis (TB) in asylum seekers from countries with a high TB prevalence. We report on the tuberculosis case notification rate (TBCNR) in Belgium in 1993, and on the results of active screening in a group of asylum seekers. The TBCNR in Belgium in 1993 increased

P. Van den Brande; M. Uydebrouck; P. Vermeire; M. Demedts; U. Z. Gasthuisberg; Dienst Longziekten



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...



Efficient heterologous expression and one-step purification of fully active c-terminal histidine-tagged uridine monophosphate kinase from Mycobacterium tuberculosis.  


Tuberculosis has long been recognized as one of the most significant public health problems. Finding novel antituberculous drugs is always a necessary approach for controlling the disease. Mycobacterium tuberculosis pyrH gene (Rv2883c) encodes for uridine monophosphate kinase (UMK), which is a key enzyme in the uridine nucleotide interconversion pathway. The enzyme is essential for M. tuberculosis to sustain growth and hence is a potential drug target. In this study, we have developed a rapid protocol for production and purification of M. tuberculosis UMK by cloning pyrH (Rv2883c) of M. tuberculosis H37Rv with the addition of 6-histidine residues to the C-terminus of the protein, and expressing in E. coli BL21-CodonPlus (DE3)-RIPL using an auto-induction medium. The enzyme was efficiently purified by a single-step TALON cobalt affinity chromatography with about 8 fold increase in specific activity, which was determined by a coupled assay with the pyruvate kinase and lactate dehydrogenase. The molecular mass of monomeric UMK was 28.2 kDa and that of the native enzyme was 217 kDa. The enzyme uses UMP as a substrate but not CMP and TMP and activity was enhanced by GTP. Measurements of enzyme kinetics revealed the kcat value of 7.6 +/- 0.4 U mg(-1) or 0.127 +/- 0.006 sec(-1).The protocol reported here can be used for expression of M. tuberculosis UMK in large quantity for formulating a high throughput target-based assay for screening anti-tuberculosis UMK compounds. PMID:22299415

Penpassakarn, Praweenuch; Chaiyen, Pimchai; Palittapongarnpim, Prasit



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

PubMed Central

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

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



Public health aspects of tuberculosis.  


This article covers public health aspects of the investigation and management of people who are infected with tuberculosis (TB). It contains a brief overview of the recent epidemiology of TB in Scotland, focusing on changes in Scottish TB incidence and describing some epidemiological associations. We then describe the initial public health assessment of those with suspected TB and responses that should be initiated. It does not address issues relating to the clinical treatment of patients with TB. PMID:22953320

Blatchford, O; Cameron, J C



Simultaneous occurrence of pulmonary tuberculosis and carcinomatous lymphangitis.  


Tuberculosis is an important cause of mortality due to its high prevalence, considering that one third of the worlds population is infected with the tuberculosis bacillus. We report the first case of carcinomatous lymphangitis associated with active pulmonary tuberculosis. Carcinomatous lymphangitis is a rare event that may be confounded with tuberculosis because of its radiographic and clinical characteristics. PMID:17486260

Tuon, Felipe Francisco; Miyaji, Karina T; de Vidal, Paula Marques; da Silva, Luiz Fernando Ferraz; Kono, Adriana; Franca, Francisco Oscar de Siqueira


The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection  

PubMed Central

It is estimated that one-third of the world’s population is infected with Mycobacterium tuberculosis. Infection typically remains latent, but it can reactivate to cause clinical disease. The only vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is largely ineffective, and ways to enhance its efficacy are being developed. Of note, the candidate booster vaccines currently under clinical development have been designed to improve BCG efficacy but not prevent reactivation of latent infection. Here, we demonstrate that administering a multistage vaccine that we term H56 in the adjuvant IC31 as a boost to vaccination with BCG delays and reduces clinical disease in cynomolgus macaques challenged with M. tuberculosis and prevents reactivation of latent infection. H56 contains Ag85B and ESAT-6, which are two of the M. tuberculosis antigens secreted in the acute phase of infection, and the nutrient stress–induced antigen Rv2660c. Boosting with H56/IC31 resulted in efficient containment of M. tuberculosis infection and reduced rates of clinical disease, as measured by clinical parameters, inflammatory markers, and improved survival of the animals compared with BCG alone. Boosted animals showed reduced pulmonary pathology and extrapulmonary dissemination, and protection correlated with a strong recall response against ESAT-6 and Rv2660c. Importantly, BCG/H56-vaccinated monkeys did not reactivate latent infection after treatment with anti-TNF antibody. Our results indicate that H56/IC31 boosting is able to control late-stage infection with M. tuberculosis and contain latent tuberculosis, providing a rationale for the clinical development of H56.

Lin, Philana Ling; Dietrich, Jes; Tan, Esterlina; Abalos, Rodolfo M.; Burgos, Jasmin; Bigbee, Carolyn; Bigbee, Matthew; Milk, Leslie; Gideon, Hannah P.; Rodgers, Mark; Cochran, Catherine; Guinn, Kristi M.; Sherman, David R.; Klein, Edwin; Janssen, Christopher; Flynn, JoAnne L.; Andersen, Peter



The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection.  


It is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis. Infection typically remains latent, but it can reactivate to cause clinical disease. The only vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is largely ineffective, and ways to enhance its efficacy are being developed. Of note, the candidate booster vaccines currently under clinical development have been designed to improve BCG efficacy but not prevent reactivation of latent infection. Here, we demonstrate that administering a multistage vaccine that we term H56 in the adjuvant IC31 as a boost to vaccination with BCG delays and reduces clinical disease in cynomolgus macaques challenged with M. tuberculosis and prevents reactivation of latent infection. H56 contains Ag85B and ESAT-6, which are two of the M. tuberculosis antigens secreted in the acute phase of infection, and the nutrient stress-induced antigen Rv2660c. Boosting with H56/IC31 resulted in efficient containment of M. tuberculosis infection and reduced rates of clinical disease, as measured by clinical parameters, inflammatory markers, and improved survival of the animals compared with BCG alone. Boosted animals showed reduced pulmonary pathology and extrapulmonary dissemination, and protection correlated with a strong recall response against ESAT-6 and Rv2660c. Importantly, BCG/H56-vaccinated monkeys did not reactivate latent infection after treatment with anti-TNF antibody. Our results indicate that H56/IC31 boosting is able to control late-stage infection with M. tuberculosis and contain latent tuberculosis, providing a rationale for the clinical development of H56. PMID:22133873

Lin, Philana Ling; Dietrich, Jes; Tan, Esterlina; Abalos, Rodolfo M; Burgos, Jasmin; Bigbee, Carolyn; Bigbee, Matthew; Milk, Leslie; Gideon, Hannah P; Rodgers, Mark; Cochran, Catherine; Guinn, Kristi M; Sherman, David R; Klein, Edwin; Janssen, Christopher; Flynn, JoAnne L; Andersen, Peter



Challenging issues in tuberculosis in solid organ transplantation.  


Solid organ transplant (SOT) recipients are at risk for opportunistic infections including tuberculosis. Although guidelines on the management of latent tuberculosis and active tuberculosis are available, there remain a number of clinical areas with limited guidance. We discuss challenges in the diagnosis, management, and treatment of latent and active tuberculosis in SOT candidates and recipients who reside in low-tuberculosis-prevalence areas. We discuss the diagnosis of latent tuberculosis in SOT candidates/recipients using tuberculin skin tests and interferon-? release assays and risk stratification of SOT candidates/recipients that would identify individuals at high risk for latent tuberculosis despite negative test results. Through a careful review of posttransplant tuberculosis cases, we identify a history of treated tuberculosis in SOT recipients as a risk factor for development of posttransplant active tuberculosis. Finally, we include comparisons of recommendations by several large transplant organizations and identify areas for future research. PMID:23899676

Horne, David J; Narita, Masahiro; Spitters, Christopher L; Parimi, Soumya; Dodson, Sherry; Limaye, Ajit P



The Spectrum of Extrapulmonary Tuberculosis  

PubMed Central

The incidence of new cases of extrapulmonary tuberculosis has remained constant, despite the decline in new cases of active pulmonary tuberculosis. This might be due to a delay in recognition, and particularly a lack of consideration of tuberculosis when the presenting symptoms are other than respiratory. Extrapulmonary tuberculosis should be considered in the differential diagnosis of bone, joint, genitourinary tract and central nervous system (CNS) diseases. To determine factors that might delay recognition and identification, 62 patients having extrapulmonary tuberculosis during 1969-1972 at the Los Angeles County-University of Southern California Medical Center were studied. Three quarters of these patients had had CNS, skeletal or genitourinary tuberculosis in equal distribution or 25 percent each. CNS involvement was seen frequently in the disseminated form. Presenting symptoms were protean and not specific, such as fever, anorexia, weight loss, cough, lymphadenopathy and neurologic abnormalities. Roentgenograms of the chest were abnormal in most. When a roentgenogram of the chest suggests pulmonary tuberculosis, signs and symptoms in other body systems should suggest extrapulmonary tuberculosis. If no abnormalities are seen on a roentgenogram of the chest, however, this does not preclude the diagnosis of extrapulmonary tuberculosis. Neither does a negative tuberculin skin test exclude the condition. Abnormal laboratory findings are common, especially in disseminated tuberculosis. These include various anemias, bone marrow disorders, hyponatremia due to inappropriate antidiuretic hormone syndrome. Analyses of pleural, peritoneal, pericardial and joint fluid usually show an exudate high in lymphocytes and occasionally low in glucose. Similar findings are seen in spinal fluid. The histological features of caseous or noncaseous granulomas are suggestive of but not specific for tuberculosis. Only culture of mycobacteria from sputum, urine, spinal fluid, pleural and other effusions and tissue biopsy specimens will yield a definitive diagnosis. Physicians must have a high index of suspicion to diagnose extrapulmonary tuberculosis, as it can resemble any disease in any organ system. Immediate therapy in the disseminated variety, sometimes even before a definite diagnosis can be made, may be lifesaving.

Baydur, Ahmet



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

PubMed Central

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



Immunological activity of a 14-kilodalton recombinant protein of Mycobacterium tuberculosis H37Rv.  

PubMed Central

A 14-kilodalton peptide antigen from Mycobacterium tuberculosis was isolated from an Escherichia coli lambda gt 11 recombinant DNA clone and was identified by Western blotting (immunoblotting) with monoclonal antibody TB68. Immunization of mice and guinea pigs with the recombinant peptide (rTB68) induced in vitro lymphoproliferative responses in draining lymph node lymphocyte cultures as well as in vivo delayed-type hypersensitivity reactions. Moreover, rTB68 was found both to induce and to cross-react with Mycobacterium leprae immune lymphocytes, but did not generate protective effects against live M. leprae challenge in mice. These findings showed that a 14-kilodalton peptide which has been characterized as specific for M. tuberculosis on the basis of B-cell recognition was capable of generating cell-mediated immune responses and moreover contained T-cell epitopes which were cross-reactive with M. leprae antigens. Images

Kingston, A E; Salgame, P R; Mitchison, N A; Colston, M J



Isolation and Biochemical Activities of Trehalose-6-Monomycolate of Mycobacterium tuberculosis  

PubMed Central

A monoester of trehalose linked at the 6-position with mycolic acids (trehalose-6-monomycolate) was isolated from the wax D fraction of virulent human Mycobacterium tuberculosis, and its biochemical action on host-cell mitochondria was studied. Trehalose-6-monomycolate showed a delayed toxicity for mice. The 50% lethal dose at 2 weeks was 452 ?g. It induced in vitro a swelling of mouse liver mitochondria and uncoupled respiration and phosphorylation in the nicotinamide adenine dinucleotide pathway of the electron transport chain. The site of functional damage was located specifically at coupling site II. Mitochondrial adenosine triphosphatase was slightly stimulated by trehalose-6-monomycolate. These findings indicate that trehalose-6-monomycolate affects mitochondrial oxidative phosphorylation in a similar manner to, but to a lesser extent than, trehalose-6, 6?-dimycolate (cord factor) of M. tuberculosis.

Kato, Masahiko; Maeda, Jiro



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



A coupled assay measuring Mycobacterium tuberculosis antigen 85C enzymatic activity  

Microsoft Academic Search

The prevalence of drug-resistant strains of Mycobacterium tuberculosis (M. tb) emphasizes the need for new antitubercular drugs. An essential component of the drug discovery process is the development of tools to rapidly screen potential drug libraries against important biological targets. Similarly to well-documented M. tb targets, the antigen 85 (Ag85) enzymes are involved in the maintenance of the mycobacterial cell

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



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


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

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



Fumarate Reductase Activity Maintains an Energized Membrane in Anaerobic Mycobacterium tuberculosis  

PubMed Central

Oxygen depletion of Mycobacterium tuberculosis engages the DosR regulon that coordinates an overall down-regulation of metabolism while up-regulating specific genes involved in respiration and central metabolism. We have developed a chemostat model of M. tuberculosis where growth rate was a function of dissolved oxygen concentration to analyze metabolic adaptation to hypoxia. A drop in dissolved oxygen concentration from 50 mmHg to 0.42 mmHg led to a 2.3 fold decrease in intracellular ATP levels with an almost 70-fold increase in the ratio of NADH/NAD+. This suggests that re-oxidation of this co-factor becomes limiting in the absence of a terminal electron acceptor. Upon oxygen limitation genes involved in the reverse TCA cycle were upregulated and this upregulation was associated with a significant accumulation of succinate in the extracellular milieu. We confirmed that this succinate was produced by a reversal of the TCA cycle towards the non-oxidative direction with net CO2 incorporation by analysis of the isotopomers of secreted succinate after feeding stable isotope (13C) labeled precursors. This showed that the resulting succinate retained both carbons lost during oxidative operation of the TCA cycle. Metabolomic analyses of all glycolytic and TCA cycle intermediates from 13C-glucose fed cells under aerobic and anaerobic conditions showed a clear reversal of isotope labeling patterns accompanying the switch from normoxic to anoxic conditions. M. tuberculosis encodes three potential succinate-producing enzymes including a canonical fumarate reductase which was highly upregulated under hypoxia. Knockout of frd, however, failed to reduce succinate accumulation and gene expression studies revealed a compensatory upregulation of two homologous enzymes. These major realignments of central metabolism are consistent with a model of oxygen-induced stasis in which an energized membrane is maintained by coupling the reductive branch of the TCA cycle to succinate secretion. This fermentative process may offer unique targets for the treatment of latent tuberculosis.

