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Sample records for suspected active tuberculosis

  1. The Incidence of Non-tuberculous Mycobacterium Lung Disease in Patients with Suspected Pulmonary Tuberculosis.

    PubMed

    Kim, Myeong Hee; Kim, Yee Hyung; Kang, So Young; Lee, Woo In

    2015-12-01

    Non-tuberculous mycobacterium (NTM) lung disease is increasing in prevalence. We analyzed the frequency of NTM lung disease among patients who are suspected of tuberculosis. NTM was isolated from about one-fourth of the mycobacterium culture-positive patients and about half of these had NTM lung disease. Therefore, NTM isolates should be routinely identified at the species level for adequate treatment. PMID:26543274

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

    PubMed Central

    2014-01-01

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

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed Central

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

    2013-01-01

    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. PMID:23485382

  5. [Investigation of the presence of Mycobacterium tuberculosis in the lymph node aspirates of the suspected tularemia lymphadenitis cases].

    PubMed

    Albayrak, Nurhan; Celebi, Bekir; Kavas, Semra; Sim?ek, Hülya; K?l?ç, Selçuk; Sezen, Figen; Arslantürk, Ahmet

    2014-01-01

    Recently reports of cervical tuberculous lymphadenitis and oropharyngeal tularemia which are the most common infectious causes of granulomatous lymphadenitis, have been significantly increased in Turkey. The differentiation of cervical tuberculous lymphadenitis and oropharyngeal tularemia is usually confusing on the basis of clinical and histopathological findings. Thus, in tularemia endemic areas, the patients are more commonly evaluated in terms of tularemia lymphadenitis leaving tuberculosis out. The aim of this study was to investigate the presence of Mycobacterium tuberculosis in cervical lymph node aspirates, obtained from tularemia suspected cases. A total of 105 oropharyngeal tularemia-suspected cases which were found negative for Francisella tularensis by bacteriological (culture), molecular (PCR) and serological (microagglutination) methods, were included in the study. The samples had been previously studied at National Tularemia Reference Laboratory, Turkish Public Health Institution, between 2009-2011. The study samples were evaluated in terms of M.tuberculosis by culture and real-time PCR (rtPCR) methods in the National Tuberculosis Reference Laboratory. Both Lowenstein-Jensen (LJ) medium and liquid-based MGIT (BD, USA) automated culture system were used for mycobacterial culture. Samples that yielded mycobacterial growth were identified as M.tuberculosis by immunochromotographic test (BD, USA). The lymph node aspirates of 65 patients who were F.tularensis PCR negative but antibody positive, were used as the control group. As a result, M.tuberculosis was found to be positive in 9 (8.6%) of 105 tularemia-negative lymph node aspirates, sent to our laboratory from different geographic regions for the investigation of tularemia. Six of the M.tuberculosis positive cases were male and the age range of the patients was 26-85 years. The presence of M.tuberculosis was detected only by culture in two samples, only by rtPCR in five samples and both by culture and rtPCR in two samples. M.tuberculosis was not identified in the control group specimens. Three of the samples which revealed tuberculosis, were from the tularemia endemic areas. In conclusion, the data of this preliminary study indicated that tuberculous lymphadenitis should be kept in mind in suspected tularemia cases and those patients should also be investigated simultaneously for the presence of tuberculous lymphadenitis. PMID:24506723

  6. Characterization of mycobacterium isolates from pulmomary tuberculosis suspected cases visiting Tuberculosis Reference Laboratory at Ethiopian Health and Nutrition Research Institute, Addis Ababa Ethiopia: a cross sectional study

    PubMed Central

    Mathewos, Biniam; Kebede, Nigatu; Kassa, Tesfu; Mihret, Adane; Getahun, Muluwork

    2015-01-01

    Objective To characterize mycobacterium isolates from pulmomary tuberculosis suspected cases visiting National Tuberculosis Reference Laboratory at Ethiopian Health and Nutrition Research Institute, for diagnosis of pulmonary tuberculosis from January 4 to February 22, 2010 with total samples of 263. Methods Sputum specimens were collected and processed; the deposits were cultured. For culturing Lowenstein Jensen medium (LJ) and Mycobacteria Growth Indicator Tube (BACTEC MGIT 960) were used. Capilia Neo was used for detecting NTM isolates from isolates of BACTEC MGIT 960. In Armauer Hansen Research Institute, Addis Ababa Ethiopia, Deletion typing PCR method for species identification (from confirmed Mycobacterium tuberculosis complex (MTBC) isolates by Capilia Neo) was done. Results Out of 263 enrolled in the study, 124 and 117 of them were positive for mycobacterium growth by BACTEC MGIT 960 and LJ culture method, respectively. From BACTEC MGIT 960 positive media of 124 isolates, 117 were randomly taken to perform Capilia TB Neo test. From these 7 (6%) of them were found to be NTM and 110 (94%) were MTBC. From these 110 MTBC isolates, 81 of them were randomly taken and run by the deletion typing RD9 PCR method of molecular technique. Out of these 78 (96.3%) were found to be species of Mycobacterium tuberculosis and 3 (3.7%) were found to be not in the MTBC. Regarding the types of methods of culture media, Mycobacteria Growth Indicator Tube (BACTEC MGIT 960) method was found to have excellent agreement (with kappa value of 0.78) with the routine method of LJ. Conclusions Pulmonary tuberculosis suspected cases visiting the National Tuberculosis Reference Laboratory at EHNRI that were confirmed to be pulmonary tuberculosis are caused by the species of Mycobacterium tuberculosis, hence treatment regimen including pyrazinamide can be applied to the patients as the first choice in the study area in Addis Ababa, Ethiopia. There is indication of the presence of NTM in patients visiting the tuberculosis reference laboratory and this is important because NTM is known to cause pulmonary disease similar with sign and symptom of pulmonary tuberculosis but different in treatment. BACTEC MGIT 960 has excellent agreement with LJ media but it has high tendency of having high contamination rate unless a better decontamination method is designed. PMID:25901922

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

    PubMed Central

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

    2013-01-01

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

  8. Plasma Calcium in Active Pulmonary Tuberculosis

    PubMed Central

    Bandele, E. O.; Afonja, O. A.

    1987-01-01

    Fifty-two patients with active pulmonary tuberculosis were studied. Seventy percent of the patients were hypocalcemic at admission, but became normocalcemic after ten weeks of therapy. The improvement in hypocalcemia was thought to be due to either improved serum protein and albumin levels, which occurred after admission, or the reduced physical activity of the patients. Care should be taken in giving patients with pulmonary tuberculosis vitamin D supplements because of the possibility of hypersensitivity to vitamin D. The possible mechanisms of hypercalcemia in active pulmonary tuberculosis are discussed. PMID:3669092

  9. Tuberculosis

    MedlinePLUS

    ... 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 ...

  10. [Cryptococcus neoformans meningitis in a HIV negative miliary tuberculosis-suspected patient].

    PubMed

    Aydemir, Hande; Pi?kin, Nihal; Oztoprak, Nefise; Celebi, Güven; Tekin, Ishak Ozel; Akduman, Deniz

    2008-07-01

    Cryptococcosis caused by Cryptococcus neoformans has a wide range of clinical presentations, varying from asymptomatic colonization of the respiratory airways to the dissemination of infection into different parts of body. It is more common among immunosupressed patients such as human immunodeficiency virus (HIV) positive ones. In this report we present a case with C. neoformans meningitis and miliary pulmonary infiltrates suggesting pulmonary tuberculosis without HIV infection. A-70-years-old male was admitted to the hospital with mental confusion, 3-weeks history of headache, weight loss, dry cough and fatigue. Physical examination was normal except neck stiffness. Cerebrospinal fluid (CSF) white cell count was 120/mm3 (80% polimorphonuclear cells). Gram staining of CSF revealed poorly stained gram-positive yeast cells. Empirical therapy with lipozomal amphotericin B, ceftriaxone and ampicillin combination was started. When C. neoformans growth was detected on CSF culture, ceftriaxone and ampicillin were discontinued. Patient became conscious at 24th hour of the treatment. Peripheric blood flow-cytometric analysis revealed a significant decrease in absolute CD4+ T lymphocytes, and in CD8+28+ T lymphocytes in addition a significant increase in natural killer cell ratio. Blood immunoglobulin and complement levels were found normal. Cranial magnetic resonance imaging and computerized tomogralphy (CT) of the abdomen were normal, however, chest CT revealed multiple parenchymal millimetric nodular infiltrations on both sides and minimal fibrotic alterations. Acid-fast staining of CSF, tuberculosis culture, tuberculosis PCR results and repeated HIV serology were found negative. Despite the lack of microbiological confirmation, empirical antituberculosis treatment was also started with the suspicion of miliary tuberculosis as the patient had a symptom of long-term dry cough, miliary infiltrations on chest CT, anergic tuberculin skin test and a history of pulmonary tuberculosis in childhood. After two weeks, amphotericin B was changed to oral fluconazole which was continued for an additional eight weeks. Antituberculosis therapy was given for nine months. Control chest CT taken after four months of antituberculosis therapy revealed improvement of the lesions. This presentation emphasizes the fact that cryptococcal infections may develop in HIV negative patients, even together with tuberculosis in certain cases and radiological findings of the two infections may be confusing when both of them invade the lungs. PMID:18822899

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

    PubMed Central

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

    2015-01-01

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

  12. T-Cell Immunophenotyping Distinguishes Active From Latent Tuberculosis

    PubMed Central

    Pollock, Katrina M.; Whitworth, Hilary S.; Montamat-Sicotte, Damien J.; Grass, Lisa; Cooke, Graham S.; Kapembwa, Moses S.; Kon, Onn M.; Sampson, Robert D.; Taylor, Graham P.; Lalvani, Ajit

    2013-01-01

    Background.?Changes in the phenotype and function of Mycobacterium tuberculosis (M. tuberculosis)-specific CD4+ and CD8+ T-cell subsets in response to stage of infection may allow discrimination between active tuberculosis and latent tuberculosis infection. Methods.?A prospective comparison of M. tuberculosis-specific cellular immunity in subjects with active tuberculosis and latent tuberculosis infection, with and without human immunodeficiency virus (HIV) coinfection. Polychromatic flow cytometry was used to measure CD4+ and CD8+ T-cell subset phenotype and secretion of interferon ? (IFN-?), interleukin 2 (IL-2), and tumor necrosis factor ? (TNF-?). Results.?Frequencies of CD4+ and CD8+ cells secreting IFN-?-only, TNF-?-only and dual IFN-?/TNF-? were greater in active tuberculosis vs latent tuberculosis infection. All M. tuberculosis-specific CD4+ subsets, with the exception of IL-2-only cells, switched from central to effector memory phenotype in active tuberculosis vs latent tuberculosis infection, accompanied by a reduction in IL-7 receptor ? (CD127) expression. The frequency of PPD-specific CD4+ TNF-?-only-secreting T cells with an effector phenotype accurately distinguished active tuberculosis from latent tuberculosis infection with an area under the curve of 0.99, substantially more discriminatory than measurement of function alone. Conclusions.?Combined measurement of T-cell phenotype and function defines a highly discriminatory biomarker of tuberculosis disease activity. Unlocking the diagnostic and monitoring potential of this combined approach now requires validation in large-scale prospective studies. PMID:23966657

  13. Discriminating between latent and active tuberculosis with multiple biomarker responses

    PubMed Central

    Frahm, Marc; Goswami, Neela D.; Owzar, Kouros; Hecker, Emily; Mosher, Ann; Cadogan, Emily; Nahid, Payam; Ferrari, Guido; Stout, Jason E.

    2011-01-01

    Summary We sought to identify biomarker responses to tuberculosis specific antigens which could 1) improve the diagnosis of tuberculosis infection and 2) allow the differentiation of active and latent infections. Seventy subjects with active tuberculosis (N=12), latent tuberculosis (N=32), or no evidence of tuberculosis infection (N=26) were evaluated. We used the Luminex Multiplexed Bead Array platform to simultaneously evaluate 25 biomarkers in the supernatant of whole blood samples following overnight stimulation using the Quantiferon® Gold In-Tube kit. We defined the response to stimulation as the difference (within an individual patient) between the response to the pooled tuberculosis antigens and the negative control. IP-10 response was significantly higher in tuberculosis-infected (active or latent) subjects compared to the uninfected group (p <0.0001). Among the 25 parameters, expression levels of IL-15 and MCP-1 were found to be significantly higher in the active tuberculosis group compared to the latent tuberculosis group (p = 0.0006 and 0.0030, respectively). When combined, IL-15 and MCP-1 accurately identified 83% of active and 88% of latent infections. The combination of IL-15 and MCP-1 responses was accurate in distinguishing persons with active tuberculosis from persons with latent tuberculosis in this study. PMID:21393062

  14. Arginine Adjunctive Therapy in Active Tuberculosis

    PubMed Central

    Shafaat, Omid; Sofian, Masoomeh; Kahbazi, Manijeh

    2015-01-01

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

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

    Code of Federal Regulations, 2014 CFR

    2014-07-01

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

  16. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

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

  17. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

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

  18. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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

  19. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

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

  20. Evaluation of the efficiency of nested q-PCR in the detection of Mycobacterium tuberculosis complex directly from tuberculosis-suspected lesions in post-mortem macroscopic inspections of bovine carcasses slaughtered in the state of Mato Grosso, Brazil.

    PubMed

    Carvalho, Ricardo César Tavares; Furlanetto, Leone Vinícius; Maruyama, Fernanda Harumy; Araújo, Cristina Pires de; Barros, Sílvia Letícia Bomfim; Ramos, Carlos Alberto do Nascimento; Dutra, Valéria; Araújo, Flábio Ribeiro de; Paschoalin, Vânia Margaret Flosi; Nakazato, Luciano; Figueiredo, Eduardo Eustáquio de Souza

    2015-08-01

    Bovine tuberculosis (BTB) is a zoonotic disease caused by Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex (MTC). The quick and specific detection of this species is of extreme importance, since BTB may cause economic impacts, in addition to presenting imminent risks to human health. In the present study a nested real-time PCR test (nested q-PCR) was used in post-mortem evaluations to assess cattle carcasses with BTB-suspected lesions. A total of 41,193 cattle slaughtered in slaughterhouses located in the state of Mato Grosso, were examined. Of the examined animals, 198 (0.48%) showed BTB-suspected lesions. M. bovis was isolated in 1.5% (3/198) of the samples. Multiplex-PCR detected MTC in 7% (14/198) of the samples. The nested q-PCR test detected MTC in 28% (56/198) of the BTB-suspected lesions, demonstrating higher efficiency when compared to the multiplex-PCR and conventional microbiology. Nested q-PCR can therefore be used as a complementary test in the national program for control and eradication of bovine tuberculosis. PMID:25863190

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

  2. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

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

  3. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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

  4. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

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

  5. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

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

  6. Gene Regulatory Networks Activated during Chronic Tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic tuberculosis represents a burden for most of world’s population. Several genes were found to be up-regulated at the late stage of chronic tuberculosis when DNA microarray protocol was used to analyze murine tuberculosis. Rv0348 is a potential transcriptional regulator that is highly expresse...

  7. Evaluation of Xpert® MTB/RIF Assay in Induced Sputum and Gastric Lavage Samples from Young Children with Suspected Tuberculosis from the MVA85A TB Vaccine Trial

    PubMed Central

    Geldenhuys, Hennie; Schmidt, Bey-Marrie; Luabeya, Angelique Kany Kany; Mulenga, Humphrey; Scriba, Thomas J.; Hanekom, Willem A.; Mahomed, Hassan; McShane, Helen; Hatherill, Mark

    2015-01-01

    Objective Diagnosis of childhood tuberculosis is limited by the paucibacillary respiratory samples obtained from young children with pulmonary disease. We aimed to compare accuracy of the Xpert® MTB/RIF assay, an automated nucleic acid amplification test, between induced sputum and gastric lavage samples from young children in a tuberculosis endemic setting. Methods We analyzed standardized diagnostic data from HIV negative children younger than four years of age who were investigated for tuberculosis disease near Cape Town, South Africa [2009–2012]. Two paired, consecutive induced sputa and early morning gastric lavage samples were obtained from children with suspected tuberculosis. Samples underwent Mycobacterial Growth Indicator Tube [MGIT] culture and Xpert MTB/RIF assay. We compared diagnostic yield across samples using the two-sample test of proportions and McNemar’s ?2 test; and Wilson’s score method to calculate sensitivity and specificity. Results 1,020 children were evaluated for tuberculosis during 1,214 admission episodes. Not all children had 4 samples collected. 57 of 4,463[1.3%] and 26 of 4,606[0.6%] samples tested positive for Mycobacterium tuberculosis on MGIT culture and Xpert MTB/RIF assay respectively. 27 of 2,198[1.2%] and 40 of 2,183[1.8%] samples tested positive [on either Xpert MTB/RIF assay or MGIT culture] on induced sputum and gastric lavage samples, respectively. 19/1,028[1.8%] and 33/1,017[3.2%] admission episodes yielded a positive MGIT culture or Xpert MTB/RIF assay from induced sputum and gastric lavage, respectively. Sensitivity of Xpert MTB/RIF assay was 8/30[26.7%; 95% CI: 14.2–44.4] for two induced sputum samples and 7/31[22.6%; 11.4–39.8] [p = 0.711] for two gastric lavage samples. Corresponding specificity was 893/893[100%;99.6–100] and 885/890[99.4%;98.7–99.8] respectively [p = 0.025]. Conclusion Sensitivity of Xpert MTB/RIF assay was low, compared to MGIT culture, but diagnostic performance of Xpert MTB/RIF did not differ sufficiently between induced sputum and gastric lavage to justify selection of one sampling method over the other, in young children with suspected pulmonary TB. Trial Registration ClinicalTrials.gov NCT00953927 PMID:26554383

  8. The relationship between chitotriosidase activity and tuberculosis.

    PubMed

    Chen, M; Deng, J; Li, W; Su, C; Xia, Y; Wang, M; Li, X; Abuaku, B K; Tan, H; Wen, S W

    2015-11-01

    Chitotriosidase, secreted by activated macrophages, is a biomarker of activated macrophages. In this study, we explored whether chitotriosidase could be adopted as a biomarker to evaluate the curative effect on tuberculosis (TB). Five counties were randomly selected out of 122 counties/cities/districts in Hunan Province, China. Our cases were all TB patients who were newly diagnosed or had been receiving treatment at the Centers for Disease Control (CDCs) of these five counties between April and August in 2009. Healthy controls were selected from a community health facility in the Kaifu district of Changsha City after frequency-matching of gender and age with the cases. Chitotriosidase activity was evaluated by a fluorometric assay. Categorical variables were analysed with the ? 2 test. Measurement data in multiple groups were tested with analysis of variance and least significant difference (LSD). Correlation between chitotriosidase activity and the degree of radiological extent (DRE) was examined by Spearman's rank correlation test. The average chitotriosidase activity levels of new TB cases, TB cases with different periods of treatment (6 months) and the control group were 54·47, 34·77, 21·54, 12·73 and 10·53 nmol/h.ml, respectively. Chitotriosidase activity in TB patients declined along with the continuity of treatment. The chitotriosidase activity of both smear-positive and the smear-negative pulmonary TB patients decreased after 6 months' treatment to normal levels (P < 0·05). Moreover, chitotriosidase activity was positively correlated with DRE (r = 0·607, P < 0·001). Our results indicate that chitotriosidase might be a marker of TB treatment effects. However, further follow-up study of TB patients is needed in the future. PMID:26418349

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

    E-print Network

    Sali, Andrej

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

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

    PubMed Central

    2010-01-01

    Background Previous health economic studies recommend either a dual screening strategy [tuberculin skin test (TST) followed by interferon-?-release assay (IGRA)] or a single one [IGRA only] for latent tuberculosis infection (LTBI), the former largely based on claims that it is more cost-effective. We sought to examine that conclusion through the use of a model that accounts for the additional costs of adverse drug reactions and directly compares two commercially available versions of the IGRA: the Quantiferon-TB-Gold-In-Tube (QFT-GIT) and T-SPOT.TB. Methods A LTBI screening model directed at screening contacts was used to perform a cost-effectiveness analysis, from a UK healthcare perspective, taking into account the risk of isoniazid-related hepatotoxicity and post-exposure TB (2 years post contact) using the TST, QFT-GIT and T-SPOT.TB IGRAs. Results Examining costs alone, the TST/IGRA dual screening strategies (TST/T-SPOT.TB and TST/QFT-GIT; £162,387 and £157,048 per 1000 contacts, respectively) cost less than their single strategy counterparts (T-SPOT.TB and QFT-GIT; £203,983 and £202,921 per 1000 contacts) which have higher IGRA test costs and greater numbers of persons undergoing LTBI treatment. However, IGRA alone strategies direct healthcare interventions and costs more accurately to those that are truly infected. Subsequently, less contacts need to be treated to prevent an active case of TB (T-SPOT.TB and QFT-GIT; 61.7 and 69.7 contacts) in IGRA alone strategies. IGRA single strategies also prevent more cases of post-exposure TB. However, this greater effectiveness does not outweigh the lower incremental costs associated with the dual strategies. Consequently, when these costs are combined with effectiveness, the IGRA dual strategies are more cost-effective than their single strategy counterparts. Comparing between the IGRAs, T-SPOT.TB-based strategies (single and dual; £39,712 and £37,206 per active TB case prevented, respectively) were more cost-effective than the QFT-GIT-based strategies (single and dual; £42,051 and £37,699 per active TB case prevented, respectively). Using the TST alone was the least cost-effective (£47,840 per active TB case prevented). Cost effectiveness values were sensitive to changes in LTBI prevalence, IGRA test sensitivities/specificities and IGRA test costs. Conclusion A dual strategy is more cost effective than a single strategy but this conclusion is sensitive to screening test assumptions and LTBI prevalence. PMID:20170555

  11. Indoleamides are active against drug-resistant Mycobacterium tuberculosis

    PubMed Central

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

    2014-01-01

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

  12. Blood or Urine IP-10 Cannot Discriminate between Active Tuberculosis and Respiratory Diseases Different from Tuberculosis in Children

    PubMed Central

    Petrone, Linda; Cannas, Angela; Aloi, Francesco; Nsubuga, Martin; Sserumkuma, Joseph; Nazziwa, Ritah Angella; Jugheli, Levan; Lukindo, Tedson; Girardi, Enrico; Reither, Klaus; Goletti, Delia

    2015-01-01

    Objectives. Interferon-? inducible protein 10 (IP-10), either in blood or in urine, has been proposed as a tuberculosis (TB) biomarker for adults. This study aims to evaluate the potential of IP-10 diagnostics in children from Uganda, a high TB-endemic country. Methods. IP-10 was measured in the blood and urine concomitantly taken from children who were prospectively enrolled with suspected active TB, with or without HIV infection. Clinical/microbiological parameters and commercially available TB-immune assays (tuberculin skin test (TST) and QuantiFERON TB-Gold In-Tube (QFT-IT)) were concomitantly evaluated. Results. One hundred twenty-eight children were prospectively enrolled. The analysis was performed on 111 children: 80 (72%) of them were HIV-uninfected and 31 (27.9%) were HIV-infected. Thirty-three healthy adult donors (HAD) were included as controls. The data showed that IP-10 is detectable in the urine and blood of children with active TB, independent of HIV status and age. However, although IP-10 levels were higher in active TB children compared to HAD, the accuracy of identifying “active TB” was low and similar to the TST and QFT-IT. Conclusion. IP-10 levels are higher in children with respiratory illness compared to controls, independent of “TB status” suggesting that the evaluation of this parameter can be used as an inflammatory marker more than a TB test. PMID:26346028

  13. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

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

  14. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

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

  15. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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

  16. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

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

  17. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

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

  18. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... active tuberculosis. 3.374 Section 3.374 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS... Considerations Relative to Specific Diseases § 3.374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service department diagnosis of active pulmonary tuberculosis will be accepted unless a board...

  19. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... active tuberculosis. 3.374 Section 3.374 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS... Considerations Relative to Specific Diseases § 3.374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service department diagnosis of active pulmonary tuberculosis will be accepted unless a board...

  20. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... active tuberculosis. 3.374 Section 3.374 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS... Considerations Relative to Specific Diseases § 3.374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service department diagnosis of active pulmonary tuberculosis will be accepted unless a board...

  1. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... active tuberculosis. 3.374 Section 3.374 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS... Considerations Relative to Specific Diseases § 3.374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service department diagnosis of active pulmonary tuberculosis will be accepted unless a board...

  2. 38 CFR 3.374 - Effect of diagnosis of active tuberculosis.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... active tuberculosis. 3.374 Section 3.374 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS... Considerations Relative to Specific Diseases § 3.374 Effect of diagnosis of active tuberculosis. (a) Service diagnosis. Service department diagnosis of active pulmonary tuberculosis will be accepted unless a board...

  3. Spooky Suspects

    ERIC Educational Resources Information Center

    Pacifici, Lara

    2011-01-01

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

  4. MicroRNA-365 in macrophages regulates Mycobacterium tuberculosis-induced active pulmonary tuberculosis via interleukin-6

    PubMed Central

    Song, Qingzhang; Li, Hui; Shao, Hua; Li, Chunling; Lu, Xiao

    2015-01-01

    The present study is to investigate the relationship between microRNA (miR)-365 expression and the levels of interleukin (IL)-6 mRNA and protein in patients with active tuberculosis. From June 2011 to June 2014, 48 patients with active pulmonary tuberculosis induced by Mycobacterium tuberculosis were included in the study. In addition, 23 healthy subjects were enrolled as control. Macrophages were collected by pulmonary alveolus lavage. In addition, serum and mononuclear cells were isolated from peripheral blood. The levels of miR-365 and IL-6 in macrophages, mononuclear cells and serum were determined using quantitative real-time polymerase chain reaction. The protein expression of IL-6 in macrophages and mononuclear cells was measured using Western blotting, while that in serum was detected by enzyme-linked immunoabsorbent assay. Expression of IL-6 mRNA and protein was significantly enhanced in patients with active pulmonary tuberculosis. Increase of IL-6 protein concentration in serum was probably due to the release of IL-6 protein from mononuclear cells in the blood. In addition, miR-365 levels were significantly lowered in patients with active pulmonary tuberculosis. Up-regulated IL-6 expression in macrophages, mononuclear cells and serum in patients with active pulmonary tuberculosis is related to the down-regulation of miR-365, suggesting that miR-365 may regulate the occurrence and immune responses of active pulmonary tuberculosis via IL-6.

  5. LL-37 Immunomodulatory Activity during Mycobacterium tuberculosis Infection in Macrophages.

    PubMed

    Torres-Juarez, Flor; Cardenas-Vargas, Albertina; Montoya-Rosales, Alejandra; González-Curiel, Irma; Garcia-Hernandez, Mariana H; Enciso-Moreno, Jose A; Hancock, Robert E W; Rivas-Santiago, Bruno

    2015-12-01

    Tuberculosis is one of the most important infectious diseases worldwide. The susceptibility to this disease depends to a great extent on the innate immune response against mycobacteria. Host defense peptides (HDP) are one of the first barriers to counteract infection. Cathelicidin (LL-37) is an HDP that has many immunomodulatory effects besides its weak antimicrobial activity. Despite advances in the study of the innate immune response in tuberculosis, the immunological role of LL-37 during M. tuberculosis infection has not been clarified. Monocyte-derived macrophages were infected with M. tuberculosis strain H37Rv and then treated with 1, 5, or 15 ?g/ml of exogenous LL-37 for 4, 8, and 24 h. Exogenous LL-37 decreased tumor necrosis factor alpha (TNF-?) and interleukin-17 (IL-17) while inducing anti-inflammatory IL-10 and transforming growth factor ? (TGF-?) production. Interestingly, the decreased production of anti-inflammatory cytokines did not reduce antimycobacterial activity. These results are consistent with the concept that LL-37 can modulate the expression of cytokines during mycobacterial infection and this activity was independent of the P2X7 receptor. Thus, LL-37 modulates the response of macrophages during infection, controlling the expression of proinflammatory and anti-inflammatory cytokines. PMID:26351280

  6. Tuberculosis

    MedlinePLUS

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

  7. Diagnostic value of antibody responses to multiple antigens from Mycobacterium tuberculosis in active and latent tuberculosis.

    PubMed

    Senoputra, Muhammad Andrian; Shiratori, Beata; Hasibuan, Fakhrial Mirwan; Koesoemadinata, Raspati Cundarani; Apriani, Lika; Ashino, Yugo; Ono, Kenji; Oda, Tetsuya; Matsumoto, Makoto; Suzuki, Yasuhiko; Alisjahbana, Bachti; Hattori, Toshio

    2015-11-01

    We investigated the antibody responses to 10 prospective Mycobacterium tuberculosis (MTB) antigens and evaluated their ability to discriminate between latent (LTBI) and active pulmonary tuberculosis (TB). Our results indicate that plasma levels of anti-?-crystallin (ACR), antilipoarabinomannan, anti-trehalose 6,6'-dimycolate, and anti-tubercular-glycolipid antigen antibodies were higher in patients with active TB, compared to those in the LTBI and control subjects. No differences in the antibodies were observed between the control and LTBI subjects. Antibodies against the glycolipid antigens could not distinguish between Mycobacterium avium complex (MAC)-negative TB patients and MAC-infected LTBI individuals. The most useful serological marker was antibodies to ACR, with MAC-negative TB patients having higher titers than those observed in MAC-positive LTBI and control subjects. Our data indicate that antibody to ACR is a promising target for the serological diagnosis of patients with active TB patients. When dealing with antiglycolipid antibodies, MAC coinfection should always be considered in serological studies. PMID:26307672

  8. Evaluation of the Characteristics of the Enzyme-Linked Immunospot Assay for Diagnosis of Active Tuberculosis in China

    PubMed Central

    Wang, Linchuan; Chen, Wei; Feng, Jin; Wang, Jinyuan; Zhao, Heping; Ma, Lietin; Yang, Bo; Ma, Yanfen; Dang, Pei

    2015-01-01

    The purpose of this study was to evaluate the characteristics of the T-SPOT.TB test for the diagnosis of active tuberculosis (ATB) and to distinguish ATB from other diseases using a receiver operating characteristic (ROC) curve. A total of 535 patients with suspected active tuberculosis were enrolled in the study and divided into ATB and nonactive tuberculosis (NATB) groups, as well as pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) subgroups. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of the T-SPOT.TB test for the diagnosis of ATB were 84.95%, 85.12%, 82.94%, 86.93%, 5.71, and 0.18, respectively. The median number of spot-forming cells (SFCs) in the ATB group was higher than that in the NATB group (71 versus 1; P < 0.0001). The sensitivities in the PTB and EPTB subgroups were 92.31% and 81.77%. The areas under the curve (AUC) for the diagnosis of ATB using the T-SPOT.TB, early secreted antigenic target 6 (ESAT-6), and culture filtrate protein 10 (CFP-10) were 0.906, 0.884, and 0.877, respectively. A cutoff of 42.5 SFCs for ATB yielded a positive predictive value of 100%. Our study shows that the T-SPOT.TB test is useful for the diagnosis of ATB. Utilizing an ROC curve to select an appropriate cutoff made it possible to discriminate ATB from NATB. PMID:25739918

  9. Direct inhibitors of InhA active against Mycobacterium tuberculosis

    PubMed Central

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

    2015-01-01

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

  10. Effect of Active Case Finding on Prevalence and Transmission of Pulmonary Tuberculosis in Dhaka Central Jail, Bangladesh

    PubMed Central

    Banu, Sayera; Rahman, Md. Toufiq; Uddin, Mohammad Khaja Mafij; Khatun, Razia; Khan, Md. Siddiqur Rahman; Rahman, Md. Mojibur; Uddin, Syed Iftekhar; Ahmed, Tahmeed; Heffelfinger, James D.

    2015-01-01

    Background Understanding tuberculosis (TB) transmission dynamics is essential for establishing effective TB control strategies in settings where the burden and risk of transmission are high. The objectives of this study were to evaluate the effect of active screening on controlling TB transmission and also to characterize Mycobacterium tuberculosis strains for investigating transmission dynamics in a correctional setting. Methods The study was carried out in Dhaka Central Jail (DCJ), from October 2005 to February 2010. An active case finding strategy for pulmonary TB was established both at the entry point to the prison and inside the prison. Three sputum specimens were collected from all pulmonary TB suspects and subjected to smear microscopy, culture, and drug susceptibility testing as well as genotyping which included deletion analysis, spoligotyping and analysis of mycobacterial interspersed repetitive units (MIRU). Results A total of 60,585 inmates were screened during the study period. We found 466 inmates with pulmonary TB of whom 357 (77%) had positive smear microscopy results and 109 (23%) had negative smear microscopy results but had positive results on culture. The number of pulmonary TB cases declined significantly, from 49 cases during the first quarter to 8 cases in the final quarter of the study period (p=0.001). Deletion analysis identified all isolates as M. tuberculosis and further identified 229 (70%) strains as ‘modern’ and 100 (30%) strains as ‘ancestral’. Analysis of MIRU showed that 347 strains (85%) exhibited unique patterns, whereas 61 strains (15%) clustered into 22 groups. The largest cluster comprised eight strains of the Beijing M. tuberculosis type. The rate of recent transmission was estimated to be 9.6%. Conclusions Implementation of active screening for TB was associated with a decline in TB cases in DCJ. Implementation of active screening in prison settings might substantially reduce the national burden of TB in Bangladesh. PMID:25933377

  11. T-SPOT.TB in Detection of Active Tuberculosis During Pregnancy: A Retrospective Study in China.

    PubMed

    Chen, Qiaopei; Guo, Xuxiao; Wang, Xinfeng; Wang, Maoshui

    2016-01-01

    BACKGROUND Interferon-gamma release assays have not been validated in active TB among pregnant women. Therefore, the objective of this retrospective study was to estimate the diagnostic value of T-SPOT.TB in active TB among pregnant women. MATERIAL AND METHODS Between May 2012 and May 2015, 26 consecutive pregnant women with suspected TB were enrolled in our study. The clinicopathological characteristics and T-SPOT.TB results were reviewed and analyzed. RESULTS Pregnant patients were divided into a TB group (n=21) and a Non-TB group (n=5). In the TB group, 5 patients had pulmonary TB, 5 had pulmonary TB+ extrapulmonary TB, and 11 had exclusively extrapulmonary TB. The most common site of extrapulmonary TB was pleural (n=11). Statistical analysis showed that the lymphocyte count in the TB group was lower than in the Non-TB group (P<0.05). For detection of active TB during pregnancy, T-SPOT.TB had a high sensitivity of 100.0% (84.5%-100.0%) and a specificity of 80.0% (37.6-96.4%). CONCLUSIONS T-SPOT.TB shows good performance in detection of active tuberculosis during pregnancy. Interferon gamma release assay for TB screening of pregnant women is recommended in clinical practice because it may be a more appropriate diagnostic tool than the tuberculin skin test. PMID:26732770

  12. Antifolate Activity of Plant Polyphenols against Mycobacterium tuberculosis.

    PubMed

    Raju, Archana; Degani, Mariam S; Khambete, Mihir P; Ray, M K; Rajan, M G R

    2015-10-01

    With the view of exploring phytochemicals as Mycobacterium tuberculosis (Mtb) dihydrofolate reductase inhibitors, known plant polyphenols from various classes were subjected to detailed docking studies. From this in-silico screening, seven polyphenols were selected and tested against Mtb H37 Rv in whole cell assays. The phytochemicals exhibited potential activity ranging from 3 to 183?µm. These molecules were then tested against the pathogenic and human enzymes in a high-throughput microtitre assay. Epigallocatechin gallate showed the best activity and selectivity. The in-silico analysis was in agreement with the assay results. Of these 7 polyphenols, 5 exhibiting minimum inhibitory concentration values of ?15?µm were tested for synergistic activity with first line drug Ethambutol and second line folate inhibitor para-amino salicylic acid. Epigallocatechin gallate, Magnolol and Bakuchiol exhibited moderate synergistic association by lowering the minimum inhibitory concentration of these drugs. These simple phytochemicals could hence be considered as leads for further studies, or for preparation of semi-synthetic derivatives to be used in combination therapy, for increased anti-tuberculosis activity after validation in-vivo. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26275674

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

    NASA Technical Reports Server (NTRS)

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

    1991-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  15. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... tuberculosis pension cases. A permanent and total disability rating in effect during hospitalization will...

  16. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2014-07-01 2014-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... tuberculosis pension cases. A permanent and total disability rating in effect during hospitalization will...

  17. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... tuberculosis pension cases. A permanent and total disability rating in effect during hospitalization will...

  18. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... tuberculosis pension cases. A permanent and total disability rating in effect during hospitalization will...

  19. 38 CFR 3.378 - Changes from activity in pulmonary tuberculosis pension cases.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2012-07-01 2012-07-01 false Changes from activity in pulmonary tuberculosis pension cases. 3.378 Section 3.378 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... tuberculosis pension cases. A permanent and total disability rating in effect during hospitalization will...

  20. MEROPENEM INHIBITS D,D-CARBOXYPEPTIDASE ACTIVITY IN MYCOBACTERIUM TUBERCULOSIS

    PubMed Central

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

    2012-01-01

    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. PMID:22906310

  1. Human CD8 T lymphocytes recognize Mycobacterium tuberculosis antigens presented by HLA-E during active tuberculosis and express type 2 cytokines.

    PubMed

    Caccamo, Nadia; Pietra, Gabriella; Sullivan, Lucy C; Brooks, Andrew G; Prezzemolo, Teresa; La Manna, Marco P; Di Liberto, Diana; Joosten, Simone A; van Meijgaarden, Krista E; Di Carlo, Paola; Titone, Lucina; Moretta, Lorenzo; Mingari, Maria C; Ottenhoff, Tom H M; Dieli, Francesco

    2015-04-01

    CD8 T cells contribute to protective immunity against Mycobacterium tuberculosis. In humans, M. tuberculosis reactive CD8 T cells typically recognize peptides associated to classical MHC class Ia molecules, but little information is available on CD8 T cells recognizing M. tuberculosis Ags presented by nonclassical MHC class Ib molecules. We show here that CD8 T cells from tuberculosis (TB) patients recognize HLA-E-binding M. tuberculosis peptides in a CD3/TCR ?? mediated and CD8-dependent manner, and represent an additional type of effector cells playing a role in immune response to M. tuberculosis during active infection. HLA-E-restricted recognition of M. tuberculosis peptides is detectable by a significant enhanced ex vivo frequency of tetramer-specific circulating CD8 T cells during active TB. These CD8 T cells produce type 2 cytokines upon antigenic in vitro stimulation, help B cells for Ab production, and mediate limited TRAIL-dependent cytolytic and microbicidal activity toward M. tuberculosis infected target cells. Our results, together with the finding that HLA-E/M. tuberculosis peptide specific CD8 T cells are detected in TB patients with or without HIV coinfection, suggest that this is a new human T-cell population that participates in immune response in TB. PMID:25631937

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

    PubMed Central

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

    2015-01-01

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

  3. Factors influencing quality of life in patients with active tuberculosis

    PubMed Central

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

    2004-01-01

    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 using focus groups and individual interviews. Methods English, Cantonese, and Punjabi-speaking subjects with active TB who were receiving treatment were eligible for recruitment into the study. Gender-based focus group sessions were conducted for the inner city participants but individual interviews were conducted for those who came to the main TB clinic or were hospitalized. Facilitators used open-ended questions and participants were asked to discuss their experiences of being diagnosed with tuberculosis, what impact it had on their lives, issues around adherence to anti-TB medications and information pertaining to their experience with side effects to these medications. All data were audio-recorded, transcribed verbatim, and analyzed using constant comparative analysis. Results 39 patients with active TB participated. The mean age was 46.2 years (SD 18.4) and 62% were male. Most were Canadian-born being either Caucasian or Aboriginal. Four themes emerged from the focus groups and interviews. The first describes issues related to the diagnosis of tuberculosis and sub-themes were identified as 'symptoms', 'health care provision', and 'emotional impact'. The second theme discusses TB medication factors and the sub-themes identified were 'adverse effects', 'ease of administration', and 'adherence'. The third theme describes social support and functioning issues for the individuals with TB. The fourth theme describes health behavior issues for the individuals with TB and the identified sub-themes were "behavior modification" and "TB knowledge." Conclusion Despite the ability to cure TB, there remains a significant impact on QOL. Since much attention is spent on preventative or curative mechanisms, the impact of this condition on QoL is often not considered. Attention to the issues experienced by patients being treated for TB may optimize adherence and treatment success. PMID:15496227

  4. Diagnostic Utility of QuantiFERON-TB Gold (QFT-G) in Active Pulmonary Tuberculosis

    PubMed Central

    Anwar, Ahmed; Hamdan, AL-Jahdali; Salim, Baharoon; Yosra, Ali; Hani, Mohamed; Abdullah, AL-Harbi

    2015-01-01

    Background: The utility of QuantiFERON-TB Gold In-Tube (QFT-G) test in the diagnosis of tuberculosis disease has been validated in high and low tuberculosis-prevalent (TB) countries. Aim: The aim of this study is to assess the performance of the QFT-G test in the diagnosis of tuberculosis disease among tuberculosis patients in an intermediate prevalent country. Setting and Design: A retrospective study at the King Abdulaziz Medical City-Riyadh (KAMC-R) Materials and Methods: We retrospectively reviewed all the patients with a diagnosis of pneumonia, including tuberculosis, admitted to KAMC-R between 1 January 2009 and 31 December 2013. We included only patients with an available result of the QFT-G test. A total of 142 tuberculosis cases and 226 pneumonia cases were studied, to assess the utility of the QFT-G test in diagnosing tuberculosis cases. Results: Among the tuberculosis (n = 142) cases, the QFT-G tested positive in 68.3%, negative in 23.2%, and indeterminate in 12 cases (8.5%). Of the 226 pneumonia cases, the QFT-G tested positive in only 20.4%, while a majority of 66.4% tested negative, with 30 cases (13.3%) being indeterminate. When we excluded 42 patients with indeterminate results, the QFT-G test achieved a sensitivity of 74.6% [95% CI: 66.09 to 81.65%] and specificity of 76.53 % [95% CI: 69.85 to 82.15%] in the diagnosis of tuberculosis cases. Conclusions: This study concludes that the QFT-G test is a useful tool for detecting tuberculosis disease when used as an adjunct tool for the diagnosis of active TB cases. It certainly cannot be used solely and indiscriminately, separate from other clinical and radiological information, in the diagnosis of active tuberculosis cases. PMID:26392718

  5. Discriminating Active Tuberculosis from Latent Tuberculosis Infection by flow cytometric measurement of CD161-expressing T cells

    PubMed Central

    Yang, Qianting; Xu, Qian; Chen, Qi; Li, Jin; Zhang, Mingxia; Cai, Yi; Liu, Haiying; Zhou, Yiping; Deng, Guofang; Deng, Qunyi; Zhou, Boping; Kornfeld, Hardy; Chen, Xinchun

    2015-01-01

    Interferon-gamma Release Assays (IGRAs) significantly increases the possibility for early diagnosis of tuberculosis, but IGRAs alone cannot discriminate active TB from LTBI. Therefore, fast and reliable discrimination of active tuberculosis, especially bacteriology negative tuberculosis, from LTBI is a great necessity. Here we established an assay based on flow cytometric multiparameter assay assessing expression of CD161 along with CD3, CD4, and CD8, whereby a set of indices formulated by the percentages of CD3+CD161+, CD3+CD4+CD161+ and CD3+CD8+CD161+ T cells multiplied with lymphocyte/monocyte ratio were established. Application of the CD3+CD8+CD161+ index to compare a cohort of active tuberculosis with a cohort of LTBI or health control yielded 0.7662 (95% confidence interval [CI] 0.6559–0.8552) or 0.7922 (95%??CI 0.6846–0.8763) for sensitivity and 0.9048 (95%??CI 0.8209–0.9580) or 0.8939 (95%?CI 0.8392–0.9349) for specificity when the TB cohort was AFB+; the corresponding results were 0.7481 (95%??CI 0.6648–0.8198) or 0.7557 (95%??CI 0.6730–0.8265) for sensitivity and 0.8571 (95%??CI 0.7637–0.9239) or 0.8603 (95%??CI 0.8008–0.9075) for specificity when the TB cohort was AFB?. Our results reveal that in combination with IGRAs, CD161-based indices provide a novel, fast diagnostic solution addressing the limitation of current tuberculosis diagnostics. PMID:26643453

  6. Discriminating Active Tuberculosis from Latent Tuberculosis Infection by flow cytometric measurement of CD161-expressing T cells.

    PubMed

    Yang, Qianting; Xu, Qian; Chen, Qi; Li, Jin; Zhang, Mingxia; Cai, Yi; Liu, Haiying; Zhou, Yiping; Deng, Guofang; Deng, Qunyi; Zhou, Boping; Kornfeld, Hardy; Chen, Xinchun

    2015-01-01

    Interferon-gamma Release Assays (IGRAs) significantly increases the possibility for early diagnosis of tuberculosis, but IGRAs alone cannot discriminate active TB from LTBI. Therefore, fast and reliable discrimination of active tuberculosis, especially bacteriology negative tuberculosis, from LTBI is a great necessity. Here we established an assay based on flow cytometric multiparameter assay assessing expression of CD161 along with CD3, CD4, and CD8, whereby a set of indices formulated by the percentages of CD3(+)CD161(+), CD3(+)CD4(+)CD161(+) and CD3(+)CD8(+)CD161(+) T cells multiplied with lymphocyte/monocyte ratio were established. Application of the CD3(+)CD8(+)CD161(+) index to compare a cohort of active tuberculosis with a cohort of LTBI or health control yielded 0.7662 (95% confidence interval [CI] 0.6559-0.8552) or 0.7922 (95%??CI 0.6846-0.8763) for sensitivity and 0.9048 (95%??CI 0.8209-0.9580) or 0.8939 (95%?CI 0.8392-0.9349) for specificity when the TB cohort was AFB(+); the corresponding results were 0.7481 (95%??CI 0.6648-0.8198) or 0.7557 (95%??CI 0.6730-0.8265) for sensitivity and 0.8571 (95%??CI 0.7637-0.9239) or 0.8603 (95%??CI 0.8008-0.9075) for specificity when the TB cohort was AFB(-). Our results reveal that in combination with IGRAs, CD161-based indices provide a novel, fast diagnostic solution addressing the limitation of current tuberculosis diagnostics. PMID:26643453

  7. The cyclic peptide ecumicin targeting ClpC1 is active against Mycobacterium tuberculosis in vivo.

    PubMed

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

    2015-02-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  10. Anti-Mycobacterial Activity of Tamoxifen Against Drug-Resistant and Intra-Macrophage Mycobacterium tuberculosis.