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



Extracellular M. tuberculosis DNA Targets Bacteria for Autophagy by Activating the Host DNA-Sensing Pathway  

PubMed Central

SUMMARY Eukaryotic cells sterilize the cytosol by using autophagy to route invading bacterial pathogens to the lysosome. During macrophage infection with Mycobacterium tuberculosis, a vacuolar pathogen, exogenous induction of autophagy can limit replication, but the mechanism of autophagy targeting and its role in natural infection remain unclear. Here we show that phagosomal permeabilization mediated by the bacterial ESX-1 secretion system allows cytosolic components of the ubiquitin-mediated autophagy pathway access to phagosomal M. tuberculosis. Recognition of extracelluar bacterial DNA by the STING-dependent cytosolic pathway is required for marking bacteria with ubiquitin, and delivery of bacilli to autophagosomes requires the ubiquitin-autophagy receptors p62 and NDP52 and the DNA-responsive kinase TBK1. Remarkably, mice with monocytes incapable of delivering bacilli to the autophagy pathway are extremely susceptible to infection. Our results reveal an unexpected link between DNA sensing, innate immunity, and autophagy and indicate a major role for this autophagy pathway in resistance to M. tuberculosis infection.

Watson, Robert O.; Manzanillo, Paolo S.; Cox, Jeffery S.



[Diagnosis of tuberculosis meningitis by detection of adenosine deaminase activity and amplification of nucleotide sequences with PCR].  


Tuberculous meningitis (TBM) is the most severe and lethal form of tuberculosis. The rapid bacteriological diagnosis with the conventional techniques is nearly impossible in TBM. There for many patients are treated with anti-TBC drugs without a definitive diagnosis. A more fast and accurate diagnostic method is necessary, in order to initiate the treatment on time to prevent the irreversible neurologic sequel or death. We evaluated the use of two rapid methods: Adenosine deaminase activity (ADA) and polymerase chain reaction (PCR) for IS6110 and mtp40 sequences on cerebrospinal fluid (CSF) from chronic meningitis patients. For ADA activity > 8.0 U/L the sensibility and specificity was 80% and 91%. PCR sensibility was 80% and specificity 97%. ADA activity and PCR on CSF could be specially useful as complementary tools in the early diagnosis of TBM. PMID:11899709

Correa, M F; Armas, E; Díaz, D; de Elguezabal, K; De la Rosa, M L; Calles, G; Adjounian, H; Pedroza, R



Fingerprinting Nearby Star Suspects  

NASA Astrophysics Data System (ADS)

To identify and characterize the Sun's neighbors, we propose to obtain red spectra (5300-9900+ Å) for suspected nearby red, brown, and white dwarfs. These spectra play an important role in a new parallax effort initiated as part of a small telescope consortium operating at CTIO. This new effort, CTIOPI2, will be an expansion of the highly successful CTIOPI effort - an NOAO Surveys Program in which we are measuring parallaxes for more than 200 southern nearby stars. Both are carried out under the RECONS (Research Consortium on Nearby Stars) effort based at Georgia State U., Johns Hopkins U., and U. Virginia. During RECONS' two previous CTIO spectroscopic observing runs, we had two partly cloudy nights in Feb 1998, and three rainy nights in Jul 2001. Nonetheless, from the earlier run's meager data we have identified six new stars within 25 pc, two of which lie within 10 pc. High quality spectra for these new nearby stars are being provided to the fundamental database of the NASA/NSF NStars Project. This proposal is similar to our previous proposal, 2001A-0270, although we now include three new samples of stars that are being examined for CTIOPI2 targets. These samples are being used for both PhD (Jao, Subasavage) and undergraduate senior (Bean, Walkowicz) theses.

Henry, Todd J.; Bean, Jacob; Golimowski, Dave; Jao, Wei-Chun; Subasavage, John; Walkowicz, Lucianne



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

PubMed Central

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

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



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


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

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



Lack of Mycobacterium tuberculosis-specific interleukin-17A-producing CD4+ T cells in active disease.  


Protective immunity to Mycobacterium tuberculosis (Mtb) is commonly ascribed to a Th1 profile; however, the involvement of Th17 cells remains to be clarified. Here, we characterized Mtb-specific CD4(+) T cells in blood and bronchoalveolar lavages (BALs) from untreated subjects with either active tuberculosis disease (TB) or latent Mtb infection (LTBI), considered as prototypic models of uncontrolled or controlled infection, respectively. The production of IL-17A, IFN-?, TNF-?, and IL-2 by Mtb-specific CD4(+) T cells was assessed both directly ex vivo and following in vitro antigen-specific T-cell expansion. Unlike for extracellular bacteria, Mtb-specific CD4(+) T-cell responses lacked immediate ex vivo IL-17A effector function in both LTBI and TB individuals. Furthermore, Mtb-specific Th17 cells were absent in BALs, while extracellular bacteria-specific Th17 cells were identified in gut biopsies of healthy individuals. Interestingly, only Mtb-specific CD4(+) T cells from 50% of LTBI but not from TB subjects acquired the ability to produce IL-17A following Mtb-specific T-cell expansion. Finally, IL-17A acquisition by Mtb-specific CD4(+) T cells correlated with the coexpression of CXCR3 and CCR6, currently associated to Th1 or Th17 profiles, respectively. Our data demonstrate that Mtb-specific Th17 cells are selectively undetectable in peripheral blood and BALs from TB patients. PMID:23436562

Perreau, Matthieu; Rozot, Virginie; Welles, Hugh C; Belluti-Enders, Felicitas; Vigano, Selena; Maillard, Michel; Dorta, Gian; Mazza-Stalder, Jesica; Bart, Pierre-Alexandre; Roger, Thierry; Calandra, Thierry; Nicod, Laurent; Harari, Alexandre



[Prognosis of patients with tuberculosis].  


The global incidence of tuberculosis peaked around the year 2003 and is currently declining gradually. However, the worldwide incidence of new tuberculosis cases is still estimated to be 8.8 million/year, with 1.5 million deaths occurring per year. Considering that previous studies have determined the risk factors for death due to tuberculosis, we aimed at reviewing the literature to collectively evaluate these risk factors. According our literature review of 12 articles published in English language and 7 articles published in Japanese, the risk factors for death due to tuberculosis are age, human immunodeficiency virus (HIV) co-infection, multi-drug resistant tuberculosis (MDR-TB), malnutrition, low activities of daily living, co-morbidities, unemployment, and drug injection. We developed a scoring system to calculate the Tuberculosis Prognostic Score using 4 risk factors, namely, age, serum albumin level, oxygen requirement, and activities of daily living, after assessing several cohorts in Japan, in which HIV co-infection and MDR-TB are rare and their associations with mortality due to tuberculosis patients are unclear. This scoring system was successfully able to estimate life prognosis of inpatients with newly diagnosed, smear-positive, lung tuberculosis without MDR-TB and/or HIV virus co-infection. PMID:23898497

Horita, Nobuyuki; Miyazawa, Naoki; Yoshiyama, Takashi; Ishigatsubo, Yoshiaki



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


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

González, Edilberto R; Armas, Luisa



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

PubMed Central

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

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



Isolation of non-tuberculous mycobacteria from the sputum of patients with active tuberculosis.  


We looked for non-tuberculous mycobacteria (NTM) in the sputum of patients diagnosed with pulmonary tuberculosis (TB) in Oregon in 2005-2006 (n = 141). Twenty (14%) patients had NTM isolated from sputum during TB treatment. Compared to those without NTM, TB patients with NTM were more likely to have cavitary disease (RR 2.7, 95%CI 1.2-6.0) and were more likely to be born in the United States (RR 2.4, 95%CI 1.1-5.3). Further study is needed to determine the clinical significance of simultaneous isolation of NTM and TB. PMID:20392362

Kendall, B A; Varley, C D; Hedberg, K; Cassidy, P M; Winthrop, K L



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


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

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



Diagnosis of active tuberculosis by e-nose analysis of exhaled air.  


Tuberculosis (TB), a highly infectious airborne disease, remains a major global health problem. Many of the new diagnostic techniques are not suited for operation in the highly-endemic low-income countries. A sensitive, fast, easy-to-operate and low-cost method is urgently needed. We performed a Proof of Principle Study (30 participants) and a Validation Study (194 participants) to estimate the diagnostic accuracy of a sophisticated electronic nose (DiagNose, C-it BV) using exhaled air to detect tuberculosis. The DiagNose uses a measurement method that enables transfer of calibration models between devices thus eliminating the most common pitfall for large scale implementation of electronic noses in general. DiagNose measurements were validated using traditional sputum smear microscopy and culture on Löwenstein-Jensen media. We found a sensitivity of 95.9% and specificity of 98.5% for the pilot study. In the validation study we found a sensitivity of 93.5% and a specificity of 85.3% discriminating healthy controls from TB patients, and a sensitivity of 76.5% and specificity of 87.2% when identifying TB patient within the entire test-population (best-case numbers). The portability and fast time-to-result of the DiagNose enables a proactive screening search for new TB cases in rural areas, without the need for highly-skilled operators or a hospital center infrastructure. PMID:23127779

Bruins, Marcel; Rahim, Zeaur; Bos, Albert; van de Sande, Wendy W J; Endtz, Hubert Ph; van Belkum, Alex



Characterization of regulatory T cells identified as CD4+CD25highCD39+ in patients with active tuberculosis  

PubMed Central

Forkhead box P3 (FoxP3) is a transcription factor whose expression characterizes regulatory T cells (Treg), but it is also present on activated T cells, thus hindering correct Treg identification. Using classical markers for Treg recognition, discordant results were found in terms of Treg expansion during active tuberculosis (TB) disease. Recently CD39 has been shown to be an accurate marker for Treg detection. The objectives of this study were: (i) to identify Treg expressing CD39 in patients with TB and to compare the results with those obtained by the standard phenotypic markers; (ii) to evaluate if Treg are expanded in vitro by exogenous interleukin (IL)-2 or by antigen-specific stimulation; and (iii) to characterize Treg function on the modulation of antigen-specific responses. We enrolled 13 patients with pulmonary TB and 12 healthy controls. Treg were evaluated by flow cytometry ex vivo and after antigen-specific in vitro stimulation using CD25, FoxP3, CD127 and CD39 markers. Results indicate that CD39+ cells within the CD4+CD25high cells have Treg properties (absence of interferon-? production and transforming growth factor-?1 release upon stimulation). Ex vivo analysis did not show significant differences between TB patients and controls of Treg by classical or novel markers. In contrast, a significantly higher percentage of Treg was found in TB patients after antigen-specific stimulation both in the presence or absence of IL-2. Depletion of CD39+ Treg increased RD1-specific responses significantly. In conclusion, CD39 is an appropriate marker for Treg identification in TB. These results can be useful for future studies to monitor Mycobacterium tuberculosis-specific response during TB.

Chiacchio, T; Casetti, R; Butera, O; Vanini, V; Carrara, S; Girardi, E; Di Mitri, D; Battistini, L; Martini, F; Borsellino, G; Goletti, D



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

PubMed Central

Background Interferon 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 the effect of HIV on the test's performance. Principal Findings Patients attending government health clinics were recruited within 1 month of starting treatment for TB. Subjects were tested with QGIT and TST. T lymphocyte counts were estimated (CD3+, CD4+, CD8+). QGIT was performed for 112 subjects. 83/112 were QGIT positive giving an overall sensitivity of 74% [95%CI: 66,82]. A marked decrease in sensitivity was observed in HIV positive patients with 37/59 (63%) being QGIT positive compared to 31/37 (84%) HIV negative patients [chi2 p?=?0.033]. Low CD4+ count was associated with increases in both indeterminate and false-negative results. Low CD4+ count in combination with high/normal CD8+ count was associated with false-negative results. TST was recorded for 92 patients, 62/92 were positive, giving a sensitivity of 67% [95%CI: 58,77]. Although there was little difference in the overall sensitivities, agreement between TST and QGIT was poor. Conclusions QGIT was technically feasible with results in HIV negative subjects comparable to those achieved elsewhere. However, where under-treated HIV is prevalent, an increased proportion of both indeterminate and false-negative QGIT results can be expected in patients with active TB. The implications of this for the diagnosis of LTBI by QGIT is unclear. The diagnostic and prognostic relevance of IGRAs in high burden settings needs to be better characterised.

Raby, Edward; Moyo, Maureen; Devendra, Akash; Banda, Joseph; De Haas, Petra; Ayles, Helen; Godfrey-Faussett, Peter



Antibacterial activity of human neutrophil peptide-1 against Mycobacterium tuberculosis H37Rv: in vitro and ex vivo study.  


The aim of the study was to investigate the activity of human neutrophil peptide (HNP)-1 to kill Mycobacterium tuberculosis H37Rv in vitro and ex vivo in the murine macrophage cell line J744A.1 on the basis of colony forming units. Macromolecular biosynthesis was studied by monitoring the incorporation of radioactive precursors into different macromolecules. The binding and localization studies were carried out with radioiodinated HNP-1 whereas the cytotoxicity of HNP-1 to macrophages was determined by trypan blue exclusion assay. A concentration dependent inhibition in the growth of M. tuberculosis H37Rv was observed in the presence of HNP-1. The minimum inhibitory concentration and median inhibitory concentration of HNP-1 were found to be 2.5 microg x mL(-1) and 0.8 microg x mL(-1). Treatment of both in vitro grown and phagocytosed mycobacterial cells with HNP-1 resulted in generalized inhibition in the macromolecular biosynthesis with maximum inhibition in deoxyribonucleic acid and lipid biosynthesis. HNP-1 exhibited equilibrium binding with respect to time and two-thirds of bound radioactivity was shown to be present inside the macrophages. Approximately 50% and 98% killing of intracellular mycobacteria was observed after 3 days of treatment with 5 microg x mL(-1) and 40 microg x mL(-1) of HNP-1, respectively. HNP-1 exhibited low cytotoxicity towards the macrophage cell line at the bactericidal concentration to mycobacteria. From the results of this study, it is concluded that human neutrophil peptide-1 possesses potent bactericidal activity against virulent mycobacteria in vitro as well as mycobacteria replicating within macrophages. PMID:10933095

Sharma, S; Verma, I; Khuller, G K



Assessing suspected spinal cord compression  

Microsoft Academic Search

The object of this work was to evaluate the assessment and document the outcomes of cancer patients with suspected spinal\\u000a cord compression (SCC). In a retrospective cohort study of 342 episodes of suspected SCC in cancer patients evaluated by computed\\u000a tomography (CT) of the spine, a multidisciplinary team of neurologists, radiologists, and oncologists assessed the impact\\u000a of varying the anatomical

James A. Talcott; Paul C. Stomper; Frank W. Drislane; Patrick Y. Wen; Caroline C. Block; Charles C. Humphrey; Charles Lu; Ferenc Jolesz



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

PubMed Central

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

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



Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients.  


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

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



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

ERIC Educational Resources Information Center

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

Connaghan, Kathryn P.; Moore, Christopher A.



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

ERIC Educational Resources Information Center

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

Connaghan, Kathryn P.; Moore, Christopher A.



An Unusual Suspect  

ERIC Educational Resources Information Center

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

Lum, Lydia



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.



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.

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



T Cell Activation and Proinflammatory Cytokine Production in Clinically Cured Tuberculosis Are Time-Dependent and Accompanied by Upregulation of IL-10  

PubMed Central

Background Th1 cytokines are essential for the control of M. tuberculosis infection. The role of IL-10 in tuberculosis is controversial and there is an increasing body of evidence suggesting that the relationship between Th1 cytokines and IL-10 is not as antagonistic as it was first believed, and that these cytokines may complement each other in infectious diseases. Methods The present study evaluated the activating capacity of CD4+ and CD8+ T cell repertoire in response to antigen stimulation through the expression of CD69 using Flow Cytometry, as well as the functionality of PBMCs by determining the cytokine profile in patients with active tuberculosis and in clinically cured patients after in vitro stimulation using ELISA. Treated patients were subdivided according to time after clinical cure (<12 months or >12 months post-treatment). Results We observed that T cell activation was higher in TB-treated patients, especially CD8+ T cell activation in TB-Treated >1 year. Th1 cytokines were significantly higher in TB-Treated, and the levels of IFN-? and TNF-? increased continuously after clinical cure. Moreover, IL-10 production was significantly higher in cured patients and it was also enhanced in cured patients over time after treatment. Th17, Th2 and Th22 cytokines showed no statistically significant differences between Healthy Donors, Active-TB and TB-Treated. Conclusions This study describes a scenario in which potentiation of CD4+ and CD8+ T cell activation and increased Th1 cytokine production are associated with the clinical cure of tuberculosis in the absence of significant changes in Th2 cytokine production and is accompanied by increased production of IL-10. In contrast to other infections with intracellular microorganisms, this response occurs later after the end of treatment.

da Silva, Marcos Vinicius; Figueiredo, Amanda A.; Machado, Juliana R.; Castellano, Lucio C.; Alexandre, Patricia B. D.; Oliveira, Rafael F.; Faria, Gladstone E. L.; Pereira, Sanivia A. L.; Rodrigues, Denise B. R.; Rodrigues, Virmondes



Erythema induratum (of Bazin) in a patient with endometrial tuberculosis  

Microsoft Academic Search

We report erythema induratum in a patient who was found to have active endometrial tuberculosis. This case report emphasizes the importance of an exhaustive search for active tuberculosis in patients with erythema induratum, especially in countries where tuberculosis is prevalent, as the indiscriminate treatment of erythema induratum with steroids may be harmful.

H. J. De Silva; A. K. Goonetilleke; N. R. De Silva; L. R. Amarasekera



Characterization of phosphofructokinase activity in Mycobacterium tuberculosis reveals that a functional glycolytic carbon flow is necessary to limit the accumulation of toxic metabolic intermediates under hypoxia.  


Metabolic versatility has been increasingly recognized as a major virulence mechanism that enables Mycobacterium tuberculosis to persist in many microenvironments encountered in its host. Glucose is one of the most abundant carbon sources that is exploited by many pathogenic bacteria in the human host. M. tuberculosis has an intact glycolytic pathway that is highly conserved in all clinical isolates sequenced to date suggesting that glucose may represent a non-negligible source of carbon and energy for this pathogen in vivo. Fructose-6-phosphate phosphorylation represents the key-committing step in glycolysis and is catalyzed by a phosphofructokinase (PFK) activity. Two genes, pfkA and pfkB have been annotated to encode putative PFK in M. tuberculosis. Here, we show that PFKA is the sole PFK enzyme in M. tuberculosis with no functional redundancy with PFKB. PFKA is required for growth on glucose as sole carbon source. In co-metabolism experiments, we report that disruption of the glycolytic pathway at the PFK step results in intracellular accumulation of sugar-phosphates that correlated with significant impairment of the cell viability. Concomitantly, we found that the presence of glucose is highly toxic for the long-term survival of hypoxic non-replicating mycobacteria, suggesting that accumulation of glucose-derived toxic metabolites does occur in the absence of sustained aerobic respiration. The culture medium traditionally used to study the physiology of hypoxic mycobacteria is supplemented with glucose. In this medium, M. tuberculosis can survive for only 7-10 days in a true non-replicating state before death is observed. By omitting glucose in the medium this period could be extended for up to at least 40 days without significant viability loss. Therefore, our study suggests that glycolysis leads to accumulation of glucose-derived toxic metabolites that limits long-term survival of hypoxic mycobacteria. Such toxic effect is exacerbated when the glycolytic pathway is disrupted at the PKF step. PMID:23409118

Phong, Wai Yee; Lin, Wenwei; Rao, Srinivasa P S; Dick, Thomas; Alonso, Sylvie; Pethe, Kevin



Cellular interactions in bovine tuberculosis: release of active mycobacteria from infected macrophages by antigen-stimulated T cells  

PubMed Central

The outcome of Mycobacterium bovis infections depends on the interactions of infected macrophages with T lymphocytes. Several studies in humans and in mouse models have suggested an important role for cytotoxicity in the protective immune response to mycobacterial infections, and both CD4+ and CD8+ T cells have been shown to elicit appropriate cytolytic activity. The present study investigated in vitro interactions of T cells with M. bovis?infected macrophages in bovine tuberculosis. The results showed that following interaction with antigen?stimulated peripheral blood mononuclear cells (PBMC) from infected cattle, there was an increased presence of M. bovis in the extracellular compartment of infected macrophage cultures, as measured by incorporation of [3H]uracil into mycobacterial RNA. Furthermore, out of a panel of T?cell clones from infected cattle, it was found that a higher proportion of CD8+ clones produced an increase in the number of metabolically active extracellular M. bovis organisms compared with CD4+ clones. Finally, a positive correlation between percentage of antigen?dependent release of mycobacteria and total uracil uptake by M. bovis within culture systems was detected. This could be regarded as an indication of preferential intracellular control of mycobacteria by activated macrophages.

Liebana, E; Aranaz, A; Aldwell, F E; McNair, J; Neill, S D; Smyth, A J; Pollock, J M



Visceral leishmaniasis masquerading as tuberculosis in a patient with AIDS  

PubMed Central

We report a case of visceral leishmaniasis presenting as significant lymphadenopathy in a patient with acquired immune deficiency syndrome. The lymphadenopathy was initially suspected to be tubercular in nature on pathological examination. This report highlights the increasing incidence of acquired immune deficiency syndrome and Leishmania co-infection in India, and the importance of demonstrating tubercle bacilli on culture before suggesting a diagnosis of tuberculosis.???Keywords: leishmaniasis; AIDS; tuberculosis

Yaduvanshi, A.; Jain, M.; Jain, S; Jain, S.; Arora, S.



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.

Wadee, A A; Clara, A M



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



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

Microsoft Academic Search

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

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



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


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



Disease-associated glycosylated molecular variants of human C-reactive protein activate complement-mediated hemolysis of erythrocytes in tuberculosis and Indian visceral leishmaniasis  

Microsoft Academic Search

Human C-reactive protein (CRP), as a mediator of innate immunity, removed damaged cells by activating the classical complement\\u000a pathway. Previous studies have successfully demonstrated that CRPs are differentially induced as glycosylated molecular variants\\u000a in certain pathological conditions. Affinity-purified CRPs from two most prevalent diseases in India viz. tuberculosis (TB) and visceral leishmaniasis (VL) have differential glycosylation in their sugar composition

Waliza Ansar; Sumi Mukhopadhyay; S. K. Hasan Habib; Shyamasree Basu; Bibhuti Saha; Asish Kumar Sen; C. N. Mandal; Chitra Mandal



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

Microsoft Academic Search

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

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



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


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



Implications of binding mode and active site flexibility for inhibitor potency against the salicylate synthase from Mycobacterium tuberculosis.  


MbtI is the salicylate synthase that catalyzes the first committed step in the synthesis of the iron chelating compound mycobactin in Mycobacterium tuberculosis. We previously developed a series of aromatic inhibitors against MbtI based on the reaction intermediate for this enzyme, isochorismate. The most potent of these inhibitors had hydrophobic substituents, ranging in size from a methyl to a phenyl group, appended to the terminal alkene of the enolpyruvyl group. These compounds exhibited low micromolar inhibition constants against MbtI and were at least an order of magnitude more potent than the parental compound for the series, which carries a native enolpyruvyl group. In this study, we sought to understand how the substituted enolpyruvyl group confers greater potency, by determining cocrystal structures of MbtI with six inhibitors from the series. A switch in binding mode at the MbtI active site is observed for inhibitors carrying a substituted enolpyruvyl group, relative to the parental compound. Computational studies suggest that the change in binding mode, and higher potency, is due to the effect of the substituents on the conformational landscape of the core inhibitor structure. The crystal structures and fluorescence-based thermal shift assays indicate that substituents larger than a methyl group are accommodated in the MbtI active site through significant but localized flexibility in the peptide backbone. These findings have implications for the design of improved inhibitors of MbtI, as well as other chorismate-utilizing enzymes from this family. PMID:22607697

Chi, Gamma; Manos-Turvey, Alexandra; O'Connor, Patrick D; Johnston, Jodie M; Evans, Genevieve L; Baker, Edward N; Payne, Richard J; Lott, J Shaun; Bulloch, Esther M M



Living with Tuberculosis  


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


Tuberculosis and Diabetes  




Functional analysis in mouse embryonic stem cells reveals wild-type activity for three msh6 variants found in suspected lynch syndrome patients.  


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



Enhanced killing of intracellular multidrug-resistant Mycobacterium tuberculosis by compounds that affect the activity of efflux pumps.  


Whereas human neutrophils are effective and efficient killers of bacteria, macrophages such as those derived from monocytes are almost devoid of killing activity. Nevertheless, monocytes can be transformed into effective killers of mycobacteria or staphylococci when exposed to clinical concentrations of a phenothiazine or to inhibitors of efflux pumps (reserpine and verapamil), or to ouabain, an inhibitor of K(+) transport. Because the rates of multidrug-resistant Mycobacterium tuberculosis (MDR-TB) continue to escalate globally, and because no new effective drug has been made available for almost 40 years, compounds that enhance the killing activity of monocytes against MDR-TB are obviously needed. This review covers the specific characteristics of MDR-TB, identifies a variety of agents that address these characteristics and therefore have potential for managing MDR-TB. Because the mechanism by which these agents enhance the killing of intracellular bacteria is important for the intelligent design of new anti-tubercular agents, the review correlates the mechanisms by which these agents manifest their effects. Lastly, a model is presented which describes the mechanisms by which distinct efflux pumps of the phagosome-lysosome complex are inhibited by agents that are known to inhibit K(+) flux. The model also predicts the existence of a K(+) activated exchange (pump) that is probably located in the membrane that delineates the lysosome. This putative pump, which is immune to inhibitors of K+ flux, is identified as being the cause for the acidification of the lysosome thereby activating its hydrolytic enzymes. Because the non-killer macrophage can be transformed into an effective killer by a variety of compounds that inhibit K(+) transport, perhaps it would be wise to develop drugs that enhance the killing activity of these cells inasmuch as this approach would not be subject to any resistance, as is the eventual case for conventional antibiotics. PMID:17218448

Amaral, Leonard; Martins, Marta; Viveiros, Miguel



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.

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



9 CFR 309.2 - Livestock suspected of being diseased or affected with certain conditions; identifying suspects...  

Code of Federal Regulations, 2010 CFR process of healing, the temperature is within normal range, and...livestock shows a return to normal appetite and activity, shall...a suspect, including its temperature when the temperature of such animal might...



Multi-drug resistant childhood tuberculosis.  


Emergence of drug resistant tuberculosis is one of the major challenges faced by health community globally. Tuberculosis is an important cause of morbidity and mortality among children in endemic areas, yet little is known regarding epidemiology of pediatric tuberculosis and even far lesser information is available about epidemiology, diagnosis, management and treatment outcome of drug resistant tuberculosis in children. Despite limited data and difficulties in its management, drug resistant tuberculosis can be successfully treated even in resource poor settings with proper use of existing technologies. A high index of suspicion and early drug susceptibility testing is the key to early diagnosis and good treatment outcome. Difficulties in establishing the diagnosis, drug toxicities and absence of pediatric formulations add challenges to the management of Pediatric MDR TB Cases. Active research is required to answer the unresolved issues of finding optimal diagnostic tools, treatment regimens and duration and chemoprophylaxis in pediatric drug resistant tuberculosis. PMID:21193973

Singh, Varinder; Kaur, Satnam



Suspect identification by facial features.  


Often during criminal investigations, witnesses must examine photographs of known offenders, colloquially called 'mug shots'. As witnesses view increasing numbers of mug shots that are presented in an arbitrary order, they become more likely to identify the wrong suspect. An alternative is a subjective feature-based mug shot retrieval system in which witnesses first complete a questionnaire about the appearance of the suspect, and then examine photographs in order of decreasing resemblance to their description. In the first experiment, this approach is found to be more efficient and more accurate than searching an album. The next three experiments show that it makes little difference if the witness has seen the suspect in person or only seen a photograph. In the last two experiments, it is shown that the feature-based retrieval system is effective even when the witness has seen the suspect in realistic natural settings. The results show that the main conclusions drawn from previous studies, where witnesses searched for faces seen only in photographs, also apply when witnesses are searching for a face that they saw live in naturalistic settings. Additionally, it is shown that is it better to have two raters than one create the database, but that more than two raters yield rapidly diminishing returns for the extra cost. PMID:15204285

Lee, Eric; Whalen, Thomas; Sakalauskas, John; Baigent, Glen; Bisesar, Chandra; McCarthy, Andrew; Reid, Glenda; Wotton, Cynthia



A Case of Sigmoid Colon Tuberculosis Mimicking Colon Cancer  

PubMed Central

Tuberculosis of the sigmoid colon is a rare disorder. An 80-year-old man visited Bongseng Memorial Hospital for medical examination. A colonoscopy was performed, and a lesion in the sigmoid colon that was suspected to be colon cancer was found. A biopsy was performed, and tuberculous enteritis with chronic granulomatous inflammation was diagnosed. Intestinal tuberculosis is most frequent in the ileocecal area, followed by the ascending colon, transverse colon, duodenum, stomach, and sigmoid colon, in descending order. Hence, we report a case of intestinal tuberculosis in the sigmoid colon, which is rare and almost indistinguishable from colon cancer.

Yu, Seong-Min; Kim, Min-Dae; Lee, Hee-Ryong; Jung, Peel; Ryu, Tae-Hyun; Choi, Seung-Ho; Lee, Il-Seon



Tuberculosis during TNF-? inhibitor therapy, despite screening.  