    PubMed

    Jang, Woong Sik; Kim, Sukyung; Podder, Biswajit; Jyoti, Md Anirban; Nam, Kung-Woo; Lee, Byung-Eui; Song, Ho-Yeon

    2015-06-01

    Recently, it has become a struggle to treat tuberculosis with the current commercial antituberculosis drugs because of the increasing emergence of multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis. We evaluated here the antimycobacterial activity of tamoxifen, known as a synthetic anti-estrogen, against eight drug-sensitive or resistant strains of Mycobacterium tuberculosis (TB), and the active intracellular killing of tamoxifen on TB in macrophages. The results showed that tamoxifen had antituberculosis activity against drug-sensitive strains (MIC, 3.125-6.25 ?g/ml) as well as drug-resistant strains (MIC, 6.25 to 12.5 ?g/ml). In addition, tamoxifen profoundly decreased the number of intracellular TB in macrophages in a dose-dependent manner. PMID:25639719

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

    PubMed Central

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

    2013-01-01

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

  12. Control measures to trace ? 15-year-old contacts of index cases of active pulmonary tuberculosis

    PubMed Central

    Oliveira, Cláudia Di Lorenzo; de Melo, Angelita Cristine; de Oliveira, Lílian Ruth Silva; Froede, Emerson Lopes; Camargos, Paulo

    2015-01-01

    This was descriptive study carried out in a medium-sized Brazilian city. In ? 15-year-old contacts of index cases of active pulmonary tuberculosis, we assessed compliance with the Brazilian national guidelines for tuberculosis control. We interviewed 43 contacts and their legal guardians. Approximately 80% of the contacts were not assessed by the municipal public health care system, and only 21% underwent tuberculin skin testing. The results obtained with the Chi-square Automatic Interaction Detector method suggest that health care teams have a biased attitude toward assessing such contacts and underscore the need for training health professionals regarding tuberculosis control programs. PMID:26578137

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

    PubMed

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

    2014-01-25

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

  14. MHEALTH INTERVENTION DEVELOPMENT TO SUPPORT PATIENTS WITH ACTIVE TUBERCULOSIS

    PubMed Central

    Iribarren, Sarah J.; Beck, Susan L.; Pearce, Patricia F.; Chirico, Cristina; Etchevarria, Mirta; Rubinstein, Fernando

    2015-01-01

    Background Mobile Health (mHealth) based interventions have been increasingly used to improve a broad range of health outcomes. However, few researchers have reported on the process or the application of theory to guide the development of mHealth based interventions, or specifically for tuberculosis (TB) treatment management. Aims To describe the steps, process, and considerations in developing a text messaging-based intervention to promote treatment adherence and provide support to patients with active TB. Methods Traditional qualitative techniques, including semi-structured interviews, field notes, content analysis, iterative coding, and thematic analysis, were used to design and document the intervention development with a multidisciplinary team of researchers, clinicians, administrators, and patients who were in active TB treatment. The Information-Motivation-Behavioral Skills (IMB) model was used to guide the coding scheme for content analysis of patient-directed TB educational material and intervention development. Results The development steps included: a) establishing intervention components, including justifications, considerations, timing and frequency of components; b) developing educational messages, including cultural adaption, text or short message service (SMS) formatting, and prioritizing message delivery order; and c) determining implementation protocol. A set of 16 IMB-based messages were developed for the educational component. Final intervention development was achieved in 3 months. Conclusion A collaborative approach and application of a theory to guide the intervention design and development is supported. Although a collaborative approach was more time consuming, it resulted in a more responsive, culturally appropriate, and comprehensive intervention. Considerations for developing a text messaging based intervention are provided and may serve as a guide for similar interventions. Further empirical evidence is needed for applying the IMB model for adherence-promotion in TB efforts. PMID:26246859

  15. 38 CFR 3.370 - Pulmonary tuberculosis shown by X-ray in active service.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... shown by X-ray in active service. 3.370 Section 3.370 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... Rating Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for grant of direct...

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

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... shown by X-ray in active service. 3.370 Section 3.370 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... Rating Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for grant of direct...

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

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... shown by X-ray in active service. 3.370 Section 3.370 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... Rating Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for grant of direct...

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

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... shown by X-ray in active service. 3.370 Section 3.370 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... Rating Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for grant of direct...

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

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... shown by X-ray in active service. 3.370 Section 3.370 Pensions, Bonuses, and Veterans' Relief DEPARTMENT... Rating Considerations Relative to Specific Diseases § 3.370 Pulmonary tuberculosis shown by X-ray in active service. (a) Active disease. X-ray evidence alone may be adequate for grant of direct...

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2015-01-01

    Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10(-7). In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole. PMID:25331696

  2. In Vitro and In Vivo Activities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis

    PubMed Central

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

    2014-01-01

    Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10?7. In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole. PMID:25331696

  3. Viral hepatitis prevalence in patients with active and latent tuberculosis

    PubMed Central

    Nooredinvand, Hesam Ahmadi; Connell, David W; Asgheddi, Mahmoud; Abdullah, Mohammed; O’Donoghue, Marie; Campbell, Louise; Wickremasinghe, Melissa I; Lalvani, Ajit; Kon, Onn Min; Khan, Shahid A

    2015-01-01

    AIM: To assess the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and association with drug induced liver injury (DILI) in patients undergoing anti-tuberculosis (TB) therapy. METHODS: Four hundred and twenty nine patients with newly diagnosed TB - either active disease or latent infection - who were due to commence anti-TB therapy between September 2008 and May 2011 were included. These patients were prospectively tested for serological markers of HBV, HCV and human immunodeficiency virus (HIV) infections - hepatitis B core antigen (HBcAg), hepatitis B surface antigen (HBsAg), hepatitis B e antigen, IgG and IgM antibody to HBcAg (anti-HBc), HCV IgG antibody and HIV antibody using a combination of enzyme-linked immunosorbent assay, Western blot assay and polymerase chain reaction techniques. Patients were reviewed at least monthly during the TB treatment initiation phase. Liver function tests were measured prior to commencement of anti-TB therapy and 2-4 wk later. Liver function tests were also performed at any time the patient had significant nausea, vomiting, rash, or felt non-specifically unwell. Fisher’s exact test was used to measure significance in comparisons of proportions between groups. A P value of less than 0.05 was considered statistically significant. RESULTS: Of the 429 patients, 270 (62.9%) had active TB disease and 159 (37.1%) had latent TB infection. 61 (14.2%) patients had isolated anti-HBc positivity, 11 (2.6%) were also HBsAg positive and 7 (1.6%) were HCV-antibody positive. 16/270 patients with active TB disease compared to 2/159 patients with latent TB infection had markers of chronic viral hepatitis (HBsAg or HCV antibody positive; P = 0.023). Similarly the proportion of HBsAg positive patients were significantly greater in the active vs latent TB infection group (10/43 vs 1/29, P = 0.04). The prevalence of chronic HBV or HCV was significantly higher than the estimated United Kingdom prevalence of 0.3% for each. We found no association between DILI and presence of serological markers of HBV or HCV. Three (5.3%) patients with serological markers of HBV or HCV infection had DILI compared to 25 (9.5%) patients without; P = 0.04. CONCLUSION: Viral hepatitis screening should be considered in TB patients. DILI risk was not increased in patients with HBV/HCV. PMID:26269682

  4. [Development and study of structure-activity relationship of drugs against Mycobacterium tuberculosis].

    PubMed

    Baska, Ferenc; Székely, Edina Rita; Szántai-Kis, Csaba; Bánhegyi, Péter; Hegymegi-Barakonyi, Bálint; Németh, Gábor; Breza, Nóra; Zsákai, Lilian; Greff, Zoltán; Pató, János; Kéri, György; Orfi, Lászlo

    2013-01-01

    Tuberculosis is considered to be one of the major health problem not only in the less developed countries but in the economically developed countries as well. Roughly one third of the world's population are infected with Mycobacterium tuberculosis and a significant part of them are carriers of latent tuberculosis. From ten percent of these latent infections are developing the active TB disease and fifty percent of them die from the illness without appropriate treatment. The drug-resistant Mycobacterium tuberculosis (MDR-TB, XDR-TB) and TB-HIV co-infection attracted attention to the most serious infectious disease. Inhibition of alternative signaling pathways were an important part of the research strategies for cancer and inflammatory diseases in recent years. In case of Mycobacterium tuberculosis such pathways were also identified, for example, three serine-threonine kinases (PknA, PknB, PknG) which are necessary and essential for bacterial growth. In this paper we summarize our best anti-TB active compounds, their biological effects and structure-activity relationships using in silico modeling, biochemical measurements and tests on active bacteria. PMID:24369587

  5. Auxiliary diagnostic value of monocyte chemoattractant protein-1 of whole blood in active tuberculosis

    PubMed Central

    Wang, Ying; Li, Hang; Bao, Hong; Jin, Yufen; Liu, Xiaoju; Wu, Xueqiong; Yu, Ting

    2015-01-01

    The aim of this study was to study the expression level of interferon-? (IFN-?) and monocyte chemoattractant protein-1 (MCP-1) in peripheral blood and its auxiliary diagnostic value in active tuberculosis. A chemiluminescence enzyme immunoassay method was used to detect the levels of IFN-? and MCP-1 in peripheral blood. Then the receiver operating characteristic curve were drawn to determine the threshold of IFN-? and MCP-1 for diagnosis of active tuberculosis and to evaluate their diagnostic performance. The specific IFN-? and MCP-1 levels in the active tuberculosis group were significantly higher than those in the non-tuberculous pulmonary disease group (P < 0.01) and those in the healthy control group (P < 0.01). The IFN-? levels in the healthy control group and the non-tuberculous respiratory disease group showed no statistically significant difference (P > 0.05), but the MCP-1 levels in the non-tuberculous respiratory disease group were significantly higher than those of the healthy control group (P < 0.05). The specific IFN-? and MCP-1 level cut off values were 256 pg/ml and 389 pg/ml as an active tuberculosis diagnostic standard. The sensitivities of IFN-? and MCP-1 were 57.3% and 92.8%, respectively; specificities were 80% and 80.7%, respectively; the positive predictive values were 76.9% and 84.9%, respectively; negative predictive values were 61.7% and 78.7%, respectively; and accuracy rates were 76.9% and 84.9%, respectively. Compared with the detection of IFN-?, we observed a better diagnostic performance of MCP-1 in peripheral blood in active tuberculosis. MCP-1 may become one of the active tuberculosis auxiliary diagnostic targets. PMID:26309608

  6. Rapid, Semiquantitative Assay To Discriminate among Compounds with Activity against Replicating or Nonreplicating Mycobacterium tuberculosis.

    PubMed

    Gold, Ben; Roberts, Julia; Ling, Yan; Quezada, Landys Lopez; Glasheen, Jou; Ballinger, Elaine; Somersan-Karakaya, Selin; Warrier, Thulasi; Warren, J David; Nathan, Carl

    2015-10-01

    The search for drugs that can kill replicating and nonreplicating Mycobacterium tuberculosis faces practical bottlenecks. Measurement of CFU and discrimination of bacteriostatic from bactericidal activity are costly in compounds, supplies, labor, and time. Testing compounds against M. tuberculosis under conditions that prevent the replication of M. tuberculosis often involves a second phase of the test in which conditions are altered to permit the replication of bacteria that survived the first phase. False-positive determinations of activity against nonreplicating M. tuberculosis may arise from carryover of compounds from the nonreplicating stage of the assay that act in the replicating stage. We mitigate these problems by carrying out a 96-well microplate liquid MIC assay and then transferring an aliquot of each well to a second set of plates in which each well contains agar supplemented with activated charcoal. After 7 to 10 days-about 2 weeks sooner than required to count CFU-fluorometry reveals whether M. tuberculosis bacilli in each well have replicated extensively enough to reduce a resazurin dye added for the final hour. This charcoal agar resazurin assay (CARA) distinguishes between bacterial biomasses in any two wells that differ by 2 to 3 log10 CFU. The CARA thus serves as a pretest and semiquantitative surrogate for longer, more laborious, and expensive CFU-based assays, helps distinguish bactericidal from bacteriostatic activity, and identifies compounds that are active under replicating conditions, nonreplicating conditions, or both. Results for 14 antimycobacterial compounds, including tuberculosis (TB) drugs, revealed that PA-824 (pretomanid) and TMC207 (bedaquiline) are largely bacteriostatic. PMID:26239979

  7. Rapid, Semiquantitative Assay To Discriminate among Compounds with Activity against Replicating or Nonreplicating Mycobacterium tuberculosis

    PubMed Central

    Roberts, Julia; Ling, Yan; Quezada, Landys Lopez; Glasheen, Jou; Ballinger, Elaine; Somersan-Karakaya, Selin; Warrier, Thulasi; Warren, J. David; Nathan, Carl

    2015-01-01

    The search for drugs that can kill replicating and nonreplicating Mycobacterium tuberculosis faces practical bottlenecks. Measurement of CFU and discrimination of bacteriostatic from bactericidal activity are costly in compounds, supplies, labor, and time. Testing compounds against M. tuberculosis under conditions that prevent the replication of M. tuberculosis often involves a second phase of the test in which conditions are altered to permit the replication of bacteria that survived the first phase. False-positive determinations of activity against nonreplicating M. tuberculosis may arise from carryover of compounds from the nonreplicating stage of the assay that act in the replicating stage. We mitigate these problems by carrying out a 96-well microplate liquid MIC assay and then transferring an aliquot of each well to a second set of plates in which each well contains agar supplemented with activated charcoal. After 7 to 10 days—about 2 weeks sooner than required to count CFU—fluorometry reveals whether M. tuberculosis bacilli in each well have replicated extensively enough to reduce a resazurin dye added for the final hour. This charcoal agar resazurin assay (CARA) distinguishes between bacterial biomasses in any two wells that differ by 2 to 3 log10 CFU. The CARA thus serves as a pretest and semiquantitative surrogate for longer, more laborious, and expensive CFU-based assays, helps distinguish bactericidal from bacteriostatic activity, and identifies compounds that are active under replicating conditions, nonreplicating conditions, or both. Results for 14 antimycobacterial compounds, including tuberculosis (TB) drugs, revealed that PA-824 (pretomanid) and TMC207 (bedaquiline) are largely bacteriostatic. PMID:26239979

  8. Purification and characterization of a functionally active Mycobacterium tuberculosis prephenate dehydrogenase.

    PubMed

    Xu, Shengfeng; Yang, Yanping; Jin, Ruiliang; Zhang, Min; Wang, Honghai

    2006-10-01

    Tuberculosis (TB) remains to be a global health problem. New drugs are badly needed to drastically reduce treatment time and overcome some of the challenges with tuberculosis treatment, such as multi-drug resistant (MDR) strain infected patients or tuberculosis/HIV co-infected patients. The essentiality of mycobacterial aromatic amino acid biosynthesis pathways and their absence from human host indicate that the member enzymes of these pathways promising drug targets for therapeutic agents against pathogen mycobacteria. Prephenate dehydrogenase (PDH) is a key regulatory enzyme in tyrosine biosynthesis, catalyzing the NAD(+)-dependent conversion of prephenate to p-hydroxyphenylpyruvate, making it a potential drug target for antibiotics discovery. The recombinant PDH with an N-terminal His-tag (His-rMtPDH) was first purified in Escherichia coli, and using enterokinase rMtPDH was obtained by cleaving the N-terminal fusion partner. The effect of pH, temperature and the cation-Na(+) on purified enzyme activity was characterized. The N-terminal fusion partner was found to have little effect on the biochemical properties of PDH. We also provide in vitro evidence that Mycobacterium tuberculosis PDH does not possess any chorismate mutase (CM) activity, which suggests that, unlike many other enteric bacteria (where PDH exists as a fusion protein with CM), M. tuberculosis PDH is a monofunctional protein. PMID:16889979

  9. An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis

    SciTech Connect

    Jastrab, Jordan B.; Wang, Tong; Murphy, J. Patrick; Bai, Lin; Hu, Kuan; Merkx, Remco; Huang, Jessica; Chatterjee, Champak; Ovaa, Huib; Gygi, Steven P.; Li, Huilin; Darwin, K. Heran

    2015-03-23

    Mycobacterium tuberculosis encodes a proteasome that is highly similar to eukaryotic proteasomes and is required to cause lethal infections in animals. The only pathway known to target proteins for proteasomal degradation in bacteria is pupylation, which is functionally analogous to eukaryotic ubiquitylation. However, evidence suggests that the M. tuberculosis proteasome contributes to pupylation-independent pathways as well. To identify new proteasome cofactors that might contribute to such pathways, we isolated proteins that bound to proteasomes overproduced in M. tuberculosis and found a previously uncharacterized protein, Rv3780, which formed rings and capped M. tuberculosis proteasome core particles. Rv3780 enhanced peptide and protein degradation by proteasomes in an adenosine triphosphate (ATP)-independent manner. We identified putative Rv3780-dependent proteasome substrates and found that Rv3780 promoted robust degradation of the heat shock protein repressor, HspR. Importantly, an M. tuberculosis Rv3780 mutant had a general growth defect, was sensitive to heat stress, and was attenuated for growth in mice. Collectively, these data demonstrate that ATP-independent proteasome activators are not confined to eukaryotes and can contribute to the virulence of one the world’s most devastating pathogens.

  10. An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis

    PubMed Central

    Jastrab, Jordan B.; Wang, Tong; Murphy, J. Patrick; Bai, Lin; Hu, Kuan; Merkx, Remco; Huang, Jessica; Chatterjee, Champak; Ovaa, Huib; Gygi, Steven P.; Li, Huilin; Darwin, K. Heran

    2015-01-01

    Mycobacterium tuberculosis encodes a proteasome that is highly similar to eukaryotic proteasomes and is required to cause lethal infections in animals. The only pathway known to target proteins for proteasomal degradation in bacteria is pupylation, which is functionally analogous to eukaryotic ubiquitylation. However, evidence suggests that the M. tuberculosis proteasome contributes to pupylation-independent pathways as well. To identify new proteasome cofactors that might contribute to such pathways, we isolated proteins that bound to proteasomes overproduced in M. tuberculosis and found a previously uncharacterized protein, Rv3780, which formed rings and capped M. tuberculosis proteasome core particles. Rv3780 enhanced peptide and protein degradation by proteasomes in an adenosine triphosphate (ATP)-independent manner. We identified putative Rv3780-dependent proteasome substrates and found that Rv3780 promoted robust degradation of the heat shock protein repressor, HspR. Importantly, an M. tuberculosis Rv3780 mutant had a general growth defect, was sensitive to heat stress, and was attenuated for growth in mice. Collectively, these data demonstrate that ATP-independent proteasome activators are not confined to eukaryotes and can contribute to the virulence of one the world's most devastating pathogens. PMID:25831519

  11. An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis

    DOE PAGESBeta

    Jastrab, Jordan B.; Wang, Tong; Murphy, J. Patrick; Bai, Lin; Hu, Kuan; Merkx, Remco; Huang, Jessica; Chatterjee, Champak; Ovaa, Huib; Gygi, Steven P.; et al

    2015-03-23

    Mycobacterium tuberculosis encodes a proteasome that is highly similar to eukaryotic proteasomes and is required to cause lethal infections in animals. The only pathway known to target proteins for proteasomal degradation in bacteria is pupylation, which is functionally analogous to eukaryotic ubiquitylation. However, evidence suggests that the M. tuberculosis proteasome contributes to pupylation-independent pathways as well. To identify new proteasome cofactors that might contribute to such pathways, we isolated proteins that bound to proteasomes overproduced in M. tuberculosis and found a previously uncharacterized protein, Rv3780, which formed rings and capped M. tuberculosis proteasome core particles. Rv3780 enhanced peptide and proteinmore »degradation by proteasomes in an adenosine triphosphate (ATP)-independent manner. We identified putative Rv3780-dependent proteasome substrates and found that Rv3780 promoted robust degradation of the heat shock protein repressor, HspR. Importantly, an M. tuberculosis Rv3780 mutant had a general growth defect, was sensitive to heat stress, and was attenuated for growth in mice. Collectively, these data demonstrate that ATP-independent proteasome activators are not confined to eukaryotes and can contribute to the virulence of one the world’s most devastating pathogens.« less

  12. Modification of Rifamycin Polyketide Backbone Leads to Improved Drug Activity against Rifampicin-resistant Mycobacterium tuberculosis*

    PubMed Central

    Nigam, Aeshna; Almabruk, Khaled H.; Saxena, Anjali; Yang, Jongtae; Mukherjee, Udita; Kaur, Hardeep; Kohli, Puneet; Kumari, Rashmi; Singh, Priya; Zakharov, Lev N.; Singh, Yogendra; Mahmud, Taifo; Lal, Rup

    2014-01-01

    Rifamycin B, a product of Amycolatopsis mediterranei S699, is the precursor of clinically used antibiotics that are effective against tuberculosis, leprosy, and AIDS-related mycobacterial infections. However, prolonged usage of these antibiotics has resulted in the emergence of rifamycin-resistant strains of Mycobacterium tuberculosis. As part of our effort to generate better analogs of rifamycin, we substituted the acyltransferase domain of module 6 of rifamycin polyketide synthase with that of module 2 of rapamycin polyketide synthase. The resulting mutants (rifAT6::rapAT2) of A. mediterranei S699 produced new rifamycin analogs, 24-desmethylrifamycin B and 24-desmethylrifamycin SV, which contained modification in the polyketide backbone. 24-Desmethylrifamycin B was then converted to 24-desmethylrifamycin S, whose structure was confirmed by MS, NMR, and X-ray crystallography. Subsequently, 24-desmethylrifamycin S was converted to 24-desmethylrifampicin, which showed excellent antibacterial activity against several rifampicin-resistant M. tuberculosis strains. PMID:24923585

  13. Modification of rifamycin polyketide backbone leads to improved drug activity against rifampicin-resistant Mycobacterium tuberculosis.