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

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



The crystal structure of Mycobacterium tuberculosis NrdH at 0.87 Å suggests a possible mode of its activity.  


Members of the NrdH family of redox proteins, which consists of small glutaredoxin-like proteins with thioredoxin-like activity, serve as the reducing partners of class Ib ribonucleotide reductases. Here, we report the crystal structure of NrdH from Mycobacterium tuberculosis, refined to a crystallographic R factor of 14.02% (Rfree = 15.53%) at 0.87 Å resolution. The tertiary structure of M. tuberculosis NrdH has a typical thioredoxin fold as expected. The extremely high resolution of the structure allows us to dissect the functionality of the protein in great depth. Structural superimposition of M. tuberculosis NrdH and thioredoxin reductase over the Escherichia coli thioredoxin reductase-thioredoxin complex suggests the ability of NrdH to accept electrons from M. tuberculosis thioredoxin reductase. This raises the important question of why glutaredoxins are unable to accept electrons from thioredoxin reductases and why thioredoxins are unable to reduce ribonucleotide reductases. Furthermore, forms of NrdH from other organisms have been shown to be a specific reductant of class Ib ribonucleotide reductases. We attempt to explain this substrate specificity by modeling the C-terminal peptide of a ribunucleotide subunit, NrdE, in the active site of NrdH using the already available Grx-NrdA-Cter-peptide structure. Statistical coupling analysis of NrdH, glutaredoxins, and thioredoxins reveals different sets of co-evolving contiguous clusters of amino acid residues, which might explain the differences in the biochemical properties of these structurally similar yet functionally distinct subclasses of proteins. PMID:23675692

Phulera, Swastik; Mande, Shekhar C



Biosynthesis of isoprenoids: characterization of a functionally active recombinant 2-C-methyl-D-erythritol 4-phosphate cytidyltransferase (IspD) from Mycobacterium tuberculosis H37Rv.  


Tuberculosis, caused by Mycobacterium tuberculosis, continues to be one of the leading infectious diseases to humans. It is urgent to discover novel drug targets for the development of antitubercular agents. The 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway for isoprenoid biosynthesis has been considered as an attractive target for the discovery of novel antibiotics for its essentiality in bacteria and absence in mammals. MEP cytidyltransferase (IspD), the third-step enzyme of the pathway, catalyzes MEP and CTP to form 4-diphosphocytidyl-2-C-methylerythritol (CDP-ME) and PPi. In the work, ispD gene from M. tuberculosis H37Rv (MtIspD) was cloned and expressed. With N-terminal fusion of a histidine-tagged sequence, MtIspD could be purified to homogeneity by one-step nickel affinity chromatography. MtIspD exists as a homodimer with an apparent molecular mass of 52 kDa. Enzyme property analysis revealed that MtIspD has high specificity for pyrimidine bases and narrow divalent cation requirements, with maximal activity found in the presence of CTP and Mg(2+). The turnover number of MtIspD is 3.4 s(-1). The Km for MEP and CTP are 43 and 92 muM, respectively. Furthermore, MtIspD shows thermal instable above 50 degrees C. Circular dichroism spectra revealed that the alteration of tertiary conformation is closely related with sharp loss of enzyme activity at higher temperature. This study is expected to help better understand the features of IspD and provide useful information for the development of novel antibiotics to treat M. tuberculosis. PMID:18047786

Shi, Wenjun; Feng, Jianfang; Zhang, Min; Lai, Xuhui; Xu, Shengfeng; Zhang, Xuelian; Wang, Honghai



Peptidoglycan remodeling in Mycobacterium tuberculosis: comparison of structures and catalytic activities of RipA and RipB.  


The success of Mycobacterium tuberculosis in sustaining long-term survival within the host macrophages partly relies on its unique cell envelop that also confers low susceptibility to several antibiotics. Remodeling of the septal peptidoglycan (PG) has been linked to the putative PG hydrolases RipA and RipB. The crystal structures of RipB (Rv1478) and the homologous module of RipA (Rv1477) were determined to 1.60 Å and 1.38 Å resolution, respectively. Both proteins contain a C-terminal core domain resembling the NlpC-type PG hydrolases. However, the structure of RipB exhibits striking differences to the structures of this domain in RipA reported here and previously by others. Major structural differences were found in the N-terminal segments of 70 amino acids and in an adjacent loop, which form part of the substrate binding groove. Both RipA and RipB are able to bind PG. RipA, its C-terminal module and RipB cleave defined PG fragments between d-glutamate and meso-diaminopimelate with pH optima of 5 and 6, respectively. The peptidase module of RipA is also able to degrade Bacillus subtilis PG, which displays peptide stems and cross-links identical with those found in mycobacterial murein. RipB did not show comparable hydrolase activity with this substrate. Removal of the N-terminal segments previously suggested to have a role in auto-inhibition did not change the activity of either RipA or RipB. A comparison of the putative active-site clefts in the two enzymes provides structural insights into the basis of the differences in their substrate specificity. PMID:21864539

Böth, Dominic; Schneider, Gunter; Schnell, Robert



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


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

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



Arthritis associated with tuberculosis  

Microsoft Academic Search

There has been a resurgence in tuberculosis (TB) worldwide. Approximately 2 billion people have latent infection, 8 million would develop active TB annually, and 2–3 million would die due to TB. With this resurgence, cases with extrapulmonary TB have also shown an increase. Approximately 10–11% of extrapulmonary TB involves joints and bones, which is approximately 1–3% of all TB cases.

P. P Kotwal



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


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

Shimao, T



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.

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



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



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


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

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



BCG-specific IgG-secreting peripheral plasmablasts as a potential biomarker of active tuberculosis in HIV negative and HIV positive patients  

PubMed Central

Background Diagnosis of active tuberculosis (TB) among sputum-negative cases, patients with HIV infection and extra-pulmonary TB is difficult. In this study, assessment of BCG-specific IgG-secreting peripheral plasmablasts, was used to identify active TB in these high-risk groups. Methods Peripheral blood mononuclear cells were isolated from patients with TB and controls and cultured in vitro using an assay called Antibodies in Lymphocyte Supernatant, which measures spontaneous IgG antibody release from migratory plasmablasts. A BCG-specific ELISA and flow cytometry were used to quantify in vivo activated plasmablasts in blood samples from Ethiopian subjects who were HIV negative or HIV positive. Patients diagnosed with different clinical forms of sputum-negative active TB or other diseases (n=96) were compared with asymptomatic individuals including latent TB and non-TB controls (n=85). Immunodiagnosis of TB also included the tuberculin skin test and the interferon (IFN)-? release assay, QuantiFERON. Results This study demonstrated that circulating IgG+ plasmablasts and spontaneous secretion of BCG-specific IgG antibodies were significantly higher in patients with active TB compared with latent TB cases and non-TB controls. BCG-specific IgG titres were particularly high among patients coinfected with TB and HIV with CD4?T-cell counts <200?cells/ml who produced low levels of Mycobacterium tuberculosis-specific IFN? in vitro. Conclusions These results suggest that BCG-specific IgG-secreting peripheral plasmablasts could be successfully used as a host-specific biomarker to improve diagnosis of active TB, particularly in people who are HIV positive, and facilitate administration of effective treatment to patients. Elevated IgG responses were associated with impaired peripheral T-cell responses, including reduced T-cell numbers and low M tuberculosis-specific IFN? production.

Ashenafi, Senait; Aderaye, Getachew; Zewdie, Martha; Raqib, Rubhana; Bekele, Amsalu; Magalhaes, Isabelle; Lema, Beede; Habtamu, Meseret; Rekha, Rokeya Sultana; Aseffa, Getachew; Maeurer, Markus; Aseffa, Abraham; Svensson, Mattias; Andersson, Jan; Brighenti, Susanna



[Tuberculosis, today].  


Tuberculosis is still a major health and social problem because, on the one hand, we have witnessed the dismantling of the sanatoriums, with a reduced level of diagnostic suspicion, knowledge and expertise on the management of the disease, while, the other side, are considered migratory flows, the lower socio-economic faced by immigrants, the states of immunosuppression associated with HIV prevalence of malnutrition and other diseases, and the phenomenon of multidrug-resistance, which often turns out to be iatrogenic. The success of the strategy of control/elimination of tuberculosis promoted by the World Health Organization requires a well coordinated multidisciplinary approach in which everyone does their part, the general practitioner, the pulmonologist, the infectious disease specialist, and the microbiologist. PMID:22688374

Scala, Raffaele



Abdominal tuberculosis.  

PubMed Central

Tuberculosis has staged a global comeback and forms a dangerous combination with AIDS. The abdomen is one of the common sites of extrapulmonary involvement. Patients with abdominal tuberculosis have a wide range and spectrum of symptoms and signs; the disease is therefore a great mimic. Diagnosis, mainly radiological and supported by endoscopy, is difficult to make and laparotomy is required in a large number of patient. Management involves judicious combination of antitubercular therapy and surgery which may be required to treat complications such as intestinal obstruction and perforation. The disease, though potentially curable, carries a significant morbidity and mortality. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13

Kapoor, V. K.



Mycobacterium tuberculosis-specific CD8+ T cells are functionally and phenotypically different between latent infection and active disease.  


Protective immunity to Mycobacterium tuberculosis (Mtb) remains poorly understood and the role of Mtb-specific CD8(+) T cells is controversial. Here we performed a broad phenotypic and functional characterization of Mtb-specific CD8(+) T cells in 326 subjects with latent Mtb infection (LTBI) or active TB disease (TB). Mtb-specific CD8(+) T cells were detected in most (60%) TB patients and few (15%) LTBI subjects but were of similar magnitude. Mtb-specific CD8(+) T cells in LTBI subjects were mostly T EMRA cells (CD45RA(+) CCR7(-)), coexpressing 2B4 and CD160, and in TB patients were mostly TEM cells (CD45RA(-) CCR7(-)), expressing 2B4 but lacking PD-1 and CD160. The cytokine profile was not significantly different in both groups. Furthermore, Mtb-specific CD8(+) T cells expressed low levels of perforin and granulysin but contained granzymes A and B. However, in vitro-expanded Mtb-specific CD8(+) T cells expressed perforin and granulysin. Finally, Mtb-specific CD8(+) T-cell responses were less frequently detected in extrapulmonary TB compared with pulmonary TB patients. Mtb-specific CD8(+) T-cell proliferation was also greater in patients with extrapulmonary compared with pulmonary TB. Thus, the activity of Mtb infection and clinical presentation are associated with distinct profiles of Mtb-specific CD8(+) T-cell responses. These results provide new insights in the interaction between Mtb and the host immune response. PMID:23456989

Rozot, Virginie; Vigano, Selena; Mazza-Stalder, Jesica; Idrizi, Elita; Day, Cheryl L; Perreau, Matthieu; Lazor-Blanchet, Catherine; Petruccioli, Elisa; Hanekom, Willem; Goletti, Delia; Bart, Pierre-Alexandre; Nicod, Laurent; Pantaleo, Giuseppe; Harari, Alexandre



Abdominal tuberculosis in children  

Microsoft Academic Search

Four boys with abdominal tuberculosis, one of whom had acquired immunodeficiency syndrome, are presented. Abdominal imaging findings on plain radiography, ultrasonography, computed tomography, and gastrointestinal contrast studies included tuberculous peritonitis and ascites in all patients, tuberculous adenopathy in two, gastrointestinal tuberculosis in two, and omental tuberculosis in two. The radiographic features particularly characteristic of abdominal tuberculosis were: (1) low attenuating

D. S. Ablin; K. A. Jain; E. M. Azouz



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

PubMed Central

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

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



Bactericidal Activity of Streptomycin and Isoniazid in Combination with p-Aminosalicylic Acid against Mycobacterium tuberculosis  

Microsoft Academic Search

SUMMARY : The bactericidal activity of streptomycin, isoniazid and combinations of streptomycin and isoniazid against tubercle bacilli growing in Tween albumin medium was measured with and without the addition of p-aminosalicylic acid (PAS). When the concentrations of these compounds were about 4 to 16 times their minimal inhibitory concentrations, PAS did not influence this activity, but it was slightly increased




Discriminating Active from Latent Tuberculosis in Patients Presenting to Community Clinics  

PubMed Central

Background Because of the high global prevalence of latent TB infection (LTBI), a key challenge in endemic settings is distinguishing patients with active TB from patients with overlapping clinical symptoms without active TB but with co-existing LTBI. Current methods are insufficiently accurate. Plasma proteomic fingerprinting can resolve this difficulty by providing a molecular snapshot defining disease state that can be used to develop point-of-care diagnostics. Methods Plasma and clinical data were obtained prospectively from patients attending community TB clinics in Peru and from household contacts. Plasma was subjected to high-throughput proteomic profiling by mass spectrometry. Statistical pattern recognition methods were used to define mass spectral patterns that distinguished patients with active TB from symptomatic controls with or without LTBI. Results 156 patients with active TB and 110 symptomatic controls (patients with respiratory symptoms without active TB) were investigated. Active TB patients were distinguishable from undifferentiated symptomatic controls with accuracy of 87% (sensitivity 84%, specificity 90%), from symptomatic controls with LTBI (accuracy of 87%, sensitivity 89%, specificity 82%) and from symptomatic controls without LTBI (accuracy 90%, sensitivity 90%, specificity 92%). Conclusions We show that active TB can be distinguished accurately from LTBI in symptomatic clinic attenders using a plasma proteomic fingerprint. Translation of biomarkers derived from this study into a robust and affordable point-of-care format will have significant implications for recognition and control of active TB in high prevalence settings.

Sandhu, Gurjinder; Battaglia, Francesca; Ely, Barry K.; Athanasakis, Dimitrios; Montoya, Rosario; Valencia, Teresa; Gilman, Robert H.; Evans, Carlton A.; Friedland, Jon S.



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



Evaluation of Clinical Parameters to Predict Mycobacterium tuberculosis in Inpatients  

Microsoft Academic Search

Background: Respiratory isolation has been recom- mended for all patients with suspected tuberculosis (TB) to avoid transmission to other patients and health care personnel. In implementing these guidelines, patients with and without TB are frequently isolated, significantly in- creasing hospital costs. The objective of this study was to derive a clinical rule to predict the need for respira- tory isolation

Juan P. Wisnivesky; Jennifer Kaplan; Claudia Henschke; Thomas G. McGinn; Ronald G. Crystal



Preliminary structure-activity relationships and biological evaluation of novel antitubercular indolecarboxamide derivatives against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains.  


Tuberculosis (TB) remains one of the leading causes of mortality and morbidity worldwide, with approximately one-third of the world's population infected with latent TB. This is further aggravated by HIV coinfection and the emergence of multidrug- and extensively drug-resistant (MDR and XDR, respectively) TB; hence the quest for highly effective antitubercular drugs with novel modes of action is imperative. We report herein the discovery of an indole-2-carboxamide analogue, 3, as a highly potent antitubercular agent, and the subsequent chemical modifications aimed at establishing a preliminary body of structure-activity relationships (SARs). These efforts led to the identification of three molecules (12-14) possessing an exceptional activity in the low nanomolar range against actively replicating Mycobacterium tuberculosis , with minimum inhibitory concentration (MIC) values lower than those of the most prominent antitubercular agents currently in use. These compounds were also devoid of apparent toxicity to Vero cells. Importantly, compound 12 was found to be active against the tested XDR-TB strains and orally active in the serum inhibition titration assay. PMID:23611124

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



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

PubMed Central

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



Hepatobiliary tuberculosis: a review of presentations and outcomes.  


Hepatobiliary tuberculosis (HTB) is uncommon and can be difficult to diagnose. We present our experience with HTB (over a 10-year period). Fourteen patients were identified from a total of 1888 cases of tuberculosis (TB) infection during this period. Five patients had isolated organ involvement [hepatic (n=3) and biliary (n=2)], and 9 had multiorgan involvement [2 organs (n=7) and 3 organs (n=2)]. The overall annual incidence ranged from 0.0% to 1.05% of all TB infections. Common clinical presentations were weight loss (64%), loss of appetite (64%), abdominal pain (57.1%), fever (50%), jaundice (42.3%), and abdominal distension (14.3%). The median delay from symptom onset to presentation was 40.5 days (range, 7-730 days), and from first presentation to diagnosis was 15 days (range, 1-420 days). Malignancy was initially suspected in 86%. Chest radiographic changes consistent with pulmonary TB were seen in 29% (n=4). Two had active pulmonary TB. Adverse effects of treatment occurred in 42.9%, mainly drug-induced hepatitis and nonspecific gastrointestinal symptoms. Three patients with biliary involvement required long-term biliary stenting. The overall mortality was 14%. In conclusion, HTB is uncommon and is often associated with other organ involvement. Presentation is often delayed, which may lead to significant morbidity and mortality. PMID:18360350

Chong, Vui Heng



Transmission of tuberculosis in the metropolitan area of Zurich: a 3 year survey based on DNA fingerprinting  

Microsoft Academic Search

Transmission of tuberculosis in the metropolitan area of Zurich: a 3 year survey based on DNA fingerprinting. G.E. Pfyffer, A. Strässle, N. Rose, R. Wirth, O. Brändli, H. Shang. ?ERS Journals Ltd 1998. ABSTRACT: Between 1991 and 1993, 444 inhabitants of the metropolitan area of Zurich were reported as confirmed or suspected cases of tuberculosis (TB). Overall, isolates of Mycobacterium

G. E. Pfyffer; A. Strässle; N. Rose; R. Wirth; O. Brändli; H. Shang



Vaccination against tuberculosis: how can we better BCG?  


Tuberculosis remains one of the most significant human diseases of the developing world, accounting for 3800 worldwide deaths per day. Although we currently have a vaccine for tuberculosis, BCG, this is insufficient at protecting from adult pulmonary tuberculosis in the parts of the world where a good vaccine is most needed. This has prompted the search for new vaccination strategies that can protect better than BCG, or can boost BCG-induced immunity. We discuss these subjects in line with what is known of the immune responses to BCG and Mycobacterium tuberculosis - the etiological agent of the disease, as well as the particular difficulties facing development of new vaccines against tuberculosis. A greater understanding of the factors constituting optimal protection against Mycobacterium tuberculosis infection, as well as which pathogenic factors facilitate active disease, will accelerate the delivery of safe vaccines able to restrict active tuberculosis and thus impede contagion. PMID:23257069

Pitt, Jonathan M; Blankley, Simon; McShane, Helen; O'Garra, Anne



Risk of Tuberculosis Reactivation With Tofacitinib (CP-690550)  

PubMed Central

Individuals with latent tuberculosis infection (LTBI) live with a risk of reactivation, and several treatments for chronic inflammatory conditions are highly associated with such reactivation. A new Janus kinase inhibitor, tofacitinib (CP-690550), has shown promising results for treatment of inflammatory disorders, thus raising concerns of risk of active tuberculosis. Our goal was to characterize the impact of tofacitinib on LTBI using a mouse model of contained tuberculosis. Our data indicate that tofacitinib reduces host containment of Mycobacterium tuberculosis and promotes bacterial replication in the lungs, suggesting tuberculosis reactivation. Tofacitinib may carry a significant risk for LTBI reactivation in humans.

Maiga, Mamoudou; Lun, Shichun; Guo, Haidan; Winglee, Kathryn; Ammerman, Nicole C.; Bishai, William R.



Risk of tuberculosis reactivation with tofacitinib (CP-690550).  


Individuals with latent tuberculosis infection (LTBI) live with a risk of reactivation, and several treatments for chronic inflammatory conditions are highly associated with such reactivation. A new Janus kinase inhibitor, tofacitinib (CP-690550), has shown promising results for treatment of inflammatory disorders, thus raising concerns of risk of active tuberculosis. Our goal was to characterize the impact of tofacitinib on LTBI using a mouse model of contained tuberculosis. Our data indicate that tofacitinib reduces host containment of Mycobacterium tuberculosis and promotes bacterial replication in the lungs, suggesting tuberculosis reactivation. Tofacitinib may carry a significant risk for LTBI reactivation in humans. PMID:22474037

Maiga, Mamoudou; Lun, Shichun; Guo, Haidan; Winglee, Kathryn; Ammerman, Nicole C; Bishai, William R



The vitro efficacy of ?-lactam and ?-lactamase inhibitors against multidrug resistant clinical strains of Mycobacterium tuberculosis  

Microsoft Academic Search

In vitro activity of ?-lactam antibiotics and their ?-lactamase inhibitor combinations were evaluated for their activity against clinical isolates of Mycobacterium tuberculosis and M. tuberculosis H37Ra. Agar dilution, the BACTEC 460 system and ?-lactamase activity tests were used. Results using the BACTEC 460 and enzyme activity tests showed the best ?-lactamase inhibitor for M. tuberculosis H37Ra to be clavulanic acid.

Irem Dinçer; Alper Ergin; Tan?l Kocagöz



Abdominal tuberculosis.  

PubMed Central

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

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



False positive tuberculosis skin test results.  

PubMed Central

The re-emergence of tuberculosis as a significant public health threat has led to greatly renewed activity in tuberculin skin testing to identify infected persons. However, even use of the preferred skin test technique (intradermal injection of purified protein derivative via the Mantoux method) can lead to either false positive or false negative results. Interpretation of a Mantoux test can be influenced by cross reactions with other mycobacteria, intertester variation, host-response variation, and product related problems. At least 25 apparent false positive purified protein derivative skin test reactions in New York State in 1992 appeared to be associated with lots of the derivative produced by one manufacturer. These unexpected skin test results led to examination of a product with an altered appearance that may have caused the unanticipated responses. After announcement of these false positive results to the press, the company removed the product from the market. Food and Drug Administration analysis later revealed particulate matter in vials of the suspected lots of purified protein derivative.

Grabau, J C; DiFerdinando, G T; Novick, L F



The Early Bactericidal Activities of Rifampin and Rifapentine in Pulmonary Tuberculosis  

Microsoft Academic Search

Rationale: Comparison of the early bactericidal activity (EBA) of rifapentine and its pharmacokinetics with those of rifampin to de- termine the cause of poor clinical response and regrowth between doses, leading to rifamycin monoresistance at relapse. Objectives: Determination of the dose size of rifapentine that gives sufficient drug exposure to prevent regrowth. Methods: EBA study over initial 5 days of

Frik A. Sirgel; P. Bernard Fourie; Peter R. Donald; Nesri Padayatchi; Roxana Rustomjee; Jonathan Levin


System and method for disrupting suspect objects  


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



Investigation of 6-fluoroquinolones activity against Mycobacterium tuberculosis using theoretical molecular descriptors: a case study  

Microsoft Academic Search

A quantitative structure-activity relationship (QSAR) study on a set of 66 structurally-similar 6-fluoroquinolones was performed\\u000a using a large pool of theoretical molecular descriptors. Ab initio geometry optimizations were carried out to reproduce the geometrical and electronic structure parameters. The resulting molecular\\u000a structures were confirmed to be minima via harmonic frequency calculations. Obtained atomic charges, HOMO and LUMO energies,\\u000a orbital electron

Nikola Minovski; Aneta Jezierska-Mazzarello; Marjan Vra?ko; Tom Šolmajer



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


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



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


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



Tuberculosis biomarkers discovery: developments, needs, and challenges.  


Biomarkers are indispensable to the development of new tuberculosis therapeutics and vaccines. The most robust biomarkers measure factors that are essential to the underlying pathological process of the disease being treated, and thus can capture the full effects of many types of interventions on clinical outcomes in multiple prospective, randomised clinical trials. Many Mycobacterium tuberculosis and human biomarkers have been studied over the past decade. Present research focuses on three areas: biomarkers predicting treatment efficacy and cure of active tuberculosis, the reactivation of latent tuberculosis infection, and the induction of protective immune responses by vaccination. Many older, non-specific markers of inflammation, when considered in isolation, do not have sufficient predictive values for clinical use in tuberculosis. Although no new accurate, tuberculosis-specific biomarkers have yet been discovered, substantial progress has been made in some areas. However, the qualification of biomarkers as a surrogate for a clinical endpoint in tuberculosis is very challenging, and, for biomarkers that are non-culture-based, impossible to pursue without the availability of well characterised biobanks containing biospecimens from patients who have had adequate follow-up to establish long-term treatment outcome. We review progress in tuberculosis biomarker development and efforts being made to harness resources to meet future challenges. PMID:23531389

Wallis, Robert S; Kim, Peter; Cole, Stewart; Hanna, Debra; Andrade, Bruno B; Maeurer, Markus; Schito, Marco; Zumla, Alimuddin



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:; Ibukuro, Kenji; Tsukiyama, Toshitaka; Ishii, Rei [Mitsui Memorial Hospital, Department of Radiology (Japan)



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

PubMed Central

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

Williams, Alan; Guthlein, Carolin; Beresford, Nicola; Bottger, Erik C.; Springer, Burkhard; Davis, Elaine O.



Development and evaluation of multiplex PCR in rapid diagnosis of abdominal tuberculosis.  


The clinical features of abdominal tuberculosis (TB) are non-specific and establishing a diagnosis remains a challenge. A delay in diagnosis is likely to increase the morbidity in these patients. We developed a multiplex polymerase chain reaction (PCR) using 16SrRNA, IS6110, and devR, and evaluated it in comparison with other conventional tests in clinical suspects of abdominal TB. A total of 183 patients with clinical suspicion of abdominal TB (96 patients with intestinal TB and 87 with peritoneal TB) were enrolled for the study. Endoscopic or intraoperative biopsies were collected from patients suspected of intestinal TB and ascitic fluid was collected from patients with a suspicion of peritoneal TB. Of the intestinal tuberculosis group, there were 40 confirmed cases and 56 controls, while of the peritoneal tuberculosis group there were 37 confirmed cases and 50 controls. Multiplex PCR showed a high sensitivity and specificity in both the intestinal TB and peritoneal TB groups. When combined with histopathology, multiplex PCR could detect 97.5% of all the cases in the intestinal tuberculosis group, while in combination adenosine deaminase levels (ADA) in cases of peritoneal tuberculosis it increased the specificity of diagnosis of peritoneal tuberculosis to 95%. In combination with histopathology in suspected intestinal TB cases, and ADA testing in suspected peritoneal TB cases, it can be used as a highly sensitive, specific, and rapid diagnostic tool with the ability to supplement the limitations of other diagnostic modalities. PMID:23608350

Hallur, Vinaykumar; Sharma, Meera; Sethi, Sunil; Sharma, Kusum; Mewara, Abhishek; Dhatwalia, Sunil; Yadav, Rakesh; Bhasin, Deepak; Sinha, Saroj Kant; Rana, Satyawati; Joshi, Kusum



What's new in tuberculosis vaccines?  

PubMed Central

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

Ginsberg, Ann M.



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.



Advances in the diagnosis of pulmonary tuberculosis in HIV-infected and HIV-uninfected children.  


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; Nicol, Mark P



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


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



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

PubMed Central

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

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



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.

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



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.

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



New insights toward the discovery of antibacterial agents: multi-tasking QSBER model for the simultaneous prediction of anti-tuberculosis activity and toxicological profiles of drugs.  


Tuberculosis (TB) constitutes one of the most dangerous and serious health problems around the world. It is a very lethal disease caused by microorganisms of the genus mycobacterium, principally Mycobacterium tuberculosis (MTB) which affects humans. A very active field for the search of more efficient anti-TB chemotherapies is the use in silico methodologies for the discovery of potent anti-TB agents. The battle against MTB by using antimicrobial chemotherapies will depend on the design of new chemicals with high anti-TB activity and low toxicity as possible. Multi-target methodologies focused on quantitative-structure activity relationships (mt-QSAR) have played a very important role for the rationalization of drug design, providing a better understanding about the molecular patterns related with diverse pharmacological profiles including antimicrobial activity. Nowadays, almost all mt-QSAR models have considered the study of biological activity or toxicity separately. In the present study, we develop by the first time, a unified multitasking model based on quantitative-structure biological effect relationships (mtk-QSBER) for the simultaneous prediction of anti-TB activity and toxicity against Mus musculus and Rattus norvegicus. The mtk-QSBER model was created by using linear discriminant analysis (LDA) for the classification of compounds as positive (high biological activity and/or low toxicity) or negative (otherwise) under many experimental conditions. Our mtk-QSBER model, correctly classified more than 90% of the case in the whole database (more than 12,000 cases), serving as a powerful tool for the computer-assisted screening of potent and safe anti-TB drugs. PMID:23376211

Speck-Planche, Alejandro; Kleandrova, Valeria V; Cordeiro, M Natália D S



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

PubMed Central

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

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



Angiogenic Activity of Sera from Pulmonary Tuberculosis Patients in Relation to IL12p40 and TNF? Serum Levels  

Microsoft Academic Search

The role of angiogenesis in the pathogenesis of tuberculosis (TB) is not clear. The aim of this study was to examine the effect\\u000a of sera from TB patients on angiogenesis induced by different subsets of normal human mononuclear cells (MNC) in relation\\u000a to IL-12p40 and TNF? serum levels. Serum samples from 36 pulmonary TB patients and from 22 healthy volunteers

Tadeusz M. Zielonka; Urszula Demkow; Dorota Michalowska-Mitczuk; Malgorzata Filewska; Beata Bialas; Katarzyna Zycinska; Michael H. Obrowski; Jan Kus; Ewa Skopinska-Rozewska


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.