    PubMed

    Nigam, Aeshna; Almabruk, Khaled H; Saxena, Anjali; Yang, Jongtae; Mukherjee, Udita; Kaur, Hardeep; Kohli, Puneet; Kumari, Rashmi; Singh, Priya; Zakharov, Lev N; Singh, Yogendra; Mahmud, Taifo; Lal, Rup

    2014-07-25

    Rifamycin B, a product of Amycolatopsis mediterranei S699, is the precursor of clinically used antibiotics that are effective against tuberculosis, leprosy, and AIDS-related mycobacterial infections. However, prolonged usage of these antibiotics has resulted in the emergence of rifamycin-resistant strains of Mycobacterium tuberculosis. As part of our effort to generate better analogs of rifamycin, we substituted the acyltransferase domain of module 6 of rifamycin polyketide synthase with that of module 2 of rapamycin polyketide synthase. The resulting mutants (rifAT6::rapAT2) of A. mediterranei S699 produced new rifamycin analogs, 24-desmethylrifamycin B and 24-desmethylrifamycin SV, which contained modification in the polyketide backbone. 24-Desmethylrifamycin B was then converted to 24-desmethylrifamycin S, whose structure was confirmed by MS, NMR, and X-ray crystallography. Subsequently, 24-desmethylrifamycin S was converted to 24-desmethylrifampicin, which showed excellent antibacterial activity against several rifampicin-resistant M. tuberculosis strains. PMID:24923585

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

    PubMed

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

    2015-08-01

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

  15. Functional analysis of TPM domain containing Rv2345 of Mycobacterium tuberculosis identifies its phosphatase activity.

    PubMed

    Sinha, Avni; Eniyan, Kandasamy; Sinha, Swati; Lynn, Andrew Michael; Bajpai, Urmi

    2015-07-01

    Mycobacterium tuberculosis (Mtb) is the causal agent of tuberculosis, the second largest infectious disease. With the rise of multi-drug resistant strains of M. tuberculosis, serious challenge lies ahead of us in treating the disease. The availability of complete genome sequence of Mtb has improved the scope for identifying new proteins that would not only further our understanding of biology of the organism but could also serve to discover new drug targets. In this study, Rv2345, a hypothetical membrane protein of M. tuberculosis H37Rv, which is reported to be a putative ortholog of ZipA cell division protein has been assigned function through functional annotation using bioinformatics tools followed by experimental validation. Sequence analysis showed Rv2345 to have a TPM domain at its N-terminal region and predicted it to have phosphatase activity. The TPM domain containing region of Rv2345 was cloned and expressed using pET28a vector in Escherichia coli and purified by Nickel affinity chromatography. The purified TPM domain was tested in vitro and our results confirmed it to have phosphatase activity. The enzyme activity was first checked and optimized with pNPP as substrate, followed by using ATP, which was also found to be used as substrate by the purified protein. Hence sequence analysis followed by in vitro studies characterizes TPM domain of Rv2345 to contain phosphatase activity. PMID:25782739

  16. Enhancement of antibiotic activity by efflux inhibitors against multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil

    PubMed Central

    Coelho, Tatiane; Machado, Diana; Couto, Isabel; Maschmann, Raquel; Ramos, Daniela; von Groll, Andrea; Rossetti, Maria L.; Silva, Pedro A.; Viveiros, Miguel

    2015-01-01

    Drug resistant tuberculosis continues to increase and new approaches for its treatment are necessary. The identification of M. tuberculosis clinical isolates presenting efflux as part of their resistant phenotype has a major impact in tuberculosis treatment. In this work, we used a checkerboard procedure combined with the tetrazolium microplate-based assay (TEMA) to study single combinations between antituberculosis drugs and efflux inhibitors (EIs) against multidrug resistant M. tuberculosis clinical isolates using the fully susceptible strain H37Rv as reference. Efflux activity was studied on a real-time basis by a fluorometric method that uses ethidium bromide as efflux substrate. Quantification of efflux pump genes mRNA transcriptional levels were performed by RT-qPCR. The fractional inhibitory concentrations (FIC) indicated synergistic activity for the interactions between isoniazid, rifampicin, amikacin, ofloxacin, and ethidium bromide plus the EIs verapamil, thioridazine and chlorpromazine. The FICs ranged from 0.25, indicating a four-fold reduction on the MICs, to 0.015, 64-fold reduction. The detection of active efflux by real-time fluorometry showed that all strains presented intrinsic efflux activity that contributes to the overall resistance which can be inhibited in the presence of the EIs. The quantification of the mRNA levels of the most important efflux pump genes on these strains shows that they are intrinsically predisposed to expel toxic compounds as the exposure to subinhibitory concentrations of antibiotics were not necessary to increase the pump mRNA levels when compared with the non-exposed counterpart. The results obtained in this study confirm that the intrinsic efflux activity contributes to the overall resistance in multidrug resistant clinical isolates of M. tuberculosis and that the inhibition of efflux pumps by the EIs can enhance the clinical effect of antibiotics that are their substrates. PMID:25972842

  17. Lung Neutrophils Facilitate Activation of Naïve Antigen Specific CD4+ T Cells During Mycobacterium tuberculosis Infection1

    PubMed Central

    Blomgran, Robert; Ernst, Joel D.

    2012-01-01

    Initiation of the adaptive immune response to Mycobacterium tuberculosis occurs in the lung-draining mediastinal lymph node, and requires transport of M. tuberculosis by migratory dendritic cells (DCs) to the local lymph node. The previously-published observations that: 1) neutrophils are a transiently prominent population of M. tuberculosis-infected cells in the lungs early in infection; and 2) that the peak of infected neutrophils immediately precedes the peak of infected DCs in the lungs, prompted us to characterize the role of neutrophils in the initiation of adaptive immune responses to M. tuberculosis. We found that, although depletion of neutrophils in vivo increased the frequency of M. tuberculosis infected DCs in the lungs, it decreased trafficking of DCs to the mediastinal lymph node. This resulted in delayed activation (CD69 expression) and proliferation of naïve M. tuberculosis Ag85B-specific CD4 T cells in the mediastinal lymph node. To further characterize the role for neutrophils in DC-migration we used a Transwell chemotaxis system and found that DCs that were directly infected by M. tuberculosis migrated poorly in response to CCL19, an agonist for the chemokine receptor CCR7. In contrast, DCs that had acquired M. tuberculosis through uptake of infected neutrophils exhibited unimpaired migration. These results reveal a mechanism wherein neutrophils promote adaptive immune responses to M. tuberculosis by delivering M. tuberculosis to DCs in a form that make DCs more effective initiators of naïve CD4 T cell activation. These observations provide insight into a mechanism for neutrophils to facilitate initiation of adaptive immune responses in tuberculosis. PMID:21555529

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

    PubMed Central

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

    2014-01-01

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

  19. Impaired CXCR1-dependent oxidative defence in active tuberculosis patients.

    PubMed

    Alaridah, Nader; Winqvist, Niclas; Håkansson, Gisela; Tenland, Erik; Rönnholm, Anna; Sturegård, Erik; Björkman, Per; Godaly, Gabriela

    2015-12-01

    Much of the pronounced host inflammatory response that occurs in tuberculosis (TB) is related to failed immunity against the invading pathogen. The G-protein coupled receptors CXCR1 and CXCR2 are implicated in important signal transduction pathways in lung inflammatory responses. We investigated the expression and function of these receptors in a simple whole blood model from 24 patients with pulmonary TB and in subjects with latent TB infection (LTBI). Healthy controls were recruited from close contacts to the pulmonary index patients. We found that pulmonary TB patients had significantly increased CXCR1 expression on blood cells compared to LTBI subjects and controls (p < 0.001). In contrast, LTBI subjects had a significant increase in CXCR2 expression compared to pulmonary TB patients (p < 0.001) and controls (p < 0.01). Leukocyte function, measured as oxidative capacity, was decreased in pulmonary TB patients compared to LTBI and controls (p < 0.001) and correlated with the increased CXCR1 expression. Leukocyte recruitment, measured as the expression of microRNA-223 was increased in pulmonary TB patients compared to LTBI (p < 0.05). We found that variations in receptor expression are linked to disease progression and affect the immune response against Mycobacterium tuberculosis (Mtb). PMID:26316141

  20. Development of cyclobutene- and cyclobutane-functionalized fatty acids with inhibitory activity against Mycobacterium tuberculosis

    PubMed Central

    Sittiwong, Wantanee; Zinniel, Denise K.; Fenton, Robert J.; Marshall, Darrel; Story, Courtney B.; Kim, Bohkyung; Lee, Ji-Young; Powers, Robert; Barletta, Raúl G.

    2014-01-01

    Eleven fatty acid analogs incorporating four-membered carbocycles (cyclobutenes, cyclobutanes, cyclobutanones, and cyclobutanols) were investigated for the ability to inhibit growth of Mycobacterium smegmatis (Msm) and Mycobacterium tuberculosis (Mtb). A number of the analogs displayed inhibitory activity against both mycobacterial species in minimal media. Several of the molecules displayed potent levels of inhibition against Mtb with MIC values equal to or below those obtained with the anti-tuberculosis drugs D-cycloserine and isoniazid. In contrast, two of the analogs displaying the greatest activity against Mtb failed to inhibit E. coli growth under either set of conditions. Thus, the active molecules identified here (1, 2, 6, and 8) may provide the basis for development of anti-mycobacterial agents against Mtb. PMID:24902951

  1. Multifunctional CD4(+) T cells correlate with active Mycobacterium tuberculosis infection.

    PubMed

    Caccamo, Nadia; Guggino, Giuliana; Joosten, Simone A; Gelsomino, Giuseppe; Di Carlo, Paola; Titone, Lucina; Galati, Domenico; Bocchino, Marialuisa; Matarese, Alessandro; Salerno, Alfredo; Sanduzzi, Alessandro; Franken, Willeke P J; Ottenhoff, Tom H M; Dieli, Francesco

    2010-08-01

    Th1 CD4(+) T cells and their derived cytokines are crucial for protection against Mycobacterium tuberculosis. Using multiparametric flow cytometry, we have evaluated the distribution of seven distinct functional states (IFN-?/IL-2/TNF-? triple expressors, IFN-?/IL-2, IFN-?/TNF-? or TNF-?/IL-2 double expressors or IFN-?, IL-2 or TNF-? single expressors) of CD4(+) T cells in individuals with latent M. tuberculosis infection (LTBI) and active tuberculosis (TB). We found that triple expressors, while detectable in 85-90%TB patients, were only present in 10-15% of LTBI subjects. On the contrary, LTBI subjects had significantly higher (12- to 15-fold) proportions of IL-2/IFN-? double and IFN-? single expressors as compared with the other CD4(+) T-cell subsets. Proportions of the other double or single CD4(+) T-cell expressors did not differ between TB and LTBI subjects. These distinct IFN-?, IL-2 and TNF-? profiles of M. tuberculosis-specific CD4(+) T cells seem to be associated with live bacterial loads, as indicated by the decrease in frequency of multifunctional T cells in TB-infected patients after completion of anti-mycobacterial therapy. Our results suggest that phenotypic and functional signatures of CD4(+) T cells may serve as immunological correlates of protection and curative host responses, and be a useful tool to monitor the efficacy of anti-mycobacterial therapy. PMID:20540114

  2. Detection of Tuberculosis Infection Hotspots Using Activity Spaces Based Spatial Approach in an Urban Tokyo, from 2003 to 2011

    PubMed Central

    Izumi, Kiyohiko; Ohkado, Akihiro; Uchimura, Kazuhiro; Murase, Yoshiro; Tatsumi, Yuriko; Kayebeta, Aya; Watanabe, Yu; Ishikawa, Nobukatsu

    2015-01-01

    Background Identifying ongoing tuberculosis infection sites is crucial for breaking chains of transmission in tuberculosis-prevalent urban areas. Previous studies have pointed out that detection of local accumulation of tuberculosis patients based on their residential addresses may be limited by a lack of matching between residences and tuberculosis infection sites. This study aimed to identify possible tuberculosis hotspots using TB genotype clustering statuses and a concept of “activity space”, a place where patients spend most of their waking hours. We further compared the spatial distribution by different residential statuses and describe urban environmental features of the detected hotspots. Methods Culture-positive tuberculosis patients notified to Shinjuku city from 2003 to 2011 were enrolled in this case-based cross-sectional study, and their demographic and clinical information, TB genotype clustering statuses, and activity space were collected. Spatial statistics (Global Moran’s I and Getis-Ord Gi* statistics) identified significant hotspots in 152 census tracts, and urban environmental features and tuberculosis patients’ characteristics in these hotspots were assessed. Results Of the enrolled 643 culture-positive tuberculosis patients, 416 (64.2%) were general inhabitants, 42 (6.5%) were foreign-born people, and 184 were homeless people (28.6%). The percentage of overall genotype clustering was 43.7%. Genotype-clustered general inhabitants and homeless people formed significant hotspots around a major railway station, whereas the non-clustered general inhabitants formed no hotspots. This suggested the detected hotspots of activity spaces may reflect ongoing tuberculosis transmission sites and were characterized by smaller residential floor size and a higher proportion of non-working households. Conclusions Activity space-based spatial analysis suggested possible TB transmission sites around the major railway station and it can assist in further comprehension of TB transmission dynamics in an urban setting in Japan. PMID:26382251

  3. High-throughput screen identifies small molecule inhibitors targeting acetyltransferase activity of Mycobacterium tuberculosis GlmU.

    PubMed

    Rani, Chitra; Mehra, Rukmankesh; Sharma, Rashmi; Chib, Reena; Wazir, Priya; Nargotra, Amit; Khan, Inshad Ali

    2015-12-01

    N-acetylglucosamine-1-phosphate uridyltransferase (GlmU) is a pivotal bifunctional enzyme, its N and C terminal domains catalyzes uridyltransferase and acetyltransferase activities, respectively. Final product of GlmU catalyzed reaction, uridine-diphospho-N-acetylglucosamine (UDP-GlcNAc), acts as sugar donor providing GlcNAc residues in the synthesis of peptidoglycan and a disaccharide linker (D-N-GlcNAc-1-rhamnose), the key structural components of Mycobacterium tuberculosis (M. tuberculosis) cell wall. In the present study, we have searched new inhibitors against acetyltransferase activity of M. tuberculosis GlmU. A subset of 1607 synthetic compounds, selected through dual approach i.e., in-silico and whole cell screen against 20,000 compounds from ChemBridge library, was further screened using an in-vitro high throughput bioassay to identify inhibitors of acetyltransferase domain of M. tuberculosis GlmU. Four compounds were found to inhibit GlmU enzyme specific to acetyltransferase activity, with IC50 values ranging from 9 to 70 ?M. Two compounds (6624116, 5655606) also exhibited whole cell activity against drug susceptible as well as drug resistant M. tuberculosis. These two compounds also exhibited increased anti-TB activity when tested in combination with rifampicin, isoniazid and ethambutol, however 5655606 was cytotoxic to eukaryotic cell line. These results demonstrate that identified chemical scaffolds can be used as inhibitors of M. tuberculosis cell wall enzyme after optimizations for future anti-TB drug development program. PMID:26318557

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

    PubMed

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

    2014-10-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2012-01-01

    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. PMID:22719887

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

    PubMed Central

    Marín, Nancy D.; París, Sara C.; Rojas, Mauricio

    2012-01-01

    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. PMID:22914361

  9. Pathophysiology of Antigen 85 in Patients with Active Tuberculosis: Antigen 85 Circulates as Complexes with Fibronectin and Immunoglobulin G

    PubMed Central

    Bentley-Hibbert, Stuart I.; Quan, Xin; Newman, Thomas; Huygen, Kris; Godfrey, Henry P.

    1999-01-01

    Antigen 85 (Ag85) complex proteins are major secretory products of Mycobacterium tuberculosis and induce strong cellular and humoral immune responses in infected experimental animals and human beings. We have previously shown that nanogram doses of these 30- to 32-kDa fibronectin-binding proteins inhibit local expression of delayed hypersensitivity by a T-cell fibronectin-dependent mechanism. Circulating levels of Ag85 might be expected to be elevated in patients with active tuberculosis and possibly to play a role in systemic anergy in these patients. To test this hypothesis, Ag85 was measured in serum and urine by a monoclonal antibody-based dot immunobinding assay in 56 patients and controls with known skin test reactivity. Median serum Ag85 levels were 50- to 150-fold higher in patients with active tuberculosis than in patients with active M. avium-intracellulare disease or other nontuberculous pulmonary disease or in healthy controls (P < 0.001). The median and range of serum Ag85 in patients with active tuberculosis was not significantly different between skin test-positive and -negative subjects. Patients with active M. avium disease could be distinguished from those with disease due to M. tuberculosis by monoclonal anti-Ag85 antibodies of appropriate specificities. No increases in urinary Ag85 were detected in any patient, regardless of the Ag85 level in serum. Chromatographic analysis and immunoprecipitation studies of serum revealed that Ag85 existed in the serum of these patients complexed to either fibronectin or immunoglobulin G (IgG). Uncomplexed circulating Ag85 was demonstrable in serum from fewer than 20% of patients with active tuberculosis. In patients with active tuberculosis, Ag85 is therefore likely to circulate primarily as complexes with plasma fibronectin and IgG rather than in unbound form. The existence of Ag85 complexes with plasma proteins would account for its lack of urinary clearance. PMID:9916062

  10. [Managment of tuberculosis in an University of Campania].

    PubMed

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

    2012-01-01

    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

  11. Biomarkers for risk of developing active tuberculosis in contacts of TB patients: a prospective cohort study.

    PubMed

    Rakotosamimanana, Niaina; Richard, Vincent; Raharimanga, Vaomalala; Gicquel, Brigitte; Doherty, T Mark; Zumla, Alimuddin; Rasolofo Razanamparany, Voahangy

    2015-10-01

    Identifying those Mycobacterium tuberculosis latent-infected individuals most at risk of developing active tuberculosis (TB) using routine clinical and laboratory tests remains a huge challenge in TB control efforts. We conducted a prospective longitudinal study of clinical and laboratory markers associated with the risk of developing active TB in contacts with latent M. tuberculosis infection.HIV-negative household contacts (n=296) of pulmonary TB patients underwent monitoring of clinical features, full blood cell counts, tuberculin skin text (TST) and chest radiography performed regularly during 18?months of follow-up. Paired statistical tests, a Kaplan-Meier analysis and Cox proportional hazard modelling were performed on variables between contacts progressing or not progressing to active TB.The appearance of TB disease symptoms in contacts was significantly associated with an elevated peripheral percentage of blood monocytes (adjusted hazard ratio (aHR) 6.25, 95% CI 1.63-23.95; p<0.01), a ?14?mm TST response (aHR 5.72, 95% CI 1.22-26.80; p=0.03) and an increased monocyte:lymphocyte ratio (aHR 4.97, 95% CI 1.3-18.99; p=0.03). Among contacts having TST ?14?mm, a strong association with risk of progression to TB was found with an elevated blood monocyte percentage (aHR 8.46, 95% CI 1.74-41.22; p<0.01).Elevated percentage of peripheral blood monocytes plus an elevated TST response are potential biomarkers for identifying contacts of TB patients at highest risk of developing active TB. PMID:26250497

  12. Identification and Characterization of Lipase Activity and Immunogenicity of LipL from Mycobacterium tuberculosis

    PubMed Central

    Cao, Jun; Dang, Guanghui; Li, Huafang; Li, Tiantian; Yue, Zhiguo; Li, Na; Liu, Yajun; Liu, Siguo; Chen, Liping

    2015-01-01

    Lipids and lipid-metabolizing esterases/lipases are highly important for the mycobacterial life cycle and, possibly, for mycobacterial virulence. In this study, we expressed 10 members of the Lip family of Mycobacterium tuberculosis. Among the 10 proteins, LipL displayed a significantly high enzymatic activity for the hydrolysis of long-chain lipids. The optimal temperature for the lipase activity of LipL was demonstrated to be 37°C, and the optimal pH was 8.0. The lipase active center was not the conserved motif G-x-S-x-G, but rather the S-x-x-K and GGG motifs, and the key catalytic amino acid residues were identified as G50, S88, and K91, as demonstrated through site-directed mutagenesis experiments. A three-dimensional modeling structure of LipL was constructed, which showed that the GGG motif was located in the surface of a pocket structure. Furthermore, the subcellular localization of LipL was demonstrated to be on the mycobacterial surface by Western blot analysis. Our results revealed that the LipL protein could induce a strong humoral immune response in humans and activate a CD8+ T cell-mediated response in mice. Overall, our study identified and characterized a novel lipase denoted LipL from M. tuberculosis, and demonstrated that LipL functions as an immunogen that activates both humoral and cell-mediated responses. PMID:26398213

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

    PubMed Central

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

    2009-01-01

    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 Mycobacterium bovis BCG vaccination is mandatory at birth. A total of 305 patients with active tuberculosis, 18 patients with nontuberculosis lung diseases, and 202 healthy controls were recruited in this study. Among them, 156 individuals were simultaneously tested for IFN-? responses by the commercial QuantiFERON-TB Gold in-tube (QFT-IT) assay. Tuberculin skin tests (TST) were performed with 202 healthy controls. The overall sensitivities of the ELISPOT and QFT-IT assays for active tuberculosis were 83.60% and 80.85%, respectively; the specificities were 76.6% and 73.26%, respectively. The IFN-? ELISPOT responses, but not those of the TST, were significantly correlated with TB exposure (r = ?0.6040, P < 0.0001). The sensitivities of the ELISPOT assay varied for patients with different forms of tuberculosis, with the highest sensitivity for patients with sputum-positive pulmonary tuberculosis (89.89%) and the lowest for those with tuberculous meningitis (62.5%). In conclusion, the IFN-? ELISPOT assay is a useful adjunct to current tests for diagnosis of active TB in China. The ELISPOT assay is more accurate than TST in identifying TB infections. PMID:19339489

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

    PubMed

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

    2013-01-01

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

  15. Distinguishing Latent from Active Mycobacterium tuberculosis Infection Using Elispot Assays: Looking Beyond Interferon-gamma

    PubMed Central

    Tincati, Camilla; Cappione III, Amedeo J.; Snyder-Cappione, Jennifer E.