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



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


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



Rationale and design of a randomized controlled trial of the effect of retinol and vitamin D supplementation on treatment in active pulmonary tuberculosis patients with diabetes  

PubMed Central

Background The association between pulmonary tuberculosis (PTB) and diabetes mellitus (DM) has been previously attracted much attention. Diabetes alters immunity to tuberculosis, leading to more frequent treatment failure in TB patients with DM. Moreover, TB and DM often coincide with micronutrients deficiencies, such as retinol and vitamin D, which are especially important to immunity of the body and may influence pancreas ?-cell function. However, the effects of retinol and vitamin D supplementation in active TB patients with diabetes on treatment outcomes, immune and nutrition state are still uncertain. We are conducting a randomized controlled trial of vitamin A and/or D in active PTB patients with DM in a network of 4 TB treatment clinics to determine whether the supplementation could improve the outcome in the patients. Methods/design This is a 2×2 factorial trial. We plan to enroll 400 active PTB patients with DM, and randomize them to VA (2000 IU daily retinol); VD (400 IU daily cholecalciferol); VAD (2000 IU daily retinol plus 400 IU cholecalciferol) or control (placebo) group. Our primary outcome measure is the efficacy of anti-tuberculosis treatment and ameliorating of glucose metabolism, and the secondary outcome measure being immune and nutrition status of the subjects. Of the first 37 subjects enrolled: 8 have been randomized to VA, 10 to VD, 9 to VAD and 10 to control. To date, the sample is 97.3% Han Chinese and 91.9% female. The average fasting plasma glucose level is 12.19 mmol/L. Discussion This paper describes the design and rationale of a randomized clinical trial comparing VA and/or VD supplementation to active pulmonary TB patients with DM. Our trial will allow rigorous evaluation of the efficacy of the supplementation to active TB and DM therapy for improving clinical outcomes and immunological condition. This detailed description of trial methodology can serve as a template for the development of future treatment scheme for active TB patient with DM. Trial registration ChiCTR-TRC-12002546



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



Suspected Brucellosis Case Prompts Investigation of Possible Bioterrorism-Related Activity: New Hampshire and Massachusetts, 1999. Morbidity and Mortality Weekly Report, Vol. 49, nO. 23, June 16, 2000.  

National Technical Information Service (NTIS)

Brucella species, particularly B. melitensis and B. suis, are potential agents of biological terrorism. This report describes the public health and law enforcement assessment of a suspected case of brucellosis in a woman, in which the atypical clinical pr...



Tuberculosis of the cuneiform  

Microsoft Academic Search

A case report discusses the presentation, diagnosis and treatment of a 22-year-old male who presented with extra-pulmonary tuberculosis of the foot involving the cuneiform bones. Tuberculosis of the foot is extremely rare and accounts for less than 10% of ostearticular tuberculosis. Radiographic and MRI correlations are introduced.

J. Terrence Jose Jerome; Mathew Varghese; Balu Sankaran



48 CFR 1203.303 - Reporting suspected antitrust violations.  

Code of Federal Regulations, 2011 CFR

...Suspected Antitrust Violations 1203.303 Reporting suspected antitrust violations. (b) The same procedures contained in (TAR) 48 CFR 1203.203 shall also be followed for suspected antitrust violations, except reports of suspected antitrust...



Down-modulation of lung immune responses by interleukin-10 and transforming growth factor beta (TGF-beta) and analysis of TGF-beta receptors I and II in active tuberculosis  

Microsoft Academic Search

Immune factors influencing progression to active tuberculosis (TB) remain poorly defined. In this study, we investigated the expression of immunoregulatory cytokines and receptors by using lung bronchoalveolar lavage cells obtained from patients with pulmonary TB, patients with other lung diseases (OLD patients), and healthy volunteers (VOL) by using reverse transcriptase PCR, a transforming growth factor beta (TGF-beta) bioactivity assay, and

M. G. Bonecini-Almeida; J. L. Ho; N. Boechat; R. C. Huard; S. Chitale; H. Doo; J. Geng; L. Rego; L. C. Lazzarini; A. L. Kritski; Jr. W. D. Johnson; T. A. McCaffrey; J. R. Silva



[Thinking about tuberculosis in Osaka City].  


The incidence rate of tuberculosis in Osaka City (104.2 per 100,000 population) is extremely high, namely 3 times higher than the national average. Why the tuberculosis situation of Osaka City is so bad? The reason could be summarized as follows: Before the end of the World War II (1945), it was the sequelae of high prevalence observed in the era of Meiji, Taisho and early years of Showa. However, after the World War II, especially from the Heisei era (1989-), it is deeply affected by the influence of socio-economic background in Japan. Osaka City is characterized as the city of merchants and small enterprises. And therefore, the city substantially has the nature of the locality that brings in or produces some kinds of social vulnerability such as temporary laborers and homeless people. Of the tuberculosis patients in Osaka City, about 20% are homeless. In addition, patients of the smear positive infectious tuberculosis are often discovered among temporary laborers who change their residences and job sites from place to place and contact widely with citizens. These two are the most difficult problems in tuberculosis control program of Osaka City. In the meantime, there are many citizens who are careless of their health and do not follow the law or social rule, and this has apparently no direct connection with the problems of tuberculosis. However, it might be one of the factors of an undesirable trend of tuberculosis in Osaka City. In order to improve such a unfavorable tuberculosis situation in Osaka City, effective and strong supporting activities to the tuberculosis program are essentially needed. And these activities must be done from the standpoint of health-promotion, namely, health education for citizens and improvement of social environmental conditions to maintain healthy and cultural life. PMID:11201140

Kameda, K



38 CFR 3.372 - Initial grant following inactivity of tuberculosis.  

Code of Federal Regulations, 2013 CFR

...following inactivity of tuberculosis. When service connection is granted initially on an original or reopened claim for pulmonary or nonpulmonary tuberculosis and there is satisfactory evidence that the condition was active previously but is...



Primary Tuberculosis of Tonsils: A Case Report  

PubMed Central

Tuberculosis is one of the major causes of ill health and death worldwide. Isolated tuberculosis of tonsil in the absence of active pulmonary tuberculosis is a very rare clinical entity. A 10-year-male child presented with recurrent episodes of upper respiratory tract infections, with 2-3 occurrences per month for the past 6 years. On general physical examination, bilateral tonsils showed grade III enlargement and congestion. Posterior pharyngeal wall was clear. Examination of the chest was within normal limits. Histopathological examination of bilateral tonsils revealed caseating and noncaseating epithelioid cell granulomas with Langhans giant cells. Ziehl-Neelsen stain for acid fast bacillus was positive. Features were consistent with a diagnosis of tuberculosis of tonsils. Tuberculosis of the oral cavity is uncommon and lesions may be either primary or secondary. Early detection and intervention is essential for cure. Isolated and primary tuberculosis of the tonsils in the absence of pulmonary tuberculosis is a rare entity, which prompted us to report this case.

Prasad, Pooja; Bhardwaj, Minakshi



CTIOPI: Fingerprinting Nearby Star Suspects  

NASA Astrophysics Data System (ADS)

The nearest stars have gained renewed scrutiny because of their role in topics as diverse as fundamental astrophysics (e.g. stellar atmospheres, the mass content of the Galaxy) and as environments for planetary systems and life (e.g. the new NASA Astrobiology initiative). The smallest stars, the M dwarfs, dominate the population of the solar neighborhood, accounting for at least 70% of all stars and comprising nearly half of the Galaxy's total stellar mass. The slightly lesser cousins of the M dwarfs, the brown dwarfs, may lurk in comparable numbers. Yet, many of the nearest red and brown dwarfs (and white dwarfs) remain unrecognized due to their low luminosity. We propose to obtain red spectra (5800-9200 Å) for suspected nearby red, brown, and white dwarfs to characterize the Sun's neighbors and to support our NOAO Survey Program to get parallaxes for southern nearby stars, CTIOPI. During previous CTIO spectroscopic observing runs we have identified more than a dozen new stars within 10 parsecs of the Sun that are now included in the CTIOPI observing list, and obtained high quality spectra of known nearby stars, thereby providing fundamental data to the NASA/NSF NStars Project. Our most exciting result to date was the discovery of the 20th nearest star, GJ 1061 (Henry et al 1997 AJ 114 388). At a distance of only 3.7 parsecs, it is only three times further away than Proxima Centauri. We currently have two candidates that are potentially even closer. This work will very likely become the senior undergraduate thesis for CoI Lucianne Walkowicz at Johns Hopkins University.

Henry, Todd J.; Walkowicz, Lucianne; Golimowski, Dave



Different Strains of Mycobacterium tuberculosis Cause Various Spectrums of Disease in the Rabbit Model of Tuberculosis  

PubMed Central

The rabbit model of tuberculosis has been used historically to differentiate between Mycobacterium tuberculosis and Mycobacterium bovis based on their relative virulence in this animal host. M. tuberculosis infection in market rabbits is cleared over time, whereas infection with M. bovis results in chronic, progressive, cavitary disease leading to death. Because of the innate resistance of commercial rabbits to M. tuberculosis, 320 to 1,890 log-phase, actively growing inhaled bacilli were required to form one grossly visible pulmonary tubercle at 5 weeks. The range of inhaled doses required to make one tubercle allows us to determine the relative pathogenicities of different strains. Fewer inhaled organisms of the M. tuberculosis Erdman strain were required than of M. tuberculosis H37Rv to produce a visible lesion at 5 weeks. Furthermore, with the Erdman strain, only 7 of 15 rabbits had healed lesions at 16 to 18 weeks; among the other animals, two had chronic, progressive cavitary disease, a phenotype usually seen only with M. bovis infection. Genotypic investigation of the Erdman strain with an H37Rv-based microarray identified gene differences in the RD6 region. Southern blot and PCR structural genetic analysis showed significant differences between M. tuberculosis strains in this region. Correlation of the relative pathogenicity, including disease severity, in the rabbit model with the strain genotype may help identify stage-specific M. tuberculosis genes important in human disease.

Manabe, Yukari C.; Dannenberg, Arthur M.; Tyagi, Sandeep K.; Hatem, Christine L.; Yoder, Mark; Woolwine, Samuel C.; Zook, Bernard C.; Pitt, M. Louise M.; Bishai, William R.



Activation of ATP binding for the autophosphorylation of DosS, a Mycobacterium tuberculosis histidine kinase lacking an ATP lid motif.  


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 Arg(440) in the DHp domain and Glu(537) 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 Arg(440) and Glu(537) 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



Epidemiology, diagnosis and treatment of tuberculosis  

Microsoft Academic Search

Tuberculosis (TB) remains a major cause of morbidity and mortality and represents the most frequent cause of death by a single infectious agent worldwide1. While the incidence of TB is slowly decreasing in Europe due to active case finding and targeted therapies, the emergence of multi-drug-resistant and extensive-drug resistant strains of Mycobacterium tuberculosis (Mtb) are a great concern for the

Christoph Lange


[Tuberculosis among Trio-Indians in Surinam  

Microsoft Academic Search

OBJECTIVE: Evaluation of the extent and possible causes of the increased incidence of tuberculosis among Amazonian Indians in Surinam. DESIGN: Descriptive. METHOD: In two cross-sectional surveys in 1998 and 2000, the inhabitants of Kwamalasamutu, a village of Trio-Indians in Surinam, were examined for the presence of active and latent tuberculosis. Previous cases from the period 1995-2000 were evaluated retrospectively by

R. van Crevel; D. J. van Doorninck; J. E. van Ams; H. T. Fat; S. G. S. Vreden



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



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



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)



Heparin-binding hemagglutinin induces IFN-?(+) IL-2(+) IL-17(+) multifunctional CD4(+) T cells during latent but not active tuberculosis disease.  


The mycobacterial heparin-binding hemagglutinin (HBHA) protein induces a potent gamma interferon (IFN-?) response in latent tuberculosis (TB) infection and is a candidate vaccine and diagnostic antigen. We have assessed HBHA-specific intracellular IFN-?, interleukin-2 (IL-2), and IL-17 production by CD4(+) T cells in TB cases and household contacts (HHCs) as well as the level of secreted IFN-? in whole-blood culture supernatant. HHCs were further classified as tuberculin skin test (TST) positive or negative, and the group was also divided as HIV positive or negative. Our study revealed that HBHA induces multifunctional IFN-?-, IL-2-, and IL-17-coexpressing CD4(+) T cells in HHCs but not in active TB cases; however, IFN-? levels in culture supernatant did not differ between participant groups. Further studies are needed to completely understand how HBHA induces immune responses in different disease groups. PMID:22461525

Loxton, André G; Black, Gillian F; Stanley, Kim; Walzl, Gerhard



Heparin-Binding Hemagglutinin Induces IFN-?+ IL-2+ IL-17+ Multifunctional CD4+ T Cells during Latent but Not Active Tuberculosis Disease  

PubMed Central

The mycobacterial heparin-binding hemagglutinin (HBHA) protein induces a potent gamma interferon (IFN-?) response in latent tuberculosis (TB) infection and is a candidate vaccine and diagnostic antigen. We have assessed HBHA-specific intracellular IFN-?, interleukin-2 (IL-2), and IL-17 production by CD4+ T cells in TB cases and household contacts (HHCs) as well as the level of secreted IFN-? in whole-blood culture supernatant. HHCs were further classified as tuberculin skin test (TST) positive or negative, and the group was also divided as HIV positive or negative. Our study revealed that HBHA induces multifunctional IFN-?-, IL-2-, and IL-17-coexpressing CD4+ T cells in HHCs but not in active TB cases; however, IFN-? levels in culture supernatant did not differ between participant groups. Further studies are needed to completely understand how HBHA induces immune responses in different disease groups.