    2012-01-01

    Mycobacterium tuberculosis (MTB) is a global heath epidemic, its threat amplified by HIV infection and the emergence of multidrug-resistant tuberculosis (MDR-TB). Interferon (IFN)-gamma release assays (IGRAs) have improved the accuracy of detection of MTB exposure in some subject groups as compared to the Tuberculin Skin Test (TST). However, as IFN-gamma is produced by both fully rested and more recently activated populations of memory T cells, it is not surprising that the measurement of this cytokine alone cannot accurately distinguish Latent TB Infected (LTBI) subjects from those with active (infectious) disease. Accurate and rapid diagnosis of infectious individuals would allow medication to be properly allocated and other actions taken to more effectively curtail MTB spread. Analysis of multi-cytokine profiles ex vivo after stimulation of PBMCs from LTBI and active MTB subjects indicate the real possibility of successfully discerning these two disease states within 24 hours of a subject’s blood draw. Due to the unparalleled sensitivity, low cost, and ease of use of Elispot assays, we propose that via a multiplex Elispot platform the accurate distinction of LTBI from active MTB-infected individuals is within reach. PMID:24710416

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

    PubMed Central

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

    2007-01-01

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

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

    PubMed

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

    2015-02-01

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

  18. Tuberculosis and nutrition

    PubMed Central

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

    2009-01-01

    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. PMID:20165588

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

    E-print Network

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

  20. Post-treatment change in Mycobacterium tuberculosis antigen-stimulated tumor necrosis factor-alpha release in patients with active tuberculosis

    PubMed Central

    Kim, Chang Ho; Yoo, Seung Soo; Lee, Shin Yup; Cha, Seung Ick; Park, Jae Yong

    2015-01-01

    Background Monitoring tuberculosis (TB) treatment response remains challenging due to lack of reliable laboratory markers. In recent years, increased efforts have been exerted toward development of new biomarkers reflecting treatment response appropriately. While performance of interferon-gamma release assays (IGRAs) to monitor anti-TB treatment has been extensively evaluated, there is no data about post-treatment changes in Mycobacterium tuberculosis (MTB) antigen-stimulated tumor necrosis factor-alpha (TNF-?) release in active TB patients. Herein, we explored whether the MTB antigen-stimulated TNF-? release would be useful for monitoring responses to anti-TB treatment. Methods We compared unstimulated (TNF-?Nil), MTB antigen-stimulated (TNF-?Ag), and MTB antigen-stimulated minus unstimulated TNF-? levels (TNF-?Ag-Nil) in supernatants from QuantiFERON-TB Gold In-Tube tests before and after treatment in 16 active TB patients, 25 latent TB infection (LTBI) subjects, and 10 healthy controls (HC). Results TNF-?Ag and TNF-?Ag-Nil levels decreased significantly after treatment in patients with active TB. In addition, TNF-?Nil, TNF-?Ag, and TNF-?Ag-Nil levels were significantly higher in untreated active TB patients compared to LTBI subjects and HC. Conclusions This finding cautiously suggests that MTB Ag-stimulated TNF-? response may be a potential adjunctive marker for monitoring treatment response in active TB patients. PMID:26101647

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

    SciTech Connect

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

    2006-01-01

    Novel chemotherapeutics for treating multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) are required to combat the spread of tuberculosis, a disease that kills more than 2 million people annually. Using structure-based drug design, we have developed a series of alkyl diphenyl ethers that are uncompetitive inhibitors of InhA, the enoyl reductase enzyme in the MTB fatty acid biosynthesis pathway. The most potent compound has a Ki{prime} value of 1 nM for InhA and MIC{sub 99} values of 2-3 {micro}g mL{sup -1} (6-10 {micro}M) for both drug-sensitive and drug-resistant strains of MTB. Overexpression of InhA in MTB results in a 9-12-fold increase in MIC{sub 99}, consistent with the belief that these compounds target InhA within the cell. In addition, transcriptional response studies reveal that the alkyl diphenyl ethers fail to upregulate a putative efflux pump and aromatic dioxygenase, detoxification mechanisms that are triggered by the lead compound triclosan. These diphenyl ether-based InhA inhibitors do not require activation by the mycobacterial KatG enzyme, thereby circumventing the normal mechanism of resistance to the front line drug isoniazid (INH) and thus accounting for their activity against INH-resistant strains of MTB.

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

    PubMed

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

    2013-05-01

    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

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

    PubMed Central

    2014-01-01

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

  4. Serological Testing Versus Other Strategies for Diagnosis of Active Tuberculosis in India: A Cost-Effectiveness Analysis

    PubMed Central

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

    2011-01-01

    Background Undiagnosed and misdiagnosed tuberculosis (TB) drives the epidemic in India. Serological (antibody detection) TB tests are not recommended by any agency, but widely used in many countries, including the Indian private sector. The cost and impact of using serology compared with other diagnostic techniques is unknown. Methods and Findings Taking a patient cohort conservatively equal to the annual number of serological tests done in India (1.5 million adults suspected of having active TB), we used decision analysis to estimate costs and effectiveness of sputum smear microscopy (US$3.62 for two smears), microscopy plus automated liquid culture (mycobacterium growth indicator tube [MGIT], US$20/test), and serological testing (anda-tb ELISA, US$20/test). Data on test accuracy and costs were obtained from published literature. We adopted the perspective of the Indian TB control sector and an analysis frame of 1 year. Our primary outcome was the incremental cost per disability-adjusted life year (DALY) averted. We performed one-way sensitivity analysis on all model parameters, with multiway sensitivity analysis on variables to which the model was most sensitive. If used instead of sputum microscopy, serology generated an estimated 14,000 more TB diagnoses, but also 121,000 more false-positive diagnoses, 102,000 fewer DALYs averted, and 32,000 more secondary TB cases than microscopy, at approximately four times the incremental cost (US$47.5 million versus US$11.9 million). When added to high-quality sputum smears, MGIT culture was estimated to avert 130,000 incremental DALYs at an incremental cost of US$213 per DALY averted. Serology was dominated by (i.e., more costly and less effective than) MGIT culture and remained less economically favorable than sputum smear or TB culture in one-way and multiway sensitivity analyses. Conclusions In India, sputum smear microscopy remains the most cost-effective diagnostic test available for active TB; efforts to increase access to quality-assured microscopy should take priority. In areas where high-quality microscopy exists and resources are sufficient, MGIT culture is more cost-effective than serology as an additional diagnostic test for TB. These data informed a recently published World Health Organization policy statement against serological tests. Please see later in the article for the Editors' Summary PMID:21857810

  5. Pulmonary Tuberculoma and Miliary Tuberculosis in Silicosis

    PubMed Central

    Verma, Sanjeev Kumar; Karmakar, Saurabh

    2013-01-01

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

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

    PubMed

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

    2015-07-13

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

  7. The association between sterilizing activity and drug distribution into tuberculosis lesions.

    PubMed

    Prideaux, Brendan; Via, Laura E; Zimmerman, Matthew D; Eum, Seokyong; Sarathy, Jansy; O'Brien, Paul; Chen, Chao; Kaya, Firat; Weiner, Danielle M; Chen, Pei-Yu; Song, Taeksun; Lee, Myungsun; Shim, Tae Sun; Cho, Jeong Su; Kim, Wooshik; Cho, Sang Nae; Olivier, Kenneth N; Barry, Clifton E; Dartois, Véronique

    2015-10-01

    Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside. In contrast, moxifloxacin, which is active in vitro against a subpopulation of Mycobacterium tuberculosis that persists in specific niches under drug pressure and has achieved treatment shortening in mice, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug-resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration may contribute to treatment outcome has wide implications for TB. PMID:26343800

  8. Host Protein Biomarkers Identify Active Tuberculosis in HIV Uninfected and Co-infected Individuals

    PubMed Central

    Achkar, Jacqueline M.; Cortes, Laetitia; Croteau, Pascal; Yanofsky, Corey; Mentinova, Marija; Rajotte, Isabelle; Schirm, Michael; Zhou, Yiyong; Junqueira-Kipnis, Ana Paula; Kasprowicz, Victoria O.; Larsen, Michelle; Allard, René; Hunter, Joanna; Paramithiotis, Eustache

    2015-01-01

    Biomarkers for active tuberculosis (TB) are urgently needed to improve rapid TB diagnosis. The objective of this study was to identify serum protein expression changes associated with TB but not latent Mycobacterium tuberculosis infection (LTBI), uninfected states, or respiratory diseases other than TB (ORD). Serum samples from 209 HIV uninfected (HIV?) and co-infected (HIV+) individuals were studied. In the discovery phase samples were analyzed via liquid chromatography and mass spectrometry, and in the verification phase biologically independent samples were analyzed via a multiplex multiple reaction monitoring mass spectrometry (MRM-MS) assay. Compared to LTBI and ORD, host proteins were significantly differentially expressed in TB, and involved in the immune response, tissue repair, and lipid metabolism. Biomarker panels whose composition differed according to HIV status, and consisted of 8 host proteins in HIV? individuals (CD14, SEPP1, SELL, TNXB, LUM, PEPD, QSOX1, COMP, APOC1), or 10 host proteins in HIV+ individuals (CD14, SEPP1, PGLYRP2, PFN1, VASN, CPN2, TAGLN2, IGFBP6), respectively, distinguished TB from ORD with excellent accuracy (AUC = 0.96 for HIV? TB, 0.95 for HIV+ TB). These results warrant validation in larger studies but provide promise that host protein biomarkers could be the basis for a rapid, blood-based test for TB. PMID:26501113

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  11. CFP-10 from Mycobacterium tuberculosis Selectively Activates Human Neutrophils through a Pertussis Toxin-Sensitive Chemotactic Receptor

    PubMed Central

    Björnsdottir, Halla; Winther, Malene; Christenson, Karin; Oprea, Tudor; Karlsson, Anna; Forsman, Huamei; Dahlgren, Claes; Bylund, Johan

    2014-01-01

    Upon infection with Mycobacterium tuberculosis, neutrophils are massively recruited to the lungs, but the role of these cells in combating the infection is poorly understood. Through a type VII secretion system, M. tuberculosis releases a heterodimeric protein complex, containing a 6-kDa early secreted antigenic target (ESAT-6) and a 10-kDa culture filtrate protein (CFP-10), that is essential for virulence. Whereas the ESAT-6 component possesses multiple virulence-related activities, no direct biological activity of CFP-10 has been shown, and CFP-10 has been described as a chaperone protein for ESAT-6. We here show that the ESAT-6:CFP-10 complex induces a transient release of Ca2+ from intracellular stores in human neutrophils. Surprisingly, CFP-10 rather than ESAT-6 was responsible for triggering the Ca2+ response, in a pertussis toxin-sensitive manner, suggesting the involvement of a G-protein-coupled receptor. In line with this, the response was accompanied by neutrophil chemotaxis and activation of the superoxide-producing NADPH-oxidase. Neutrophils were unique among leukocytes in responding to CFP-10, as monocytes and lymphocytes failed to produce a Ca2+ signal upon stimulation with the M. tuberculosis protein. Hence, CFP-10 may contribute specifically to neutrophil recruitment and activation during M. tuberculosis infection, representing a novel biological role for CFP-10 in the ESAT-6:CFP-10 complex, beyond the previously described chaperone function. PMID:25332123

  12. Evaluation of Gamma Interferon Release Assays Using Mycobacterium tuberculosis Antigens for Diagnosis of Latent and Active Tuberculosis in Mycobacterium bovis BCG-Vaccinated Populations?

    PubMed Central

    Zhang, Shu; Shao, Lingyun; Mo, Ling; Chen, Jiazhen; Wang, Feifei; Meng, Chengyan; Zhong, Min; Qiu, Lihua; Wu, Meiying; Weng, Xinhua; Zhang, Wenhong

    2010-01-01

    T-cell-based gamma interferon (IFN-?) release assays (IGRAs) using Mycobacterium tuberculosis-specific antigens have shown higher sensitivity and specificity than the routine tuberculin skin test (TST). However, the effects of Mycobacterium bovis BCG vaccination and anti-tuberculosis (TB) treatment on dynamic T-cell responses to M. tuberculosis-specific antigens in active TB cases have rarely been investigated in regions where TB is endemic. Eighty-nine patients with active pulmonary TB (ATB) and 57 healthy controls (HC) from China were recruited and tested by sputum smear and culture, TSTs, and IGRAs with M. tuberculosis-specific antigens ESAT-6 and CFP-10 (T-SPOT.TB) as well as purified protein derivative (PPD) stimulation. All 146 participants were screened by the T-SPOT.TB assay at recruitment. T-SPOT.TB-positive rates in ATB and HC groups were 87.6% (78/89) and 21.1% (12/57), respectively. Of 38 ATB patients who were both TST and T-SPOT.TB tested, the positive rates were 73.7% (28/38) and 94.7% (36/38), respectively (P = 0.0215), and those in the HC group were 62.3% (33/53) and 18.9% (10/53), respectively (P < 0.0001). The T-SPOT.TB-positive rates declined during TB treatment and were 94.4% (51/54), 86.4% (19/22), and 61.5% (8/13) for ATB patients receiving 0- to 1-month, 1- to 3-month, and 3- to 6-month anti-TB treatment, respectively. The IGRA is a most promising test for both active TB and latent TB infection (LTBI) diagnosis due to the improvement of its specificity and convenience, especially in the Mycobacterium bovis BCG-vaccinated population. Furthermore, the T-SPOT.TB assay using ESAT-6 and CFP-10 in ATB patients during anti-TB treatment could serve as a potential predictor of therapeutic efficacy. PMID:20943878

  13. Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response

    PubMed Central

    Adekambi, Toidi; Ibegbu, Chris C.; Cagle, Stephanie; Kalokhe, Ameeta S.; Wang, Yun F.; Hu, Yijuan; Day, Cheryl L.; Ray, Susan M.; Rengarajan, Jyothi

    2015-01-01

    BACKGROUND. The identification and treatment of individuals with tuberculosis (TB) is a global public health priority. Accurate diagnosis of pulmonary active TB (ATB) disease remains challenging and relies on extensive medical evaluation and detection of Mycobacterium tuberculosis (Mtb) in the patient’s sputum. Further, the response to treatment is monitored by sputum culture conversion, which takes several weeks for results. Here, we sought to identify blood-based host biomarkers associated with ATB and hypothesized that immune activation markers on Mtb-specific CD4+ T cells would be associated with Mtb load in vivo and could thus provide a gauge of Mtb infection. METHODS. Using polychromatic flow cytometry, we evaluated the expression of immune activation markers on Mtb-specific CD4+ T cells from individuals with asymptomatic latent Mtb infection (LTBI) and ATB as well as from ATB patients undergoing anti-TB treatment. RESULTS. Frequencies of Mtb-specific IFN-?+CD4+ T cells that expressed immune activation markers CD38 and HLA-DR as well as intracellular proliferation marker Ki-67 were substantially higher in subjects with ATB compared with those with LTBI. These markers accurately classified ATB and LTBI status, with cutoff values of 18%, 60%, and 5% for CD38+IFN-?+, HLA-DR+IFN-?+, and Ki-67+IFN-?+, respectively, with 100% specificity and greater than 96% sensitivity. These markers also distinguished individuals with untreated ATB from those who had successfully completed anti-TB treatment and correlated with decreasing mycobacterial loads during treatment. CONCLUSION. We have identified host blood-based biomarkers on Mtb-specific CD4+ T cells that discriminate between ATB and LTBI and provide a set of tools for monitoring treatment response and cure. TRIAL REGISTRATION. Registration is not required for observational studies. FUNDING. This study was funded by Emory University, the NIH, and the Yerkes National Primate Center. PMID:25822019

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

    PubMed

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

    2004-01-30

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

  15. Comparison of tuberculin skin testing and T-SPOT.TB for diagnosis of latent and active tuberculosis.

    PubMed

    Simsek, Hulya; Alpar, Sibel; Ucar, Nazire; Aksu, Funda; Ceyhan, Ismail; Gözalan, Aysegul; Cesur, Salih; Ertek, Mustafa

    2010-03-01

    The T-SPOT.TB test does not cross-react with Bacille Calmette-Guérin or most non-tuberculosis mycobacterium species, and is based on IFN-gamma responses to Mycobacterium tuberculosis-specific antigens. The objective of this study was to compare tuberculin skin test (TST) with T-SPOT.TB results used in the diagnosis of active tuberculosis (TB) as well as latent tuberculosis infection (LTBI). A total of 136 subjects participated in three different groups (47 patients with active pulmonary TB, 47 healthy persons without M. tuberculosis exposure, and 42 hospital members with a history of close contact with active TB patients). The T-SPOT.TB sensitivity (83.0%) and the negative predictive value (NPV) (82.6%) in the diagnosis of active TB were significantly higher than those of TST. The sensitivity and NPV of the TST were 38.3 and 60.8%, respectively. The T-SPOT.TB specificity (80.9%) and positive predictive value (81.3%) were lower than those of TST (95.7 and 90.0%, respectively). The performance of T-SPOT.TB and TST for diagnosing LTBI was the same (54.8%). T-SPOT.TB was superior in terms of sensitivity (83.0%); TST detected only 18, whereas T-SPOT.TB test detected 39 out of 47 patients with active TB. T-SPOT.TB is thought to have better performance than TST due to false-negative results in diagnosing active TB. However, it is considered that large prospective longitudinal studies are needed for diagnosing LTBI. PMID:20332570

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

    PubMed Central

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

    2014-01-01

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

  17. The increased risk of active tuberculosis disease in patients with dermatomyositis - a nationwide retrospective cohort study.

    PubMed

    Wu, Ping-Hsun; Lin, Yi-Ting; Yang, Yi-Hsin; Lin, Yu-Chih; Lin, Yi-Ching

    2015-01-01

    The risk of active tuberculosis (TB) in patients with dermatomyositis (DM) is poorly understood. The cohort study aimed to investigate the association between DM and the risk of active TB disease. We conducted a population based study on 4,958 patients with newly diagnosed DM and 19,832 matched controls according to age, sex, and index date between 1998 and 2008. The hazard ratios (HRs) and cumulative incidences of active TB disease between DM patients and controls were analyzed. During the study period, a total of 85 (1.7%) DM patients developed active TB disease, which was significantly higher than that of non-DM patients (0.64%). The incidence rate of active TB disease was higher among DM patients than controls (incidence rate ratio 2.95; 95% confidence interval [CI], 2.24 to 3.88). The Cox regression model demonstrated significantly higher active TB disease rate among DM patients compared with controls (adjusted HR, 2.64; 95% CI, 1.97 to 3.54; p?active TB included male sex, diabetes mellitus comorbidity, and use of corticosteroids and azathioprine in DM patients. In conclusion, DM patients are at a greater risk for active TB disease. PMID:26573418

  18. The increased risk of active tuberculosis disease in patients with dermatomyositis – a nationwide retrospective cohort study

    PubMed Central

    Wu, Ping-Hsun; Lin, Yi-Ting; Yang, Yi-Hsin; Lin, Yu-Chih; Lin, Yi-Ching

    2015-01-01

    The risk of active tuberculosis (TB) in patients with dermatomyositis (DM) is poorly understood. The cohort study aimed to investigate the association between DM and the risk of active TB disease. We conducted a population based study on 4,958 patients with newly diagnosed DM and 19,832 matched controls according to age, sex, and index date between 1998 and 2008. The hazard ratios (HRs) and cumulative incidences of active TB disease between DM patients and controls were analyzed. During the study period, a total of 85 (1.7%) DM patients developed active TB disease, which was significantly higher than that of non-DM patients (0.64%). The incidence rate of active TB disease was higher among DM patients than controls (incidence rate ratio 2.95; 95% confidence interval [CI], 2.24 to 3.88). The Cox regression model demonstrated significantly higher active TB disease rate among DM patients compared with controls (adjusted HR, 2.64; 95% CI, 1.97 to 3.54; p?active TB included male sex, diabetes mellitus comorbidity, and use of corticosteroids and azathioprine in DM patients. In conclusion, DM patients are at a greater risk for active TB disease. PMID:26573418

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

    PubMed Central

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

    2014-01-01

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

  20. Tuberculosis among Children in Alaska.

    ERIC Educational Resources Information Center

    Gessner, Bradford D.

    1997-01-01

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

  1. PPE2 protein of Mycobacterium tuberculosis may inhibit nitric oxide in activated macrophages.

    PubMed

    Bhat, Khalid Hussain; Das, Arghya; Srikantam, Aparna; Mukhopadhyay, Sangita

    2013-04-01

    Although the pathophysiological role of PE/PPE proteins of Mycobacterium tuberculosis is yet to be fully understood, recent evidence shows that these proteins play important roles in antigenic diversity, as well as in host-pathogen interactions and mycobacterial pathogenesis. Most of the PE/PPE proteins are highly expressed in pathogenic bacteria, pointing to their role in the pathogenesis of mycobacteria. Here, we provide an overview of our work in progress on a specific PPE protein, PPE2 (Rv0256c), which may inhibit nitric oxide (NO) production in activated macrophages. As NO and its by-products are considered to be toxic to bacilli, it is possible that the bacilli recruit Rv0256c in order to inhibit higher production of NO during infection. PMID:23448669

  2. Guanidinium compounds with sub-micromolar activities against Mycobacterium tuberculosis. Synthesis, characterization and biological evaluations.

    PubMed

    Massimba-Dibama, Hugues; Mourer, Maxime; Constant, Patricia; Daffé, Mamadou; Regnouf-de-Vains, Jean-Bernard

    2015-09-01

    Seven polycharged species, incorporating 1, 2, 3, 4 and 6 guanidine arms organized around a benzene core were synthesized and assayed as anti-mycobacterial agents against Mycobacterium tuberculosis. They display MIC values comprised between 25 and 12.5 ?M (close to ethambutol EMB) for the mono- and the hexa-substituted derivatives, and 0.8 ?M (close to isoniazid and streptomycin) for the tri-substituted derivative. The three bi- and the tetra-substituted analogs displayed MIC values of ca. 6.5-3.0 ?M. The latter were also evaluated against the isoniazid-resistant MYC5165 strain, resulting in highly interesting micromolar or sub-micromolar MIC, ca. 4-125 times more active than isoniazid. These preliminary results are attractive for the development of new anti-TB agents. PMID:26254828

  3. Prevalence of Pulmonary Tuberculosis among Prison Inmates in Ethiopia, a Cross-Sectional Study

    PubMed Central

    Ali, Solomon; Haileamlak, Abraham; Wieser, Andreas; Pritsch, Michael; Heinrich, Norbert; Loscher, Thomas; Hoelscher, Michael; Rachow, Andrea

    2015-01-01

    Setting Tuberculosis (TB) is one of the major health problems in prisons. Objective This study was done to assess the prevalence and determinants of active tuberculosis in Ethiopian prisons. Design A cross-sectional study was conducted from January 2013 to December 2013 in 13 zonal prisons. All incarcerated inmates underwent TB symptom screening according to WHO criteria. From identified TB-suspects two sputum samples were analyzed using smear microscopy and solid culture. A standardized questionnaire assessing TB risk factors was completed for each TB suspect. Results 765 (4.9%) TB suspects were identified among 15,495 inmates. 51 suspects were already on anti-TB treatment (6.67%) and 20 (2.8%) new culture-confirmed TB cases were identified in the study, resulting in an overall TB prevalence of 458.1/100,000 (95%CI: 350-560/100,000). Risk factors for active TB were alcohol consumption, contact with a TB case before incarceration and no window in prison cell. HIV prevalence was not different between TB suspects and active TB cases. Further, the TB burden in prisons increased with advancing distance from the capital Addis Ababa. Conclusions The overall TB prevalence in Ethiopian prisons was high and extremely variable among different prisons. TB risk factors related to conditions of prison facilities and the impact of implemented TB control measures need to be further studied in order to improve TB control among inmates. PMID:26641654

  4. Noninvasive Test for Tuberculosis Detection among Primates

    PubMed Central

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

    2015-01-01

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

  5. Hepatitis C Virus Infection Is Associated With an Increased Risk of Active Tuberculosis Disease

    PubMed Central

    Wu, Ping-Hsun; Lin, Yi-Ting; Hsieh, Kun-Pin; Chuang, Hung-Yi; Sheu, Chau-Chyun

    2015-01-01

    Abstract Tuberculosis (TB) and hepatitis C virus (HCV) infection contribute to major disease mortality and morbidity worldwide. However, the causal link between HCV infection and TB risk remains unclear. We conducted a population-based cohort study to elucidate the association between HCV infection and TB disease by analyzing Taiwan National Health Insurance Database. We enrolled 5454 persons with HCV infection and 54,274 age- and sex-matched non-HCV-infected persons between January 1998 and December 2007. Time-dependent Cox proportional hazards regression analysis was used to measure the association between HCV infection and active TB disease. Incidence rate of active TB disease was higher among HCV infection than in control (134.1 vs 89.1 per 100,000 person-years; incidence rate ratio 1.51; P?=?0.014). HCV infection was significantly associated with active TB disease in multivariate Cox regression (adjusted hazard ratio [HR] 3.20; 95% confidence interval [CI], 1.85–5.53; P?active TB disease in most strata. This nationwide cohort study suggests that HCV infection is associated with a higher risk of developing active TB disease. PMID:26287416

  6. Modulation of the Activity of Mycobacterium tuberculosis LipY by Its PE Domain.

    PubMed

    Garrett, Christopher K; Broadwell, Lindsey J; Hayne, Cassandra K; Neher, Saskia B

    2015-01-01

    Mycobacterium tuberculosis harbors over 160 genes encoding PE/PPE proteins, several of which have roles in the pathogen's virulence. A number of PE/PPE proteins are secreted via Type VII secretion systems known as the ESX secretion systems. One PE protein, LipY, has a triglyceride lipase domain in addition to its PE domain. LipY can regulate intracellular triglyceride levels and is also exported to the cell wall by one of the ESX family members, ESX-5. Upon export, LipY's PE domain is removed by proteolytic cleavage. Studies using cells and crude extracts suggest that LipY's PE domain not only directs its secretion by ESX-5, but also functions to inhibit its enzymatic activity. Here, we attempt to further elucidate the role of LipY's PE domain in the regulation of its enzymatic activity. First, we established an improved purification method for several LipY variants using detergent micelles. We then used enzymatic assays to confirm that the PE domain down-regulates LipY activity. The PE domain must be attached to LipY in order to effectively inhibit it. Finally, we determined that full length LipY and the mature lipase lacking the PE domain (LipY?PE) have similar melting temperatures. Based on our improved purification strategy and activity-based approach, we concluded that LipY's PE domain down-regulates its enzymatic activity but does not impact the thermal stability of the enzyme. PMID:26270534

  7. Cytokine and chemokine expression profiles in response to Mycobacterium tuberculosis stimulation are altered in HIV-infected compared to HIV-uninfected subjects with active tuberculosis.