Black, Gillian F.; Stanley, Kim; Walzl, Gerhard



Time to Treatment and Patient Outcomes among TB Suspects Screened by a Single Point-of-Care Xpert MTB/RIF at a Primary Care Clinic in Johannesburg, South Africa  

PubMed Central

Introduction In December 2010, the World Health Organization recommended a single Xpert MTB/RIF assay as the initial diagnostic in people suspected of HIV-associated or drug resistant tuberculosis. Few data are available on the impact of this recommendation on patient outcomes. We describe the diagnostic follow-up, clinical characteristics and outcomes of a cohort of tuberculosis suspects screened using a single point-of-care Xpert. Methods Consecutive tuberculosis suspects at a primary care clinic in Johannesburg, South Africa were assessed for tuberculosis using point-of-care Xpert. Sputum smear microscopy and liquid culture were performed as reference standards. Xpert-negatives were evaluated clinically, and further assessed at the discretion of clinicians. Participants were followed for six months. Results From July-September 2011, 641 tuberculosis suspects were enrolled, of whom 69% were HIV-infected. Eight percent were positive by a single Xpert. Among 116 individuals diagnosed with TB, 66 (57%) were Xpert negative, of which 44 (67%) were empirical or radiological diagnoses and 22 (33%) were Xpert negative/culture-positive. The median time to tuberculosis treatment was 0 days (IQR: 0–0) for Xpert positives, 14 days (IQR: 5–35) for those diagnosed empirically, 14 days (IQR: 7–29) for radiological diagnoses, and 144 days (IQR: 28–180) for culture positives. Xpert negative tuberculosis cases were clinically similar to Xpert positives, including HIV status and CD4 count, and had similar treatment outcomes including mortality and time to antiretroviral treatment initiation. Conclusions In a high HIV-burden setting, a single Xpert identified less than half of those started on tuberculosis treatment, highlighting the complexity of TB diagnosis even in the Xpert era. Xpert at point-of-care resulted in same day treatment initiation in Xpert-positives, but had no impact on tuberculosis treatment outcomes or mortality.

Hanrahan, Colleen F.; Selibas, Katerina; Deery, Christopher B.; Dansey, Heather; Clouse, Kate; Bassett, Jean; Scott, Lesley; Stevens, Wendy; Sanne, Ian; Van Rie, Annelies



Antibody Profiles Characteristic of Mycobacterium tuberculosis Infection State  

PubMed Central

The relationship between specific antibody profiles and tuberculosis (TB) state was investigated by measuring serum antibody levels to six Mycobacterium tuberculosis antigens in human subjects grouped into four diagnostic categories: active disease, inactive (past) tuberculosis, latent infection without radiographic chest abnormalities, and infection free. Statistical data analyses showed that the latter two groups were serologically indistinguishable and that active tuberculosis and inactive tuberculosis were characterized by different antibody profiles. Antibodies to the 38-kDa antigen, alanine dehydrogenase, and Rv2626c were associated with active TB, while antibodies to the 16-kDa antigen, ferredoxin A, and ESAT-6 were associated with inactive TB. Thus, the targets of the immune response vary with tuberculosis state. The correlation between bacterial antigen production and infection stage was investigated in mice infected with M. tuberculosis by bacterial transcription profiling. It was found that levels of transcripts encoding the six M. tuberculosis antigens varied during infection. Together, the data indicate that antigen composition of tubercle bacilli varies with stage of infection and that immunoprofiling can distinguish between tuberculosis states.

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



Tuberculosis Facts - Testing for TB  


... 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 ...


Tuberculosis in the lung (image)  


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, ...


Tuberculosis Facts - Exposure to TB  


... 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 ...


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


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

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



Foot ulcer caused by multidrug-resistant Mycobacterium tuberculosis in a diabetic patient.  


Osteoarticular tuberculosis is the fourth leading type of extrapulmonary tuberculosis. The disease has a progressive course and the diagnosis is often made in the later stages of bone destruction. We describe a case of a foot ulcer caused by drug-resistant Mycobacterium tuberculosis in a patient with known diabetes where the diagnosis was not suspected initially. Although tuberculous foot ulcers are rare, they should be included in the differential diagnosis of unknown foot ulcers. A greater awareness of this rare clinical entity may help in commencing specific evidence-based therapy quickly and preventing undue morbidity and mortality. PMID:20576746

Baveja, C P; Gumma, Vidya Nidhi; Jain, Manisha; Jha, Himanshu



[Tuberculosis morbidity among military personnel in modern conditions].  


Among identified in the army for one year of active tuberculosis patients constitute 38.7% of the number of soldiers from young recruits, including 59.7% of infiltrative pulmonary tuberculosis. At the same time during the examination of these individuals revealed only about half of patients. Timely delivery of fluorographic examination recruitment plays a crucial role in preventing the spread of tuberculosis in the Armed Forces. From the military doctors need more work in groups at increased risk of tuberculosis, early identification of need in the dispensary dynamic observation and conducting a full range of therapeutic and preventive measures in foci of tuberculous infection. PMID:22686023

Beznosik, R V; Grishin, V K; Savitski?, G G; Grishin, A V



Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest.  


The tubercle bacillus parasitizes macrophages by inhibiting phagosome maturation into the phagolysosome. This phenomenon underlies the tuberculosis pandemic involving 2 billion people. We report here how Mycobacterium tuberculosis causes phagosome maturation arrest. A glycosylated M. tuberculosis phosphatidylinositol [mannose-capped lipoarabinomannan (ManLAM)] interfered with the phagosomal acquisition of the lysosomal cargo and syntaxin 6 from the trans-Golgi network. ManLAM specifically inhibited the pathway dependent on phosphatidylinositol 3-kinase activity and phosphatidylinositol 3-phosphate-binding effectors. These findings identify ManLAM as the M. tuberculosis product responsible for the inhibition of phagosomal maturation. PMID:12702770

Fratti, Rutilio A; Chua, Jennifer; Vergne, Isabelle; Deretic, Vojo



In vitro T-cell activation of monocyte-derived macrophages by soluble messengers or cell-to-cell contact in bovine tuberculosis  

PubMed Central

The macrophage plays a dual role in tuberculosis, promoting not only protection against mycobacteria, but also survival of the pathogen. Macrophages inhibit multiplication of mycobacteria but also act in concert with lymphocytes through presentation of antigens to T cells. Studies in animal and human infections have suggested a correlation of in vitro growth rates of mycobacteria with in vivo virulence, using uracil uptake to assess mycobacterial metabolism. This study found that blood-derived, non-activated bovine macrophages were capable of controlling Mycobacterium bovis bacillus Calmette–Guérin growth for up to 96 hr, but were permissive to intracellular growth of virulent M. bovis. The present investigation compared the in vitro modulation of these macrophage activities by cytokine-rich T-cell supernatants or cell-to-cell contact. On the one hand, treatment of cultured monocytes with mitogen-produced T-cell supernatants promoted morphological changes suggestive of an activation status, enhanced the antigen presentation capabilities of monocytes and up-regulated major histocompatibility complex class II expression. However, this activation was not associated with enhanced anti-M. bovis activity. On the other hand, incubation of infected monocytes with T-cell populations resulted in proportionally increased inhibition of M. bovis uracil uptake. This inhibition was also seen using cells from uninfected animals and indicated the necessity for cell-to-cell contact to promote antimycobacterial capability.

Liebana, E; Aranaz, A; Welsh, M; Neill, S D; Pollock, J M



DNA Vaccine Combinations Expressing Either Tissue Plasminogen Activator Signal Sequence Fusion Proteins or Ubiquitin-Conjugated Antigens Induce Sustained Protective Immunity in a Mouse Model of Pulmonary Tuberculosis  

Microsoft Academic Search

DNA vaccination has emerged as a powerful approach in the search for a more efficacious vaccine against tuberculosis. In this study, we evaluated the effectiveness of immunizing with combinations of 10 different tuberculosis DNA vaccines that expressed mycobacterial proteins fused at the N terminus to eukaryotic intracellular targeting sequences. In one vaccine combination, the genes were fused to the tissue

Giovanni Delogu; Amy Li; Charlene Repique; Frank Collins; Sheldon L. Morris



Characterization of CD4 and CD8 T cells producing IFN-? in human latent and active tuberculosis.  


Patients with pulmonary tuberculosis (PTB) frequently have reduced IFN-? production in response to mycobacterial antigens, compared to individuals with latent Mycobacterium tuberculosis infection (LTBi). However, it is not clear whether this reduced responsiveness is restricted to a particular T cell subset. Herein, PBMCs from 26 PTB patients, 30 household contacts (HHCs) of PTB, and 30 tuberculin positive (TST+) healthy subjects not recently exposed to PTB, were stained with CFSE and stimulated non-specific (PPD) for 120 h, and specific (CFP-10/ESAT-6) and latency (HSpX) mycobacterial antigens for 144 h and the percentage of CD4(+) and CD8(+)IFN-?(+) T cells responding determined by flow cytometry, in addition to their memory phenotype by the CD45RO and CD27 expression. PTB had decreased frequency of both CD4(+) and CD8(+) precursor cells, as well as decreased number of CD4(+)IFN-?(+) cells in response to all antigens, whereas CD8(+)IFN-?(+) cells were decreased in response to PPD and ESAT-6, but not to CFP-10 and HSpX. HHCs exhibited the highest precursor frequencies and IFN-? responses, irrespective of the antigen employed. The CD4(+)/CD8(+) cell ratios showed that in response to PPD CD4(+) precursor and IFN-?-producer cells are more frequent than their CD8(+) counterparts, and that PTB have a decreased CD4(+)IFN-?(+)/CD8(+)IFN-?(+) ratio in response to PPD, CFP-10, and ESAT-6. CD4(+)IFN-?(+) and CD8(+)IFN-?(+) cells exhibited a central memory phenotype (CD45RO(+)CD27(+)), irrespective of the group of subjects and the antigen used for stimulation. In conclusion, PTB patients had a decreased percentage of CD4(+) and CD8(+) precursor cells and CD4(+)IFN-?(+). HHCs exhibited the highest frequency of CD4(+) and CD8(+) precursors and CD4(+)IFN-?(+)-producing cells. PMID:20933471

Rueda, Cesar M; Marín, Nancy D; García, Luis F; Rojas, Mauricio



Drug Susceptibility of Mycobacterium tuberculosis Beijing Genotype and Association with MDR TB  

PubMed Central

To determine differences in the ability of Mycobacterium tuberculosis strains to withstand antituberculosis drug treatment, we compared the activity of antituberculosis drugs against susceptible Beijing and East-African/Indian genotype M. tuberculosis strains. Beijing genotype strains showed high rates of mutation within a wide range of drug concentrations, possibly explaining this genotype’s association with multidrug-resistant tuberculosis.

ten Kate, Marian T.; de Knegt, Gerjo J.; Kremer, Kristin; Aarnoutse, Rob E.; Boeree, Martin J.; Verbrugh, Henri A.; van Soolingen, Dick; Bakker-Woudenberg, Irma A.J.M.



Detection of immune cell response to M. tuberculosis–specific antigens by quantitative polymerase chain reaction  

Microsoft Academic Search

One third of the world's population is latently infected with Mycobacterium tuberculosis (Mtb) and up to 10% of infected individuals develop active tuberculosis (TB) in their lifetime. Among the major challenges in the control of TB is the implementation of sensitive methods for detection of latent tuberculosis infection (LTBI). Currently, in vitro interferon gamma release assays, yielding single value readout,

Ilona Bibova; Irena Linhartova; Ondrej Stanek; Vendula Rusnakova; Mikael Kubista; Miloslav Suchanek; Martina Vasakova; Peter Sebo


Childhood tuberculosis and malnutrition.  


Despite the burden of both malnutrition and tuberculosis in children worldwide, there are few studies on the mechanisms that underlie this relationship. From available research, it appears that malnutrition is a predictor of tuberculosis disease and is associated with worse outcomes. This is supported through several lines of evidence, including the role of vitamin D receptor genotypes, malnutrition's effects on immune development, respiratory infections among malnourished children, and limited work specifically on pediatric tuberculosis and malnutrition. Nutritional supplementation has yet to suggest significant benefits on the course of tuberculosis in children. There is a critical need for research on childhood tuberculosis, specifically on how nutritional status affects the risk and progression of tuberculosis and whether nutritional supplementation improves clinical outcomes or prevents disease. PMID:23033147

Jaganath, Devan; Mupere, Ezekiel



Identification of T-Cell Antigens Specific for Latent Mycobacterium Tuberculosis Infection  

Microsoft Academic Search

BackgroundT-cell responses against dormancy-, resuscitation-, and reactivation-associated antigens of Mycobacterium tuberculosis are candidate biomarkers of latent infection in humans.Methodology\\/Principal FindingsWe established an assay based on two rounds of in vitro restimulation and intracellular cytokine analysis that detects T-cell responses to antigens expressed during latent M. tuberculosis infection. Comparison between active pulmonary tuberculosis (TB) patients and healthy latently M. tuberculosis-infected donors

Sebastian D. Schuck; Henrik Mueller; Frank Kunitz; Albert Neher; Harald Hoffmann; Kees L. C. M. Franken; Dirk Repsilber; Tom H. M. Ottenhoff; Stefan H. E. Kaufmann; Marc Jacobsen; Derya Unutmaz



[Tuberculosis: yesterday, today, tomorrow].  


The historical aspects of phisiology are briefly outlined. The main factors that promote the prevalence of tuberculosis are characterized. The present-day tuberculosis epidemiological situation makes one to correct antituberculous measures and with the use of new investigations and developments to improve the identification of patients with tuberculosis, primarily those with contagious types of the disease, to introduce the currently available short-term regimens of 2-stage drug therapy, to design novel agents and depot formulations of the well known ones. Further investigations are required to search for a new tuberculosis vaccine. PMID:9503920

Khomenko, A G



Treatment of childhood tuberculosis.  


The aim of tuberculosis treatment is to cure the individual patient with antituberculosis drugs (ATT) in a short time without emergence of drug resistance. The anti tuberculosis drugs are selected in a combination to attack all the subpopulations of tubercle bacilli with first line drugs which include isoniazid, rifampicin, pyrazinamide, and ethambutol. Intermittent ATT regimens have been documented to be as effective as daily regimen. World Health Organization (WHO) has suggested a category based treatment of tuberculosis given in two phases, intensive phase and continuation phase. As per WHO, Revised National Tuberculosis Control Programme (RNTCP) recommends directly observed therapy short course strategy (DOTS) for the treatment of both adult and pediatric tuberculosis. In DOTS the patient is asked to swallow ATT under the direct observation of health personnel. Drug dosage for daily and intermittent therapy varies. To simplify the prescription, fixed drug combination (FDC) and patient-wise boxes (PWB) are available under RNTCP, free of cost. Each patient's management plan should be individualized to incorporate measures that facilitate adherence. The knowledge of drug resistant tuberculosis, HIV-related tuberculosis, and latent tuberculosis infection are the areas that need to be updated. Private practioners may play a significant role by referring the children with tuberculosis to the DOTS centers early which will not only benefit the affected family but also the society. PMID:21049292

Vijayasekaran, D



Multiplex PCR for Rapid Diagnosis of Gastrointestinal Tuberculosis  

PubMed Central

Background: Rapid and specific diagnosis of gastrointestinal tuberculosis (GITB) is of utmost importance. Aim: To evaluate Multiplex PCR (MPCR) using MPB64 and IS6110 primers specific for M. tuberculosis for rapid diagnosis of GITB. Materials and Methods: MPCR was performed on colonoscopy biopsy specimens on 11 GITB confirmed (culture/AFB/histopathology was positive), 29 GITB suspected and 30 Non GITB (control group) patients. Results: MPB64 PCR had sensitivity and specificity of 90% and 100% for confirmed GITB cases. In 29 clinically diagnosed but unconfirmed GITB cases, MPCR was positive in 72.41%. MPCR was negative in all control group patients. The overall sensitivity and specificity of microscopy, culture, histopathology and MPCR was 5%, 2% 20% and 77.5% and 100%, 100%, 100% and 100% respectively. Conclusion: MPCR has good sensitivity and specificity in diagnosing gastrointestinal tuberculosis.