    PubMed

    Waruk, Jillian L M; Machuki, Zipporah; Mesa, Christine; Juno, Jennifer A; Anzala, Omu; Sharma, Meenu; Ball, T Blake; Oyugi, Julius; Kiazyk, Sandra

    2015-09-01

    Mycobacterium tuberculosis (Mtb) infects nearly 2 million people annually and is the most common cause of death in HIV-infected individuals. Tuberculosis (TB) diagnostics cater to HIV-uninfected individuals in non-endemic countries, are expensive, slow, and lack sensitivity for those most affected. Patterns of soluble immune markers from Mtb-stimulated immune cells are not well defined in HIV co-infection. We assessed immune differences between HIV-infected and HIV-uninfected individuals with active TB utilizing IFN?-based QuantiFERON®-TB Gold In-Tube (QFT) testing in Nairobi, Kenya. Excess QFT supernatants were used to measure cytokine and chemokine responses by a 17-plex bead array. Mtb/HIV co-infected participants were significantly less likely to be QFT+ (47.2% versus 84.2% in the HIV-uninfected group), and demonstrated lower expression of all cytokines except for IFN?2. Receiver operator characteristic analyses identified IL-1? as a potential marker of co-infection. Among HIV-infected individuals, CD4+ T cell count correlated weakly with the expression of several analytes. Co-expression analysis highlighted differences in immune profiles between the groups. These data suggest that there is a unique and detectable Mtb-specific immune response in co-infection. A better understanding of Mtb immunology can translate into much needed immunodiagnostics with enhanced sensitivity in HIV-infected individuals, facilitating their opportunity to obtain live-saving treatment. PMID:26073895

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

    PubMed

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

    2015-02-01

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

  9. Discrimination between Active and Latent Tuberculosis Based on Ratio of Antigen-Specific to Mitogen-Induced IP-10 Production

    PubMed Central

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

    2014-01-01

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

  10. Tuberculosis of the pubic symphysis.

    PubMed

    Gothwal, Sudarshan; Varshney, Peeyush; Mathur, Shivank; Songra, Bhupen

    2014-01-01

    Tuberculosis is one of India's public health problems. It involves various systems of the body, including the skeletal system. Osteoarticular tuberculosis is the second most common form of extrapulmonary tuberculosis next to lymph nodes and constitutes about 13% of all extrapulmonary cases. It is generally accepted that osteoarticular tuberculosis is the result of a haematogenous or lymphatic spread from a reactivated latent focus, usually pulmonary; however, previous infection is not always encountered, and in only 40-50% of the cases, it is possible to demonstrate another active infection site. The commonest site for skeletal tuberculosis is the spine followed by the hip, knee and ankle joints. Tuberculosis can involve literally any bone or joint. Pubic symphysis is an uncommon site for tuberculosis in the case of the skeletal system. We present a rare case of pubic symphysis tuberculosis in a 25-year-old woman presented to the general surgical department with a swelling in the right thigh region. PMID:24515233

  11. Tim-3 pathway affects NK cell impairment in patients with active tuberculosis.

    PubMed

    Wang, Feng; Hou, Hongyan; Wu, Shiji; Tang, Qing; Huang, Min; Yin, Botao; Huang, Jing; Liu, Weiyong; Mao, Lie; Lu, Yanfang; Sun, Ziyong

    2015-12-01

    Active tuberculosis (TB) patients show impaired NK cell function, and the underlying mechanism remains largely unknown. In this study, we confirmed the decrease in activation, cytokine secretion, and degranulation potential of NK cells in active TB patients. We further investigated whether coinhibitory receptor Tim-3 was involved with impairment of NK cells. Our results revealed that the expression of Tim-3 on NK cells was increased in active TB patients. Tim-3 expression was inversely correlated with IL-12-stimualted IFN-? production. Moreover, blocking the Tim-3 pathway restored IFN-? secretion and degranulation of NK cells. Blocking this pathway also increased NK cell cytotoxicity against K562 target cells, and improved the ability of NK cells to control Mtb growth in monocyte-derived macrophages. The Tim-3 expression on NK cells was also observed to be significantly decreased in TB patients post-treatment. In this study, we have identified that Tim-3 is involved with NK cell impairment in TB patients. PMID:26050547

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2010-08-01

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

  14. Activity against Mycobacterium tuberculosis with concomitant induction of cellular immune responses by a tetraaza-macrocycle with acetate pendant arms.

    PubMed

    David, S; Ordway, D; Arroz, M J; Costa, J; Delgado, R

    2001-01-01

    The novel tetraaza-macrocyclic compound 3,7,11-tris(carboxymethyl)-3,7,11,17-tetraaza-bicyclo[11.3.1]heptadeca-1(17),13,15-triene, abbreviated as ac3py14, was investigated for its activity against Mycobacterium tuberculosis and for induction of protective cellular immune responses. Perspective results show that ac3py14 and its Fe3+ 1:1 complex, [Fe(ac3py14)], inhibited radiometric growth of several strains of M. tuberculosis. Inhibition with 25 microg/mL varied from 99% for H37Rv to 80% and above for multiple drug-resistant clinical isolates. The capacity of ac3py14 to elicit a beneficial immune response without cellular apoptosis was assessed and compared to the effects of virulent M. tuberculosis. The present study produces evidence that after stimulation with ac3py14 there was significant production of interferon gamma (IFN-gamma), whereas the production of interleukin-5 (IL-5) remained low, and there was development of a memory population (CD45RO). The level of binding of Annexin V, a marker of apoptosis, was not sufficient to result in toxic effects toward alphabeta and gammadelta T cells and CD14+ macrophages. This preliminary study is the first report of a compound that simultaneously exerts an inhibitory effect against M. tuberculosis and induces factors associated with protective immune responses. PMID:11501675

  15. Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infection

    PubMed Central

    Di Liberto, Diana; Locati, Massimo; Caccamo, Nadia; Vecchi, Annunciata; Meraviglia, Serena; Salerno, Alfredo; Sireci, Guido; Nebuloni, Manuela; Caceres, Neus; Cardona, Pere-Joan; Dieli, Francesco; Mantovani, Alberto

    2008-01-01

    D6 is a decoy and scavenger receptor for inflammatory CC chemokines. D6-deficient mice were rapidly killed by intranasal administration of low doses of Mycobacterium tuberculosis. The death of D6?/? mice was associated with a dramatic local and systemic inflammatory response with levels of M. tuberculosis colony-forming units similar to control D6-proficient mice. D6-deficient mice showed an increased numbers of mononuclear cells (macrophages, dendritic cells, and CD4 and CD8 T lymphocytes) infiltrating inflamed tissues and lymph nodes, as well as abnormal increased concentrations of CC chemokines (CCL2, CCL3, CCL4, and CCL5) and proinflammatory cytokines (tumor necrosis factor ?, interleukin 1?, and interferon ?) in bronchoalveolar lavage and serum. High levels of inflammatory cytokines in D6?/? infected mice were associated with liver and kidney damage, resulting in both liver and renal failure. Blocking inflammatory CC chemokines with a cocktail of antibodies reversed the inflammatory phenotype of D6?/? mice but led to less controlled growth of M. tuberculosis. Thus, the D6 decoy receptor plays a key role in setting the balance between antimicrobial resistance, immune activation, and inflammation in M. tuberculosis infection. PMID:18695004

  16. Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infection.

    PubMed

    Di Liberto, Diana; Locati, Massimo; Caccamo, Nadia; Vecchi, Annunciata; Meraviglia, Serena; Salerno, Alfredo; Sireci, Guido; Nebuloni, Manuela; Caceres, Neus; Cardona, Pere-Joan; Dieli, Francesco; Mantovani, Alberto

    2008-09-01

    D6 is a decoy and scavenger receptor for inflammatory CC chemokines. D6-deficient mice were rapidly killed by intranasal administration of low doses of Mycobacterium tuberculosis. The death of D6(-/-) mice was associated with a dramatic local and systemic inflammatory response with levels of M. tuberculosis colony-forming units similar to control D6-proficient mice. D6-deficient mice showed an increased numbers of mononuclear cells (macrophages, dendritic cells, and CD4 and CD8 T lymphocytes) infiltrating inflamed tissues and lymph nodes, as well as abnormal increased concentrations of CC chemokines (CCL2, CCL3, CCL4, and CCL5) and proinflammatory cytokines (tumor necrosis factor alpha, interleukin 1beta, and interferon gamma) in bronchoalveolar lavage and serum. High levels of inflammatory cytokines in D6(-/-) infected mice were associated with liver and kidney damage, resulting in both liver and renal failure. Blocking inflammatory CC chemokines with a cocktail of antibodies reversed the inflammatory phenotype of D6(-/-) mice but led to less controlled growth of M. tuberculosis. Thus, the D6 decoy receptor plays a key role in setting the balance between antimicrobial resistance, immune activation, and inflammation in M. tuberculosis infection. PMID:18695004

  17. Characterization of a novel esterase Rv1497 of Mycobacterium tuberculosisH37Rv demonstrating ?-lactamase activity.

    PubMed

    Singh, Gurpreet; Kumar, Arbind; Arya, Stuti; Gupta, Umesh Dutt; Singh, Kashmir; Kaur, Jagdeep

    2016-01-01

    The Rv1497 (LipL) of the Mycobacterium tuberculosis H37Rv was predicted to be similar to hypothetical esterases and penicillin binding proteins ofM. tuberculosis as well as to be involved in lipid metabolism. Sequence alignment revealed that Rv1497 protein contains characteristic consensus ?-lactamase motif 'SXXK' in addition to a conserve pentapeptide -GXSXG-, characteristic of lipolytic enzymes, at the C-terminus of protein in contrast to its usual N-terminus location. For detailed characterization of protein, the rv1497 gene was cloned, expressed with N-terminal His-tag and purified to homogeneity on Ni-NTA column. Rv1497 demonstrated both esterase and ?-lactamase activities. A serine located within consensus ?-lactamase motif 'SXXK' was identified as catalytic residue in both esterase and ?-lactamase enzymatic activities whereas serine residue located within conserved pentapeptide did not show any effect on both enzyme activities. The catalytic residues of Rv1497 for ?-lactamase activity were determined to be Ser88, Tyr-175 and His355 residues by site-directed mutagenesis. The enzyme demonstrated preference for short chain esters (pNP-butyrate). The expression of lipL gene was significantly up-regulated during acidic stress as compared to normal conditions in in vitro culture of M. tuberculosis H37Ra. This is perhaps the first report demonstrating an esterase of mycobacterium showing ?-lactamase activity. PMID:26672466

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

    PubMed Central

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

    2014-01-01

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

  19. Untreated Active Tuberculosis in Pregnancy with Intraocular Dissemination: A Case Report and Review of the Literature

    PubMed Central

    LoBue, Stephen; Adams, Daniel; Oladipo, Yewande; Posso, Ramses; Mapp, Tiffany; Santiago, Crystal; Jain, Manisha; Marino, William D.; Henderson, Cassandra E.

    2015-01-01

    Background. Tuberculosis (TB) is a disease that affects hundreds of millions of people across the world. However, the incidence in developed countries has decreased over the past decades causing physicians to become unfamiliar with its unspecific symptoms. Pregnant individuals are especially difficult because many symptoms of active TB can mimic normal physiological changes of pregnancy. We present a case report of a 26-year-old multiparous woman, G4P3003, at 38-week gestation with a history of positive PPD who emigrated from Ghana 6 years ago. She came to the hospital with an initial complaint of suprapubic pain, pressure, and possible leakage of amniotic fluid for the past week. Patient also complained of a productive cough for the past 3 to 4 months with a decrease in vision occurring with the start of pregnancy. Visual acuity was worse than 20/200 in both eyes. Definitive diagnosis of active TB was delayed due to patient refusal of chest X-ray. Fortunately, delay in diagnosis was minimized since patient delivered within 24 hours of admission. Active TB was confirmed with intraocular dissemination. Patient had optic atrophy OS (left eye) and papillitis, choroiditis, and uveitis OD (right eye) due to TB infiltration. Fetus was asymptomatic and anti-TB therapy was started for both patients. PMID:26693374

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  2. Feasibility of a combined camp approach for vector control together with active case detection of visceral leishmaniasis, post kala-azar dermal leishmaniasis, tuberculosis, leprosy and malaria in Bangladesh, India and Nepal: an exploratory study

    PubMed Central

    Banjara, Megha R.; Kroeger, Axel; Huda, Mamun M.; Kumar, Vijay; Gurung, Chitra K.; Das, Murari L.; Rijal, Suman; Das, Pradeep; Mondal, Dinesh

    2015-01-01

    Background We assessed the feasibility and results of active case detection (ACD) of visceral leishmaniasis (VL), post kala-azar dermal leishmaniasis (PKDL) and other febrile diseases as well as of bednet impregnation for vector control. Methods Fever camps were organized and analyzed in twelve VL endemic villages in Bangladesh, India, and Nepal. VL, PKDL, tuberculosis, malaria and leprosy were screened among the febrile patients attending the camps, and existing bednets were impregnated with a slow release insecticide. Results Among the camp attendees one new VL case and two PKDL cases were detected in Bangladesh and one VL case in Nepal. Among suspected tuberculosis cases two were positive in India but none in the other countries. In India, two leprosy cases were found. No malaria cases were detected. Bednet impregnation coverage during fever camps was more than 80% in the three countries. Bednet impregnation led to a reduction of sandfly densities after 2 weeks by 86% and 32%, and after 4 weeks by 95% and 12% in India and Nepal respectively. The additional costs for the control programmes seem to be reasonable. Conclusion It is feasible to combine ACD camps for VL and PKDL along with other febrile diseases, and vector control with bednet impregnation. PMID:25918216

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  5. Accuracy of Immunodiagnostic Tests for Active Tuberculosis Using Single and Combined Results: A Multicenter TBNET-Study

    PubMed Central

    Goletti, Delia; Stefania, Carrara; Butera, Ornella; Amicosante, Massimo; Ernst, Martin; Sauzullo, Ilaria; Vullo, Vincenzo; Cirillo, Daniela; Borroni, Emanuele; Markova, Roumiana; Drenska, Roumiana; Dominguez, José; Latorre, Irene; Angeletti, Claudio; Navarra, Assunta; Petrosillo, Nicola; Lauria, Francesco Nicola; Ippolito, Giuseppe; Migliori, Giovanni Battista; Lange, Christoph; Girardi, Enrico

    2008-01-01

    Background The clinical application of IFN-? release assays (IGRAs) has recently improved the diagnosis of latent tuberculosis infection. In a multicenter study of the Tuberculosis Network European Trialsgroup (TBNET) we aimed to ascertain in routine clinical practice the accuracy of a novel assay using selected peptides encoded in the mycobacterial genomic region of difference (RD) 1 for the diagnosis of active tuberculosis in comparison with tuberculin skin test (TST), QuantiFERON-TB GOLD In-Tube (Cellestis Ltd., Carnegie, Australia) and T-SPOT.TB (Oxfordimmunotec, Abingdon, UK). Principal Findings 425 individuals from 6 different European centres were prospectively enrolled. We found that sensitivity of the novel test, TST, QuantiFERON-TB GOLD In-Tube and T-SPOT.TB was respectively 73.1%, 85.3%, 78.1%, and 85.2%; specificity was respectively 70.6%, 48.0%, 61.9% and 44.3%; positive likelihood ratios were respectively 2.48, 1.64, 2.05, and 1.53; negative likelihood ratios were respectively 0.38, 0.31, 0.35, 0.33. Sensitivity of TST combined with the novel test, QuantiFERON-TB GOLD In-Tube and T-SPOT.TB increased up to 92.4%, 97.7% and 97.1%, respectively. The likelihood ratios of combined negative results of TST with, respectively, the novel test, QuantiFERON-TB GOLD In-Tube and T-SPOT.TB were 0.19, 0.07 and 0.10. Conclusions The assay based on RD1 selected peptides has similar accuracy for active tuberculosis compared with TST and commercial IGRAs. Then, independently of the spectrum of antigens used in the assays to elicit mycobacterial specific immune responses, the novel test, IGRAs, and the TST do not allow an accurate identification of active tuberculosis in clinical practice. However, the combined use of the novel assay or commercial IGRAs with TST may allow exclusion of tuberculosis. PMID:18923709

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

    PubMed Central

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

    2010-01-01

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

  7. Tuberculosis screening and compliance with return for skin test reading among active drug users.

    PubMed Central

    Malotte, C K; Rhodes, F; Mais, K E

    1998-01-01

    OBJECTIVES: This study assessed the independent and combined effects of different levels of monetary incentives and a theory-based educational intervention on return for tuberculosis (TB) skin test reading in a sample of active injection drug and crack cocaine users. Prevalence of TB infection in this sample was also determined. METHODS: Active or recent drug users (n = 1004), recruited via street outreach techniques, were skin tested for TB. They were randomly assigned to 1 of 2 levels of monetary incentive ($5 and $10) provided at return for skin test reading, alone or in combination with a brief motivational education session. RESULTS: More than 90% of those who received $10 returned for skin test reading, in comparison with 85% of those who received $5 and 33% of those who received no monetary incentive. The education session had no impact on return for skin test reading. The prevalence of a positive tuberculin test was 18.3%. CONCLUSIONS: Monetary incentives dramatically increase the return rate for TB skin test reading among drug users who are at high risk of TB infection. PMID:9585747

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

    PubMed

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

    2014-12-01

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

  9. Modulation of the Activity of Mycobacterium tuberculosis LipY by Its PE Domain

    PubMed Central

    Garrett, Christopher K.; Broadwell, Lindsey J.; Hayne, Cassandra K.; Neher, Saskia B.

    2015-01-01

    Mycobacterium tuberculosis harbors over 160 genes encoding PE/PPE proteins, several of which have roles in the pathogen’s virulence. A number of PE/PPE proteins are secreted via Type VII secretion systems known as the ESX secretion systems. One PE protein, LipY, has a triglyceride lipase domain in addition to its PE domain. LipY can regulate intracellular triglyceride levels and is also exported to the cell wall by one of the ESX family members, ESX-5. Upon export, LipY’s PE domain is removed by proteolytic cleavage. Studies using cells and crude extracts suggest that LipY’s PE domain not only directs its secretion by ESX-5, but also functions to inhibit its enzymatic activity. Here, we attempt to further elucidate the role of LipY’s PE domain in the regulation of its enzymatic activity. First, we established an improved purification method for several LipY variants using detergent micelles. We then used enzymatic assays to confirm that the PE domain down-regulates LipY activity. The PE domain must be attached to LipY in order to effectively inhibit it. Finally, we determined that full length LipY and the mature lipase lacking the PE domain (LipY?PE) have similar melting temperatures. Based on our improved purification strategy and activity-based approach, we concluded that LipY’s PE domain down-regulates its enzymatic activity but does not impact the thermal stability of the enzyme. PMID:26270534

  10. Tuberculosis (For Parents)

    MedlinePLUS

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

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

    PubMed Central

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

    2015-01-01

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

  12. Cutaneous Tuberculosis

    PubMed Central

    Frankel, Amylynne; Penrose, Carolin

    2009-01-01

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

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

    PubMed Central

    2013-01-01

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

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

    PubMed

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

    2012-05-01

    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. PMID:22771604

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

    PubMed Central

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

    2014-01-01

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

  16. 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...

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

    PubMed Central

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

    2014-01-01

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

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

    ERIC Educational Resources Information Center

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

    2011-01-01

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

  19. Tuberculosis (TB)

    MedlinePLUS

    ... Skip Content Marketing Share this: Main Content Area Tuberculosis Research The New Challenge for TB Research NIAID ... HIV/AIDS Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis Research Agenda (PDF) TB Research at NIAID Research ...

  20. Tuberculosis (TB)

    MedlinePLUS

    ... Skip Content Marketing Share this: Main Content Area Tuberculosis (TB) Overview In developed countries, such as the ... thought to be infected with TB bacteria, Mycobacterium tuberculosis ( Mtb ). TB is a chronic bacterial infection. It ...

  1. Tuberculosis Prevention

    MedlinePLUS

    ... Skip Content Marketing Share this: Main Content Area Tuberculosis (TB) Prevention TB is an airborne disease and ... patients. Many people who are infected with Mycobacterium tuberculosis ( Mtb ) do not get sick or spread the ...