Sharma, Kusum; Sinha, Saroj Kant; Sharma, Aman; Nada, Ritambra; Prasad, Kaushal K; Goyal, Kapil; Rana, Surinder Singh; Bhasin, Deepak Kumar; Sharma, Meera



CXCL10\\/IP10 release is induced by incubation of whole blood from tuberculosis patients with ESAT-6, CFP10 and TB7.7  

Microsoft Academic Search

IFN-? responses to Mycobacterium tuberculosis specific antigens are used as in vitro diagnostic tests for tuberculosis infection. The tests are sensitive and specific for latent and active tuberculosis disease, but sensitivity may be reduced during immunosuppression. The objective of the study was to explore new ways to improve the diagnosis of tuberculosis infection using CXCL10 and IL-2 as alternative markers

Morten Ruhwald; Morten Bjerregaard-Andersen; Paulo Rabna; Kristian Kofoed; Jesper Eugen-Olsen; Pernille Ravn



Porins Increase Copper Susceptibility of Mycobacterium tuberculosis.  


Copper resistance mechanisms are crucial for many pathogenic bacteria, including Mycobacterium tuberculosis, during infection because the innate immune system utilizes copper ions to kill bacterial intruders. Despite several studies detailing responses of mycobacteria to copper, the pathways by which copper ions cross the mycobacterial cell envelope are unknown. Deletion of porin genes in Mycobacterium smegmatis leads to a severe growth defect on trace copper medium but simultaneously increases tolerance for copper at elevated concentrations, indicating that porins mediate copper uptake across the outer membrane. Heterologous expression of the mycobacterial porin gene mspA reduced growth of M. tuberculosis in the presence of 2.5 ?M copper by 40% and completely suppressed growth at 15 ?M copper, while wild-type M. tuberculosis reached its normal cell density at that copper concentration. Moreover, the polyamine spermine, a known inhibitor of porin activity in Gram-negative bacteria, enhanced tolerance of M. tuberculosis for copper, suggesting that copper ions utilize endogenous outer membrane channel proteins of M. tuberculosis to gain access to interior cellular compartments. In summary, these findings highlight the outer membrane as the first barrier against copper ions and the role of porins in mediating copper uptake in M. smegmatis and M. tuberculosis. PMID:24013632

Speer, Alexander; Rowland, Jennifer L; Haeili, Mehri; Niederweis, Michael; Wolschendorf, Frank



Diagnostic performance of multiplex cytokine and chemokine assay for tuberculosis.  


Simultaneous detection of multiple biomarkers might lead to improved diagnostic performance for Mycobacterium tuberculosis infection. In this study, we screened soluble biomarkers that had significant differences in patients with active tuberculosis and healthy controls and evaluated the diagnostic performance of the multiplex cytokine/chemokine assay. Overall, 178 patients with active pulmonary tuberculosis, 156 healthy individuals and 35 patients with bacterial pneumonia or lung cancer were evaluated. Among the 16 soluble biomarkers screened by the microbead-based multiplex assay, five cytokines/chemokines including IFN-?, IP-10, MIG, TNF-? and IL-2 that showed most significant differences between active pulmonary tuberculosis patients and healthy controls were selected for further analysis. When analyzed individually, both IP-10 and MIG had sensitivity and specificity comparable to IFN-? in detection of active TB. Combined detection of IFN-?, IP-10 and MIG had significantly improved sensitivity and specificity as compared with individual cytokine and chemokine detection. The responsive levels of IFN-?, IP-10, MIG, TNF-? and IL-2 were significantly lower in re-treatment pulmonary tuberculosis patients than in new tuberculosis patients. It is concluded that combined IFN-?, IP-10, MIG multiplex detection had better diagnostic performance for tuberculosis than the individual cytokine/chemokine assays. The re-treatment pulmonary tuberculosis patients had poor responses to ESAT-6/CFP-10 peptides stimulation. PMID:22824465

Wang, Xinjing; Jiang, Jing; Cao, Zhihong; Yang, Bingfen; Zhang, Jinhua; Cheng, Xiaoxing



Prospects for elimination of childhood tuberculosis: the role of new vaccines.  


Control of childhood tuberculosis must be considered in the context of active tuberculosis disease among adults, who form the main reservoir of transmission. The elimination target of the Stop TB Partnership is a reduction of global incidence to less than one case per million per year by 2050. There is an urgent need for a new, safe and effective tuberculosis vaccine that prevents all forms of tuberculosis, in all age groups and in HIV-infected people. Bacillus Calmette-Guérin (BCG) vaccination protects against disseminated forms of childhood tuberculosis, but protection is variable against pulmonary tuberculosis and adult disease. 14 new tuberculosis vaccines have entered human clinical trials, including viral-vectored vaccines, recombinant fusion proteins, recombinant BCG vaccines and inactivated whole or fragmented mycobacteria. Effective pre-exposure and postexposure vaccination, in conjunction with mass campaigns, is the most promising tuberculosis control strategy to approach the elimination target by the middle of the 21st century. PMID:21450742

Hatherill, Mark



Childhood bronchial tuberculosis: report of one case and literature review  

PubMed Central

Objective To explore the early diagnosis of childhood bronchial tuberculosis (BTB). Methods The clinical data of a 9-year-old boy with long-term chronic cough were retrospectively analyzed, and the relevant literature was reviewed. Results The pediatric patient was suspected to be with bronchial asthma due to long-term chronic cough, and was confirmed to be with “nasopharyngeal tuberculosis” during surgery. Purified protein derivative (PPD) (5 IU) showed moderately positive results. Chest X-ray showed the atelectasis of left lower lobe, which was suspected to be caused by bronchial tuberculosis. Chest CT and three-dimensional airway reconstruction showed atelectasis of left lower lobe, increased air volume of the left upper lung, left deviation of the mediastinum, bronchiolitis obliterans in the left lower lobe, and narrowing of the left upper lobe bronchus, suggesting the presence of bronchial tuberculosis. The bronchoscopy showed necrosis of the left main bronchus and mucosal congestion and edema, and then bronchial tuberculosis was confirmed. In addition to the systemic anti-TB treatment, transluminal interventions including local drug injection and balloon angioplasty under bronchoscope were applied routinely and achieved good effectiveness. Conclusions Patients with long-term chronic cough should be cautiously managed in clinical settings. Examinations including PPD test, chest CT, three-dimensional airway reconstruction, and bronchoscopy should be performed as early as possible to confirm the potential existence of bronchial tuberculosis. Meanwhile, appropriate interventional treatment under bronchoscopy should be promptly applied to provide optimal protection of bronchi and lung, restore the damaged lung function, and minimize the complications.

Hu, Chun-Mei; Yin, Chun-Yang; Gu, Xiao-Yan



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.




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



Mycobacterium tuberculosis RsdA provides a conformational rationale for selective regulation of ?-factor activity by proteolysis  

PubMed Central

The relative levels of different ? factors dictate the expression profile of a bacterium. Extracytoplasmic function ? factors synchronize the transcriptional profile with environmental conditions. The cellular concentration of free extracytoplasmic function ? factors is regulated by the localization of this protein in a ?/anti-? complex. Anti-? factors are multi-domain proteins with a receptor to sense environmental stimuli and a conserved anti-? domain (ASD) that binds a ? factor. Here we describe the structure of Mycobacterium tuberculosis anti-?D (RsdA) in complex with the -35 promoter binding domain of ?D (?D4). We note distinct conformational features that enable the release of ?D by the selective proteolysis of the ASD in RsdA. The structural and biochemical features of the ?D/RsdA complex provide a basis to reconcile diverse regulatory mechanisms that govern ?/anti-? interactions despite high overall structural similarity. Multiple regulatory mechanisms embedded in an ASD scaffold thus provide an elegant route to rapidly re-engineer the expression profile of a bacterium in response to an environmental stimulus.

Jaiswal, Ravi K.; Prabha, Tangirala Surya; Manjeera, Gowravaram; Gopal, Balasubramanian



"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



Tuberculosis of the knee  

PubMed Central

Extrapulmonary manifestations of tuberculosis are reported in less than one in five cases with the knee affected in 8% after the spine and hip. We report a case of isolated highly erosive tuberculosis of the knee presenting in a previously fit Vietnamese woman. The difficulties of diagnosis, modalities of chemotherapeutic management, and surgical treatment are discussed.

Lidder, Surjit; Lang, Kathryn; Haroon, Mallick; Shahidi, Mitra; El-Guindi, Magdi



Improving vaccines against tuberculosis  

Microsoft Academic Search

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

Warwick J Britton; Umaimainthan Palendira



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.




Cost implications of delays to tuberculosis diagnosis among pulmonary tuberculosis patients in Ethiopia  

PubMed Central

Background Delays seeking care worsen the burden of tuberculosis and cost of care for patients, families and the public health system. This study investigates costs of tuberculosis diagnosis incurred by patients, escorts and the public health system in 10 districts of Ethiopia. Methods New pulmonary tuberculosis patients ? 15 years old were interviewed regarding their health care seeking behaviour at the time of diagnosis. Using a structured questionnaire patients were interviewed about the duration of delay at alternative care providers and the public health system prior to diagnosis. Costs incurred by patients, escorts and the public health system were quantified through patient interview and review of medical records. Results Interviews were held with 537 (58%) smear positive patients and 387 (42%) smear negative pulmonary patients. Of these, 413 (45%) were female; 451 (49%) were rural residents; and the median age was 34 years. The mean (median) days elapsed for consultation at alternative care providers and public health facilities prior to tuberculosis diagnosis was 5 days (0 days) and 3 (3 days) respectively. The total median cost incurred from first consultation to diagnosis was $27 per patient (mean = $59). The median costs per patient incurred by patient, escort and the public health system were $16 (mean = $29), $3 (mean = $23) and $3 (mean = $7) respectively. The total cost per patient diagnosed was higher for women, rural residents; those who received government food for work support, patients with smear negative pulmonary tuberculosis and patients who were not screened for TB in at least one district diagnostic centers. Conclusions The costs of tuberculosis diagnosis incurred by patients and escorts represent a significant portion of their monthly income. The costs arising from time lost in seeking care comprised a major portion of the total cost of diagnosis, and may worsen the economic position of patients and their families. Getting treatment from alternative sources and low index of suspicion public health providers were key problems contributing to increased cost of tuberculosis diagnosis. Thus, the institution of effective systems of referral, ensuring screening of suspects across the district public health system and the involvement of alternative care providers in district tuberculosis control can reduce delays and the financial burden to patients and escorts.



Advances in the diagnosis of latent tuberculosis infection.  


Accurate diagnosis of tuberculosis (TB) infection is an important component of tuberculosis control programs in many countries. Identification of persons with asymptomatic, or latent, tuberculosis infection allows for treatment of individuals at high risk for progressing to active disease so that the overall burden of tuberculosis disease is diminished. In the United States, targeted testing and treatment of latent tuberculosis infection (LTI) are major components of the Centers for Disease Control and Prevention's efforts at TB elimination. This review focuses on the comparative utility of tuberculin skin testing and interferon-gamma release assays (IGRAs) to diagnose LTI. Commercially available IGRAs have superior sensitivity and specificity compared with conventional tuberculin skin testingin some settings (particularly bacille-Calmette Guérin-vaccinated individuals). Also discussed are the performance characteristics of these tests in specific populations, including foreign-born persons from high-prevalence countries, close contacts of actively infected patients, immunocompromised populations, and health care workers. PMID:23460006

Schluger, Neil W



Peritoneal tuberculosis: diagnostic options.  

PubMed Central

BACKGROUND: Extrapulmonary tuberculosis has vague symptoms and few signs. It is essential to recognize and diagnose this curable disease prior to performing definitive surgery. Newer tests such as DNA or RNA amplification allow for early diagnosis but have limitations. CASE: We report a case of peritoneal tuberculosis in an immigrant woman. She had vague symptoms of low-grade fever, mild abdominal pain, obstipation, and bloating. Diagnostic laparoscopy was performed to establish the diagnosis. Tuberculosis was confirmed by DNA extraction from the frozen section specimen with subsequent analysis using polymerase chain reaction. CONCLUSION: Peritoneal tuberculosis is a disease that often simulates malignancies. With the increasing prevalence of human immunodeficiency virus in developed countries, tuberculosis is also on the rise and should be considered in the differential diagnosis of a patient with an abdominal/pelvic mass and ascites.

Lal, N; Soto-Wright, V



New issues in tuberculosis  

PubMed Central

Tuberculosis remains a major health problem worldwide. The disease is caused by Mycobacteriumtuberculosis whose preferred habitat is the host macrophage. The immune response against tuberculosis is mediated by different subsets of T cells including both conventional CD4 and CD8 T cells as well as unconventional CD1 restricted and ?? T cells. The CD1 restricted T cells are particularly remarkable because they recognise the glycolipids abundant in the mycobacterial cell wall. Although a vaccine, M.bovis BCG, is available which protects toddlers against miliary tuberculosis, it is ineffective in preventing pulmonary tuberculosis in adults. Therefore, a novel vaccine is urgently required. Knowledge about the functioning of different T cell populations during infection and disease provides the basis for rational vaccine design. We have constructed a recombinant BCG vaccine which, compared with wild-type BCG, induces superior protection not only against laboratory strains but also against clinical isolates of M. tuberculosis.

Kaufmann, S



Active site structure of the catalase-peroxidases from Mycobacterium tuberculosis and Escherichia coli by extended X-ray absorption fine structure analysis.  


The catalase-peroxidase encoded by katG of Mycobacterium tuberculosis is a more effective activator of the antibiotic isoniazid than is the equivalent enzyme from Escherichia coli. The environment of the heme iron was investigated using X-ray absorption spectroscopy to determine if differences in this region were associated with the differences in reactivity. The variation in the distal side Fe-ligand distances between the two enzymes was the same within experimental error indicating that it was not the heme iron environment that produced the differences in reactivity. Analysis of variants of the E. col