  2. Using Commercial Activity Monitors to Measure Gait in Patients with Suspected iNPH: Implications for Ambulatory Monitoring

    PubMed Central

    Gaglani, Shiv; Haynes, M Ryan; Hoffberger, Jamie B; Rigamonti, Daniele

    2015-01-01

    Objectives: This study seeks to validate the use of activity monitors to detect and record gait abnormalities, potentially identifying patients with idiopathic normal pressure hydrocephalus (iNPH) prior to the onset of cognitive or urinary symptoms. Methods: This study compared the step counts of four common activity monitors (Omron Step Counter HJ-113, New Lifestyles 2000, Nike Fuelband, and Fitbit Ultra) to an observed step count in 17 patients with confirmed iNPH. Results: Of the four devices, the Fitbit Ultra (Fitbit, Inc., San Francisco, CA) provided the most accurate step count. The correlation with the observed step count was significantly higher (p<0.009) for the Fitbit Ultra than for any of the other three devices. Conclusions: These preliminary findings suggest that existing activity monitors have variable efficacy in the iNPH patient population and that the MEMS tri-axial accelerometer and algorithm of the Fitbit Ultra provides the most accurate gait measurements of the four devices tested. PMID:26719825

  3. Spectrum of urogenital tuberculosis.

    PubMed

    Kulchavenya, Ekaterina; Zhukova, Irina; Kholtobin, Denis

    2013-10-01

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

  4. Suspected Pesticide Poisoning

    PubMed Central

    Sellar, Christine; Ferguson, Joyce A.

    1991-01-01

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

  5. Cordilleran suspect terranes

    USGS Publications Warehouse

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

    1980-01-01

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

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

    PubMed Central

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

    2013-01-01

    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. PMID:23544075

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

    PubMed Central

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

    2015-01-01

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

  8. 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...

  9. Rv2466c mediates the activation of TP053 to kill replicating and non-replicating Mycobacterium tuberculosis.

    PubMed

    Albesa-Jové, David; Chiarelli, Laurent R; Makarov, Vadim; Pasca, Maria Rosalia; Urresti, Saioa; Mori, Giorgia; Salina, Elena; Vocat, Anthony; Comino, Natalia; Mohorko, Elisabeth; Ryabova, Svetlana; Pfieiffer, Bernhard; Lopes Ribeiro, Ana Luisa de Jesus; Rodrigo-Unzueta, Ane; Tersa, Montse; Zanoni, Giuseppe; Buroni, Silvia; Altmann, Karl-Heinz; Hartkoorn, Ruben C; Glockshuber, Rudi; Cole, Stewart T; Riccardi, Giovanna; Guerin, Marcelo E

    2014-07-18

    The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis highlights the need to discover new antitubercular agents. Here we describe the synthesis and characterization of a new series of thienopyrimidine (TP) compounds that kill both replicating and non-replicating M. tuberculosis. The strategy to determine the mechanism of action of these TP derivatives was to generate resistant mutants to the most effective compound TP053 and to isolate the genetic mutation responsible for this phenotype. The only non-synonymous mutation found was a g83c transition in the Rv2466c gene, resulting in the replacement of tryptophan 28 by a serine. The Rv2466c overexpression increased the sensitivity of M. tuberculosis wild-type and resistant mutant strains to TP053, indicating that TP053 is a prodrug activated by Rv2466c. Biochemical studies performed with purified Rv2466c demonstrated that only the reduced form of Rv2466c can activate TP053. The 1.7 Å resolution crystal structure of the reduced form of Rv2466c, a protein whose expression is transcriptionally regulated during the oxidative stress response, revealed a unique homodimer in which a ?-strand is swapped between the thioredoxin domains of each subunit. A pronounced groove harboring the unusual active-site motif CPWC might account for the uncommon reactivity profile of the protein. The mutation of Trp28Ser clearly predicts structural defects in the thioredoxin fold, including the destabilization of the dimerization core and the CPWC motif, likely impairing the activity of Rv2466c against TP053. Altogether our experimental data provide insights into the molecular mechanism underlying the anti-mycobacterial activity of TP-based compounds, paving the way for future drug development programmes. PMID:24877756

  10. Impact of Fluoroquinolone Resistance on Bactericidal and Sterilizing Activity of a Moxifloxacin-Containing Regimen in Murine Tuberculosis

    PubMed Central

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

    2013-01-01

    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

  11. Primary gastric tuberculosis mimicking gastric cancer

    PubMed Central

    Eray, ?smail Cem; Rencüzo?ullar?, Ahmet; Yalav, Orçun; Dalc?, Kubilay; Kakil, Erdem; Ba??r, Emine; Parsak, Cem Kaan

    2015-01-01

    A 42-year-old female patient with no previous known diseases who had complaints of postprandial epigastric pain and weight loss and who could not be diagnosed by endoscopic biopsy, although gastric cancer was suspected radiologically and endoscopically, was diagnosed with primary gastric tuberculosis by laparotomy and frozen section. Following anti-tuberculosis treatment, a complete clinical, radiological, and endoscopic response was achieved. PMID:26504425

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2011-07-01

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

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

    PubMed

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

    2015-07-23

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

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

    2009-12-01

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

  20. Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules

    PubMed Central

    Davidge, Kelly S; Singh, Sandip; Bowman, Lesley AH; Tinajero-Trejo, Mariana; Carballal, Sebastián; Radi, Rafael; Poole, Robert K; Dikshit, Kanak; Estrin, Dario A; Marti, Marcelo A; Boechi, Leonardo

    2015-01-01

    Mycobacterium tuberculosis, the causative agent of human tuberculosis, has two proteins belonging to the truncated hemoglobin (trHb) family. Mt-trHbN presents well-defined internal hydrophobic tunnels that allow O 2 and •NO to migrate easily from the solvent to the active site, whereas Mt-trHbO possesses tunnels that are partially blocked by a few bulky residues, particularly a tryptophan at position G8. Differential ligand migration rates allow Mt-trHbN to detoxify •NO, a crucial step for pathogen survival once under attack by the immune system, much more efficiently than Mt-trHbO. In order to investigate the differences between these proteins, we performed experimental kinetic measurements, •NO decomposition, as well as molecular dynamics simulations of the wild type Mt-trHbN and two mutants, VG8F and VG8W. These mutations introduce modifications in both tunnel topologies and affect the incoming ligand capacity to displace retained water molecules at the active site. We found that a single mutation allows Mt-trHbN to acquire ligand migration rates comparable to those observed for Mt-trHbO, confirming that ligand migration is regulated by the internal tunnel architecture as well as by water molecules stabilized in the active site. PMID:26478812

  1. Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules.

    PubMed

    Boron, Ignacio; Bustamante, Juan Pablo; Davidge, Kelly S; Singh, Sandip; Bowman, Lesley Ah; Tinajero-Trejo, Mariana; Carballal, Sebastián; Radi, Rafael; Poole, Robert K; Dikshit, Kanak; Estrin, Dario A; Marti, Marcelo A; Boechi, Leonardo

    2015-01-01

    Mycobacterium tuberculosis, the causative agent of human tuberculosis, has two proteins belonging to the truncated hemoglobin (trHb) family. Mt-trHbN presents well-defined internal hydrophobic tunnels that allow O 2 and (•)NO to migrate easily from the solvent to the active site, whereas Mt-trHbO possesses tunnels that are partially blocked by a few bulky residues, particularly a tryptophan at position G8. Differential ligand migration rates allow Mt-trHbN to detoxify (•)NO, a crucial step for pathogen survival once under attack by the immune system, much more efficiently than Mt-trHbO. In order to investigate the differences between these proteins, we performed experimental kinetic measurements, (•)NO decomposition, as well as molecular dynamics simulations of the wild type Mt-trHbN and two mutants, VG8F and VG8W. These mutations introduce modifications in both tunnel topologies and affect the incoming ligand capacity to displace retained water molecules at the active site. We found that a single mutation allows Mt-trHbN to acquire ligand migration rates comparable to those observed for Mt-trHbO, confirming that ligand migration is regulated by the internal tunnel architecture as well as by water molecules stabilized in the active site. PMID:26478812

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

    PubMed Central

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

    2014-01-01

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

  3. 38 CFR 3.959 - Tuberculosis.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

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

  4. 38 CFR 3.959 - Tuberculosis.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

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

  5. 38 CFR 3.959 - Tuberculosis.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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

  6. 38 CFR 3.959 - Tuberculosis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

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

  7. 38 CFR 3.959 - Tuberculosis.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

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

  8. Hepatobiliary tuberculosis

    PubMed Central

    Chaudhary, Poras

    2014-01-01

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

  9. Tuberculosis on the flight deck.

    PubMed

    Parmet, A J

    1999-08-01

    Tuberculosis in commercial aircraft has been a concern since a 1995 incident of possible transmission from an active case of tuberculosis to passengers in the cabin of a 747. Subsequently, commercial air carriers have been vigilant in cooperating with public health authorities in tracking all known exposures to tuberculosis. In 1998, a pilot of a commercial airliner was diagnosed with active tuberculosis. Company records demonstrated that in the previous 6 mo, the pilot had flown with 48 other pilots. Every exposed pilot was contacted and evaluated by skin testing (IPPD) or chest x-ray if previously positive. There were no skin test conversions and no changes on x-rays. This study demonstrates that transmission of tuberculosis in the aircraft cabin environment, even under close and continuous exposure to an active case, is a rare event. PMID:10447057

  10. Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization.

    PubMed

    Candice, Soares de Melo; Feng, Tzu-Shean; van der Westhuyzen, Renier; Gessner, Richard K; Street, Leslie J; Morgans, Garreth L; Warner, Digby F; Moosa, Atica; Naran, Krupa; Lawrence, Nina; Boshoff, Helena I M; Barry, Clifton E; Harris, C John; Gordon, Richard; Chibale, Kelly

    2015-11-15

    Whole-cell high-throughput screening of a diverse SoftFocus library against Mycobacterium tuberculosis (Mtb) generated a novel aminopyrazolo[1,5-a]pyrimidine hit series. The synthesis and structure activity relationship studies identified compounds with potent antimycobacterial activity. The SAR of over 140 compounds shows that the 2-pyridylmethylamine moiety at the C-7 position of the pyrazolopyrimidine scaffold was important for Mtb activity, whereas the C-3 position offered a higher degree of flexibility. The series was also profiled for in vitro cytotoxicity and microsomal metabolic stability as well as physicochemical properties. Consequently liabilities to be addressed in a future lead optimization campaign have been identified. PMID:26522089

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

    PubMed

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

    2015-03-01

    Biomarkers that can identify tuberculosis (TB) disease and serve as markers for efficient therapy are requested. We have studied T cell cytokine production [interferon (IFN)-?, interleukin (IL)-2, tumour necrosis factor (TNF)-?] and degranulation (CD107a) as well as subsets of CD4(+) T regulatory cells (Tregs ) after in-vitro Mycobacterium tuberculosis (Mtb) antigen stimulation [early secretory antigenic target (ESAT)-6, culture filtrate protein (CFP)-10, antigen 85 (Ag85)] in 32 patients with active tuberculosis (TB) disease throughout 24 weeks of effective TB treatment. A significant decline in the fraction of Mtb-specific total IFN-? and single IFN-?-producing T cells was already observed after 2 weeks of treatment, whereas the pool of single IL-2(+) cells increased over time for both CD4(+) and CD8(+) T cells. The Treg subsets CD25(high) CD127(low) , CD25(high) CD147(++) and CD25(high) CD127(low) CD161(+) expanded significantly after Mtb antigen stimulation in vitro at all time-points, whereas the CD25(high) CD127(low) CD39(+) Tregs remained unchanged. The fraction of CD25(high) CD127(low) Tregs increased after 8 weeks of treatment. Thus, we revealed an opposing shift of Tregs and intracellular cytokine production during treatment. This may indicate that functional signatures of the CD4(+) and CD8(+) T cells can serve as immunological correlates of early curative host responses. Whether such signatures can be used as biomarkers in monitoring and follow-up of TB treatment needs to be explored further. PMID:25313008

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    2014-01-01

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

  14. Antigenic differences between extracts of actively replicating and synchronized resting cells of Mycobacterium tuberculosis.

    PubMed Central

    Wayne, L G; Sramek, H A

    1979-01-01

    Protein extracts were prepared from aerobically replicating cells of Mycobacterium tuberculosis and from synchronized non-replicating cells derived from the sediments of non-agitated cultures. Although both preparations share a number of antigens, the extracts of the non-replicating cells also contain antigenic components that are not shared by the replicating cells, and which can be isolated and visualized by immunoaffinity chromatography and immunoelectrophoretic techniques. Images PMID:110697

  15. Diagnostic utility of interferon-gamma release assay in extrapulmonary tuberculosis.

    PubMed

    Shin, Jung Ar; Chang, Yoon Soo; Kim, Hyung Jung; Ahn, Chul Min; Byun, Min Kwang

    2015-05-01

    Early diagnosis of extrapulmonary tuberculosis (EP-TB) is essential. However, diagnosis of EP-TB is difficult. We evaluated the diagnostic utility of an interferon-gamma release assay (IGRA) in diagnosing active EP-TB among suspected patients in Korea. We retrospectively reviewed the clinical records of all patients with suspected EP-TB at Gangnam Severance Hospital in Seoul, Korea. Of the 418 patients with suspected EP-TB, 324 had active EP-TB. The tuberculosis (TB) group had a higher percentage of positive IGRAs (70.2%, 33/47) than the non-TB group (33.3%, 3/9) (P=0.034). The IGRA sensitivity and specificity were 70.2% (63.7-74.8%) and 66.7% (32.9-90.6%), respectively. The sensitivity and specificity of IGRAs in patients with TB lymphadenitis were 81.8% (61.4-90.4%) and 80.0% (35.1-98.9%), but 38.5% (31.2-45.7%) and 50.0% (2.7-97.3%) in patients with TB pleurisy. The diagnostic performance of IGRAs may vary depending on the site of EP-TB involvement. IGRA was potentially valuable for diagnosis of active EP-TB in TB lymphadenopathy. PMID:25724852

  16. Esters of Pyrazinoic Acid Are Active against Pyrazinamide-Resistant Strains of Mycobacterium tuberculosis and Other Naturally Resistant Mycobacteria In Vitro and Ex Vivo within Macrophages.

    PubMed

    Pires, David; Valente, Emília; Simões, Marta Filipa; Carmo, Nuno; Testa, Bernard; Constantino, Luís; Anes, Elsa

    2015-12-01

    Pyrazinamide (PZA) is active against major Mycobacterium tuberculosis species (M. tuberculosis, M. africanum, and M. microti) but not against M. bovis and M. avium. The latter two are mycobacterial species involved in human and cattle tuberculosis and in HIV coinfections, respectively. PZA is a first-line agent for the treatment of human tuberculosis and requires activation by a mycobacterial pyrazinamidase to form the active metabolite pyrazinoic acid (POA). As a result of this mechanism, resistance to PZA, as is often found in tuberculosis patients, is caused by point mutations in pyrazinamidase. In previous work, we have shown that POA esters and amides synthesized in our laboratory were stable in plasma (M. F. Simões, E. Valente, M. J. Gómez, E. Anes, and L. Constantino, Eur J Pharm Sci 37:257-263, 2009, http://dx.doi.org/10.1016/j.ejps.2009.02.012). Although the amides did not present significant activity, the esters were active against sensitive mycobacteria at concentrations 5- to 10-fold lower than those of PZA. Here, we report that these POA derivatives possess antibacterial efficacy in vitro and ex vivo against several species and strains of Mycobacterium with natural or acquired resistance to PZA, including M. bovis and M. avium. Our results indicate that the resistance probably was overcome by cleavage of the prodrugs into POA and a long-chain alcohol. Although it is not possible to rule out that the esters have intrinsic activity per se, we bring evidence here that long-chain fatty alcohols possess a significant antimycobacterial effect against PZA-resistant species and strains and are not mere inactive promoieties. These findings may lead to candidate dual drugs having enhanced activity against both PZA-susceptible and PZA-resistant isolates and being suitable for clinical development. PMID:26438493

  17. Validation of a homology model of Mycobacterium tuberculosis DXS: rationalization of observed activities of thiamine derivatives as potent inhibitors of two orthologues of DXS.

    PubMed

    Masini, T; Lacy, B; Monjas, L; Hawksley, D; de Voogd, A R; Illarionov, B; Iqbal, A; Leeper, F J; Fischer, M; Kontoyianni, M; Hirsch, A K H

    2015-12-14

    The enzyme DXS catalyzes the first, rate-limiting step of the 2-C-methyl-d-erythritol-4-phosphate (MEP, 1) pathway using thiamine diphosphate (ThDP) as cofactor; the DXS-catalyzed reaction constitutes also the first step in vitamin B1 and B6 metabolism in bacteria. DXS is the least studied among the enzymes of this pathway in terms of crystallographic information, with only one complete crystal structure deposited in the Protein Data Bank (Deinococcus radiodurans DXS, PDB: ). We synthesized a series of thiamine and ThDP derivatives and tested them for their biochemical activity against two DXS orthologues, namely D. radiodurans DXS and Mycobacterium tuberculosis DXS. These experimental results, combined with advanced docking studies, led to the development and validation of a homology model of M. tuberculosis DXS, which, in turn, will guide medicinal chemists in rationally designing potential inhibitors for M. tuberculosis DXS. PMID:26411373

  18. Antigen smuggling in tuberculosis.

    PubMed

    Hudrisier, Denis; Neyrolles, Olivier

    2014-06-11

    The importance of CD4 T lymphocytes in immunity to M. tuberculosis is well established; however, how dendritic cells activate T cells in vivo remains obscure. In this issue of Cell Host & Microbe, Srivastava and Ernst (2014) report a mechanism of antigen transfer for efficient activation of antimycobacterial T cells. PMID:24922567

  19. A Bayesian Nonlinear Mixed-Effects Regression Model for the Characterization of Early Bactericidal Activity of Tuberculosis Drugs

    PubMed Central

    Burger, Divan Aristo; Schall, Robert

    2015-01-01

    Trials of the early bactericidal activity (EBA) of tuberculosis (TB) treatments assess the decline, during the first few days to weeks of treatment, in colony forming unit (CFU) count of Mycobacterium tuberculosis in the sputum of patients with smear-microscopy-positive pulmonary TB. Profiles over time of CFU data have conventionally been modeled using linear, bilinear, or bi-exponential regression. We propose a new biphasic nonlinear regression model for CFU data that comprises linear and bilinear regression models as special cases and is more flexible than bi-exponential regression models. A Bayesian nonlinear mixed-effects (NLME) regression model is fitted jointly to the data of all patients from a trial, and statistical inference about the mean EBA of TB treatments is based on the Bayesian NLME regression model. The posterior predictive distribution of relevant slope parameters of the Bayesian NLME regression model provides insight into the nature of the EBA of TB treatments; specifically, the posterior predictive distribution allows one to judge whether treatments are associated with monolinear or bilinear decline of log(CFU) count, and whether CFU count initially decreases fast, followed by a slower rate of decrease, or vice versa. PMID:25322214

  20. The adjuvant activity of a non-toxic, water-soluble glycopeptide present in large quantities in the culture filtrate of Mycobacterium tuberculosis strain DT.

    PubMed Central

    Stewart-Tull, D E; Shimono, T; Kotani, S; Kato, M; Ogawa, Y; Yamamura, Y; Koga, T; Pearson, C M

    1975-01-01

    A water-soluble mycobacterial glycopeptide was obtained in large quantities from the culture supernatant fluid of M. tuberculosis strain DT. This glycopeptide was strongly adjuvant-active when injected, in a water-in-oil emulsion contianing ovalbumin, into guinea-pigs. In addition, it was devoid of cord factor toxicity in mice, polyarthritogenic activity in rats and cavity stimulating activity in rabbit lungs. Images FIG. 2 FIG. 3 FIG. 4 FIG. 5 FIG. 6 FIG. 8 PMID:806515

  1. Evaluation of a monoclonal antibody (TB72) based serological test for tuberculosis.

    PubMed Central

    Ivanyi, J; Krambovitis, E; Keen, M

    1983-01-01

    A serological test for tuberculosis (TB), based on competitive inhibition by human sera of antigen binding by a murine monoclonal antibody (TB72) has been performed using solid phase radioimmunoassay. The test was evaluated on sera from patients with pulmonary or extra-pulmonary active TB as well as from control hospitalized patients--half of whom had various chest complaints. Positive values were found in 74% of all or 55% of untreated active pulmonary TB. Patients with extrapulmonary TB segregated, whereby antibody titres were increased in cases of pleural, peritoneal, pericardial or bone infection but only marginal or negative values were found in the majority of patients with lymphatic and genitourinary infection. None of the subjects with suspected but excluded tuberculosis or sarcoidosis had demonstrable TB72 antibodies. Generally there was a positive correlation between the levels of TB72 like and 'total' Mycobacterium tuberculosis sonicate binding antibodies. In particular, the titre of sonicate binding antibodies did not exceed background levels in patients with active pulmonary tuberculosis who were negative in the TB72 competition test. None of these false negative patients received drug therapy whereas most patients with the highest antibody levels were under chemotherapy for 1-8 months prior to serum testing. The serodiagnostic value of the TB72 based competition test has been discussed. PMID:6197217

  2. 29 CFR 1904.11 - Recording criteria for work-related tuberculosis cases.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

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

  3. 29 CFR 1904.11 - Recording criteria for work-related tuberculosis cases.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

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

  4. 29 CFR 1904.11 - Recording criteria for work-related tuberculosis cases.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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

  5. 29 CFR 1904.11 - Recording criteria for work-related tuberculosis cases.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

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

  6. 29 CFR 1904.11 - Recording criteria for work-related tuberculosis cases.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

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

  7. Modulation of pro- and anti-inflammatory cytokines in active and latent tuberculosis by coexistent Strongyloides stercoralis infection.

    PubMed

    George, Parakkal Jovvian; Pavan Kumar, Nathella; Jaganathan, Jeeva; Dolla, Chandrakumar; Kumaran, Paul; Nair, Dina; Banurekha, Vaithilingam V; Shen, Kui; Nutman, Thomas B; Babu, Subash

    2015-12-01

    Helminth infections are known to induce modulation of both innate and adaptive immune responses in active and latent tuberculosis (TB). However, the role of helminth infections in modulating systemic cytokine responses in active and latent tuberculosis (LTB) is not known. To define the systemic cytokine levels in helminth-TB coinfection, we measured the circulating plasma levels of Type 1, Type 2, Type 17, other pro-inflammatory and regulatory cytokines in individuals with active TB (ATB) with or without coexistent Strongyloides stercoralis (Ss) infection by multiplex ELISA. Similarly, we also measured the same cytokine levels in individuals with LTB with or without concomitant Ss infection in a cross-sectional study. Our data reveal that individuals with ATB or LTB and coexistent Ss infection have significantly lower levels of Type 1 (IFN?, TNF? and IL-2) and Type 17 (IL-17A and IL-17F) cytokines compared to those without Ss infection. In contrast, those with ATB and LTB with Ss infection have significantly higher levels of the regulatory cytokines (IL-10 and TGF?), and those with LTB and Ss infection also have significantly higher levels of Type 2 cytokines (IL-4, IL-5 and IL-13) as well. Finally, those with LTB (but not ATB) exhibit significantly lower levels of other pro-inflammatory cytokines (IFN?, IFN?, IL-6, IL-12 and GM-CSF). Our data therefore reveal a profound effect of Ss infection on the systemic cytokine responses in ATB and LTB and indicate that coincident helminth infections might influence pathogenesis of TB infection and disease. PMID:26542223

  8. The identification of tuberculosis biomarkers in human urine samples.

    PubMed

    Young, Brandy L; Mlamla, Zandile; Gqamana, Putuma P; Smit, Salome; Roberts, Teri; Peter, Jonathan; Theron, Grant; Govender, Ureshnie; Dheda, Keertan; Blackburn, Jonathan

    2014-06-01

    We aimed to determine whether shotgun proteomic approaches could be used to identify tuberculosis (TB)-specific biomarkers in the urine of well-characterised patients with active TB versus no TB. Patients with suspected TB (n=63) were classified as: definite TB (Mycobacterium tuberculosis positive culture, n=21); presumed latent-TB infection (LTBI) (M. tuberculosis negative culture, no radiological features of active TB, a positive QuantiFERON-TB Gold In-Tube (QFT-IT) test and a positive T-SPOT.TB test, n=24); and presumed non-TB/non-LTBI (M. tuberculosis negative culture, no radiological features of active TB, a negative QFT-IT test and a negative T-SPOT.TB test, n=18). Urine proteins, in the range of 3-50 kDa, were collected, separated by a one-dimensional SDS-PAGE gel and digested using trypsin, after which high-performance liquid chromatography-tandem mass spectrometry was used to identify the urinary proteome. 10 mycobacterial proteins were observed exclusively in the urine of definite TB patients, while six mycobacterial proteins were found exclusively in the urine of presumed LTBI patients. In addition, a gene ontology enrichment analysis identified a panel of 20 human proteins that were significant discriminators (p<0.05) for TB disease compared to no TB disease. Furthermore, seven common human proteins were differentially over- or under-expressed in the TB versus the non-TB group. These biomarkers hold promise for the development of new point-of-care diagnostics for TB. PMID:24743962

  9. Rapid diagnosis of pulmonary tuberculosis

    PubMed Central

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

    2014-01-01

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

  10. Fingerprinting Nearby Star Suspects

    NASA Astrophysics Data System (ADS)

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

    2002-02-01

    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.

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

    PubMed

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

    2004-08-15

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

  12. Controlling the seedbeds of tuberculosis: diagnosis and treatment of tuberculosis infection.

    PubMed

    Rangaka, Molebogeng X; Cavalcante, Solange C; Marais, Ben J; Thim, Sok; Martinson, Neil A; Swaminathan, Soumya; Chaisson, Richard E

    2015-12-01

    The billions of people with latent tuberculosis infection serve as the seedbeds for future cases of active tuberculosis. Virtually all episodes of tuberculosis disease are preceded by a period of asymptomatic Mycobacterium tuberculosis infection; therefore, identifying infected individuals most likely to progress to disease and treating such subclinical infections to prevent future disease provides a crucial opportunity to interrupt tuberculosis transmission and reduce the global burden of tuberculosis disease. Programmes focusing on single strategies rather than comprehensive programmes that deliver an integrated arsenal for tuberculosis control might continue to struggle. Tuberculosis preventive therapy is a poorly used method that is essential for controlling the reservoirs of disease that drive the epidemic. Comprehensive control strategies that combine preventive therapy for the most high-risk populations and communities with improved case-finding and treatment, control of transmission, and health systems strengthening could ultimately lead to worldwide tuberculosis elimination. In this Series paper we outline challenges to implementation of preventive therapy and provide pragmatic suggestions for overcoming them. We further advocate for tuberculosis preventive therapy as the core of a renewed worldwide focus to implement a comprehensive epidemic control strategy that would reduce new tuberculosis cases to elimination targets. This strategy would be underpinned by accelerated research to further understand the biology of subclinical tuberculosis infections, develop novel diagnostics and drug regimens specifically for subclinical tuberculosis infection, strengthen health systems and community engagement, and enhance sustainable large scale implementation of preventive therapy programmes. PMID:26515679

  13. Secondary laryngeal tuberculosis revisited

    PubMed Central

    Lodha, Jaini V; Sharma, Arpit; Virmani, Nitish; Bihani, Ameya; Dabholkar, Jyoti P

    2015-01-01

    Introduction: Laryngeal tuberculosis is often misdiagnosed and is a highly contagious public health problem. The changing pattern of the clinical involvement of this disease poses a diagnostic challenge. The authors report four cases of laryngeal tuberculosis encountered in a short span of one month. Materials and Methods: All the four patients who presented to us with hoarseness had underlying active lesions in the lung. In spite of that they presented with mainly laryngeal symptoms and a multitude of findings on laryngeal examination. A diagnosis could be established owing to a high index of clinical suspicion, and due consideration given to the chest findings and positive sputum examination. The patients showed an excellent response to antituberculous therapy. Results and Conclusions: This study underlines the varied nature of laryngeal tuberculosis and the importance of addressing the hoarseness of a patient at the earliest, for the prompt diagnosis of this infectious condition.

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

    SciTech Connect

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

    2009-05-26

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

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

    PubMed

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

    2014-12-01

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

  16. Three new phenylpropanoids from the roots of Piper taiwanense and their inhibitory activities on platelet aggregation and Mycobacterium tuberculosis.

    PubMed

    Chen, Si; Cheng, Ming-Jen; Wu, Chin-Chung; Peng, Chien-Fang; Huang, Hung-Yi; Chang, Hsun-Shuo; Wang, Chyi-Jia; Chen, Ih-Sheng

    2014-05-01

    Bioassay-guided fractionation of the active AcOEt-soluble fraction from the roots of Piper taiwanense has led to the isolation of two new phenylpropanoids, taiwanensols A and B (1 and 2, resp.), a new natural product, taiwanensol C (3), and 3-acetoxy-4-hydroxy-1-allylbenzene (4). The compounds were obtained as two isomer mixtures (1/2 and 3/4, resp.). Their structures were elucidated by spectroscopic analyses, including 1D- and 2D-NMR spectroscopy and mass spectrometry, and by the comparison of their NMR data with those of related compounds. Compounds 1-4 were evaluated for their antiplatelet and antitubercular activities. The mixtures 1/2 and 3/4 showed potent inhibitory activities against platelet aggregation induced by collagen, with IC50 values of 35.2 and 8.8 ?M, respectively. In addition, 1/2 and 3/4 showed antitubercular activities against Mycobacterium tuberculosis H37Rv, with MIC values of 30.0 and 48.0 ?g/ml, respectively. PMID:24827689

  17. Active case finding for tuberculosis among people who inject drugs on methadone treatment in Dar es Salaam, Tanzania

    PubMed Central

    Gupta, A.; Mbwambo, J.; Mteza, I.; Shenoi, S.; Lambdin, B.; Nyandindi, C.; Doula, B. I.; Mfaume, S.; Bruce, R. D.

    2015-01-01

    SUMMARY SETTING Active case finding is a World Health Organization (WHO) endorsed strategy for improving tuberculosis (TB) case detection. Despite WHO recommendations for active case finding among people who inject drugs (PWID), few studies have been published. The historical focus of case finding has been in populations that are human immunodeficiency virus-positive, incarcerated or at higher occupational risk. OBJECTIVE We sought to examine the yield of active case finding among PWID newly started on methadone in Tanzania. DESIGN Of 222 methadone clients, 156 (70%) met with study administrators; 150 consented to participate, 139 (93%) of whom were male. The median age was 34 years. A symptom-based questionnaire was developed by the investigators and administered to every consenting patient by a native Swahili speaker. RESULTS Of the 150 patients surveyed, 16 (11%) had one or more TB symptoms and were referred for laboratory testing. Six new TB cases were identified in this active case finding program, with a prevalence of 4%. CONCLUSION This study presents the first data on TB prevalence in a population of PWID in Tanzania. This prevalence is 23 times that of the general Tanzanian TB prevalence of 0.2%. These results have significant implications for TB control. PMID:24902554

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

    PubMed Central

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

    2015-01-01

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

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

    ERIC Educational Resources Information Center

    Connaghan, Kathryn P.; Moore, Christopher A.

    2013-01-01

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

  20. Cost-Effectiveness of a Tuberculosis Active Case Finding Program Targeting Household and Neighborhood Contacts in Cambodia

    PubMed Central

    Yadav, Rajendra P.; Nishikiori, Nobuyuki; Satha, Peou; Eang, Mao T.; Lubell, Yoel

    2014-01-01

    In many high-risk populations, access to tuberculosis (TB) diagnosis and treatment is limited and pockets of high prevalence persist. We estimated the cost-effectiveness of an extensive active case finding program in areas of Cambodia where TB notifications and household poverty rates are highest and access to care is restricted. Thirty operational health districts with high TB incidence and household poverty were randomized into intervention and control groups. In intervention operational health districts, all household and symptomatic neighborhood contacts of registered TB patients of the past two years were encouraged to attend screening at mobile centers. In control districts, routine passive case finding activities continued. The program screened more than 35,000 household and neighborhood contacts and identified 810 bacteriologically confirmed cases. The cost-effectiveness analysis estimated that in these cases the reduction in mortality from 14% to 2% would result in a cost per daily adjusted life year averted of $330, suggesting that active case finding was highly cost-effective. PMID:24615134

  1. Characterization of suspected illegal skin whitening cosmetics.

    PubMed

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

    2014-03-01

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

  2. [Tuberculosis in the crew of a submarine].

    PubMed

    Suzuki, S; Nakabayashi, K; Ohkouchi, H; Hatada, J; Kawaguchi, S; Sakai, M; Sasaki, N; Ito, A

    1997-01-01

    We report the apparent spread of mycobacterial tuberculosis among a submarine crew from a crew member with a low grade of infectivity. The air-conditioning system of submarines requires completely closed recirculation of ambient air. If a person with pulmonary tuberculosis were in a submarine, one would expect to find a high incidence of tuberculosis among others on the ship. The index patient was a 35-year-old member of a submarine crew. An abnormal shadow was found on a chest roentgenogram during an annual medical checkup, and he was hospitalized for examination. Acid-fast bacilli were found in his gastric secretions, but he did not complain of coughing and no tuberculosis bacilli were found in his sputum. All members of the submarine crew were examined, and some who were on board with the index patient reacted strongly. Because those who were also suspected to be infected were usually not close to the index patient's living quarters and had little contact with the patient in the submarine, we strongly suspect that the closed ventilation system contributed to the spread of the infection. Control of tuberculosis in a sealed environment requires detailed investigation of the environment and completion of chemoprophylaxis. Adequate ventilation and ultraviolet radiation are more effective than decontamination with disinfectants for the control of infectious droplet nuclei. Ships should be equipped with those systems. PMID:9071158

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

    SciTech Connect

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

    2009-03-02

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

  4. Childhood tuberculosis in general practice.

    PubMed

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

    2015-04-01

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

  5. Renal tuberculosis: a case report

    PubMed Central

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

    2015-01-01

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

  6. Lower Pre-Treatment T Cell Activation in Early- and Late-Onset Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

    PubMed Central

    Goovaerts, Odin; Jennes, Wim; Massinga-Loembé, Marguerite; Ondoa, Pascale; Ceulemans, Ann; Vereecken, Chris; Worodria, William; Mayanja-Kizza, Harriet; Colebunders, Robert; Kestens, Luc

    2015-01-01

    Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an inflammatory complication in HIV-TB co-infected patients receiving antiretroviral therapy (ART). The role of disturbed T cell reconstitution in TB-IRIS is not well understood. We investigated T cell activation and maturation profiles in patients who developed TB-IRIS at different intervals during ART. Methods Twenty-two HIV-TB patients who developed early-onset TB-IRIS and 10 who developed late-onset TB-IRIS were matched for age, sex and CD4 count to equal numbers of HIV-TB patients who did not develop TB-IRIS. Flow cytometry analysis was performed on fresh blood, drawn before and after ART initiation and during TB-IRIS events. T cell activation and maturation was measured on CD4+ and CD8+ T cells using CD45RO, CD38, HLA-DR, CCR7 and CD27 antibodies. Results CD8+ T cell activation before ART was decreased in both early-onset (77% vs. 82%, p = 0.014) and late-onset (71% vs. 83%, p = 0.012) TB-IRIS patients compared to non-IRIS controls. After ART initiation, the observed differences in T cell activation disappeared. During late-onset, but not early-onset TB-IRIS, we observed a skewing from memory to terminal effector CD4+ and CD8+ T cell populations (p?0.028). Conclusion Our data provide evidence of reduced CD8+ T cell activation before ART as a common predisposing factor of early- and late-onset TB-IRIS. The occurrence of TB-IRIS itself was not marked by an over-activated CD8+ T cell compartment. Late- but not early-onset TB-IRIS was characterized by a more terminally differentiated T cell phenotype. PMID:26208109

  7. [Extrapulmonary tuberculosis].

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2011-11-01

    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

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

    PubMed

    2013-03-22

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

  10. Activism on rifapentine pricing: removing cost barriers to improve the uptake of tuberculosis research innovations

    PubMed Central

    Frick, M.; Lessem, E.; Kanouse, J.; Wegener, D.; Mingote, L. Ruiz

    2014-01-01

    As recent advances have been made in developing tools to fight tuberculosis (TB), there is also a trend towards increasing advocacy by the civil society for TB research and access. One recent successful effort to increase access to treatment options for TB involved a collaborative effort to identify the need for and barriers to the use of rifapentine (RPT) use in the United States. Survey responses confirmed the under-utilization of RPT: 82% of survey respondents selected cost as a significant or potential barrier to use. Survey results provided data to support a year-long advocacy campaign urging the drug company Sanofi to lower the price of RPT. This campaign was based on a common evidence base built in part by the stakeholders themselves. After multiple engagements with communities and providers, Sanofi US announced on 12 December 2013 that they would drop the price of RPT to US$32 per blister pack of 32 tablets for US public health programs. While further work remains to secure access to RPT in the United States and worldwide, the lowering of the price of RPT reflects the positive impact that collaborative advocacy can accomplish, and sets an example for other drug companies to follow. PMID:26400702

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

    PubMed

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

    2008-01-01

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

  12. Tuberculosis control activities after Hurricane Katrina--New Orleans, Louisiana, 2005.

    PubMed

    2006-03-31

    On August 29, 2005, when Hurricane Katrina struck the U.S. Gulf Coast, 130 Louisiana residents in the greater New Orleans area were known to be undergoing treatment for tuberculosis (TB) disease. Standard treatment and cure of TB requires a multidrug regimen administered under directly observed therapy (DOT) for at least 6 months. This report updates previous information and summarizes TB cases reported as of December 31, 2005, among persons undergoing TB treatment in the New Orleans area when Hurricane Katrina made landfall and among persons who were evacuated and subsequently received a diagnosis of TB in other parts of the country. By October 13, 2005, through intensive local, state, and national efforts involving both government and private sector partners, all 130 TB patients from the New Orleans area had been located and, if still indicated, had resumed TB treatment. As a result of heightened public health surveillance among Hurricane Katrina evacuees, six other New Orleans evacuees began treatment (i.e., two persons with known TB and four with previously undiagnosed TB) after arriving in other states. The success of these post-disaster TB control measures affirms the utility of alternative data sources during health-related emergencies and the importance of maintaining a strong TB control component in the public health sector. PMID:16572101

  13. Roflumilast, a Type 4 Phosphodiesterase Inhibitor, Shows Promising Adjunctive, Host-Directed Therapeutic Activity in a Mouse Model of Tuberculosis.

    PubMed

    Maiga, Mariama C; Ahidjo, Bintou Ahmadou; Maiga, Mamoudou; Bishai, William R

    2015-12-01

    With phosphodiesterase inhibitors (PDE-Is) showing significant promise in shortening tuberculosis treatment, we assessed the effect of roflumilast, an FDA-approved type 4 PDE-I, in both acute and chronic murine models of tuberculosis. Alone, roflumilast had no effect on lung bacillary burden and mortality. However, when roflumilast was used in combination with isoniazid, a reduction in lung bacillary burden was observed. These data suggest that roflumilast may be a good candidate for tuberculosis host-directed therapy (HDT). PMID:26438491

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

    PubMed

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

    2013-08-01

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

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

    PubMed

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

    2010-04-01

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

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

    PubMed Central

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

    2014-01-01

    Tuberculosis (TB) is the second most common cause of death from infectious diseases. About 90% of those infected are asymptomatic—the so-called latent TB infections (LTBI), with a 10% lifetime chance of progressing to active TB. To further understand the molecular pathogenesis of TB, several molecular studies have attempted to compare the expression profiles between healthy controls and active TB or LTBI patients. However, the results vary due to diverse genetic backgrounds and study designs and the inherent complexity of the disease process. Thus, developing a sensitive and efficient method for the detection of LTBI is both crucial and challenging. For the present study, we performed a systematic analysis of the gene and microRNA profiles of healthy individuals versus those affected with TB or LTBI. Combined with a series of in silico analysis utilizing publicly available microRNA knowledge bases and published literature data, we have uncovered several microRNA-gene interactions that specifically target both the blood and lungs. Some of these molecular interactions are novel and may serve as potential biomarkers of TB and LTBI, facilitating the development for a more sensitive, efficient, and cost-effective diagnostic assay for TB and LTBI for the Taiwanese population. PMID:25276827

  17. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19... Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19...date of inactivity, following active tuberculosis 100 Thereafter: Rate...

  18. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19... Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19...date of inactivity, following active tuberculosis 100 Thereafter: Rate...

  19. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19... Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19...date of inactivity, following active tuberculosis 100 Thereafter: Rate...

  20. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19... Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19...date of inactivity, following active tuberculosis 100 Thereafter: Rate...

  1. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19... Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19...date of inactivity, following active tuberculosis 100 Thereafter: Rate...

  2. [Mycobacterium tuberculosis].

    PubMed

    Ohara, Naoya

    2012-02-01

    The emergence and spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has become an important health problem and threatens TB control worldwide. World Health Organization reported that there were an estimated 440,000 cases of MDR-TB in 2008. By July 2010, 58 countries and territories had reported at least one case of XDR-TB. The emergence of MDR/XDR-TB strains is reflection of poor tuberculosis management. To avoid the emergence of more resistant strains that may lead to almost untreatable TB, we must focus our efforts on the right management of drug susceptible TB. PMID:22413525

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

    PubMed Central

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

    2013-01-01

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

  4. Contribution of the Nitroimidazoles PA-824 and TBA-354 to the Activity of Novel Regimens in Murine Models of Tuberculosis

    PubMed Central

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

    2014-01-01

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

  5. Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure-activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-?-d-ribose 2'-oxidase.

    PubMed

    Landge, Sudhir; Mullick, Amrita B; Nagalapur, Kavitha; Neres, João; Subbulakshmi, Venkita; Murugan, Kannan; Ghosh, Anirban; Sadler, Claire; Fellows, Mick D; Humnabadkar, Vaishali; Mahadevaswamy, Jyothi; Vachaspati, Prakash; Sharma, Sreevalli; Kaur, Parvinder; Mallya, Meenakshi; Rudrapatna, Suresh; Awasthy, Disha; Sambandamurthy, Vasan K; Pojer, Florence; Cole, Stewart T; Balganesh, Tanjore S; Ugarkar, Bheemarao G; Balasubramanian, V; Bandodkar, Balachandra S; Panda, Manoranjan; Ramachandran, Vasanthi

    2015-12-15

    We report the discovery of benzothiazoles, a novel anti-mycobacterial series, identified from a whole cell based screening campaign. Benzothiazoles exert their bactericidal activity against Mycobacterium tuberculosis (Mtb) through potent inhibition of decaprenylphosphoryl-?-d-ribose 2'-oxidase (DprE1), the key enzyme involved in arabinogalactan synthesis. Specific target linkage and mode of binding were established using co-crystallization and protein mass spectrometry studies. Most importantly, the current study provides insights on the utilization of systematic medicinal chemistry approaches to mitigate safety liabilities while improving potency during progression from an initial genotoxic hit, the benzothiazole N-oxides (BTOs) to the lead-like AMES negative, crowded benzothiazoles (cBTs). These findings offer opportunities for development of safe clinical candidates against tuberculosis. The design strategy adopted could find potential application in discovery of safe drugs in other therapy areas too. PMID:26643218

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

    PubMed

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

    2015-06-01

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

  7. Interaction of DevR with multiple binding sites synergistically activates divergent transcription of narK2-Rv1738 genes in Mycobacterium tuberculosis.

    PubMed

    Chauhan, Santosh; Tyagi, Jaya Sivaswami

    2008-08-01

    Under hypoxic conditions or upon exposure to low concentrations of nitric oxide, DevR transcriptional regulator mediates the activation of approximately 50 genes that are believed to assist in dormancy development in Mycobacterium tuberculosis. Most of the strongly induced genes are characterized by the presence of one to four copies of a Dev box-like sequence at an upstream location. Among these are several gene pairs that are transcribed in opposite directions. This arrangement could provide for coordinated control of the adjacent genes under inducing conditions. In this work, we report the first detailed analysis of DevR-mediated hypoxic regulation of narK2-Rv1738 genes that are oppositely oriented in M. tuberculosis. Phosphorylated DevR interacts with intergenic sequences and protects approximately 80 bp of DNA that contains three binding sites, designated Dev boxes D1, D2, and D3. The hypoxia-specific transcription start points of narK2 and Rv1738 were mapped, and it was noted that the -35 elements of both promoters overlapped with the proximally placed Dev box. DevR bound cooperatively to adjacently placed D2 and D3 boxes while binding to D1 was independent of DevR interaction with the D2 and D3 boxes. Mutational analysis and green fluorescent protein reporter assays established that the three Dev boxes function synergistically to mediate maximal transcriptional induction of both narK2 and Rv1738 in hypoxic cultures of M. tuberculosis. Analysis of narK2 promoter activity indicates that it is under negative regulation in addition to DevR-mediated positive regulation and also reveals differences between M. tuberculosis and Mycobacterium bovis BCG. PMID:18502855

  8. Global Tuberculosis Report 2015

    MedlinePLUS

    ... Feed Youtube Twitter Facebook Google + iTunes Play Store Tuberculosis (TB) Menu Tuberculosis The End TB Strategy Areas ... data News, events and features About us Global tuberculosis report 2015 This is the twentieth global report ...

  9. Tuberculosis: General Information

    MedlinePLUS

    TB Elimination Tuberculosis: General Information What is TB? Tuberculosis (TB) is a disease caused by germs that are spread from person ... Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination CS227840_A What Does a Positive Test ...

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

    PubMed Central

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

    2015-01-01

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

  11. Rapid diagnosis of Mycobacterium tuberculosis bacteremia by PCR.

    PubMed Central

    Folgueira, L; Delgado, R; Palenque, E; Aguado, J M; Noriega, A R

    1996-01-01

    A method based on DNA amplification and hybridization has been used for the rapid detection of Mycobacterium tuberculosis in blood samples from 38 hospitalized patients (15 human immunodeficiency virus [HIV] positive and 23 HIV negative) in whom localized or disseminated forms of tuberculosis were suspected. In 32 of these patients, the diagnosis of tuberculosis was eventually confirmed by conventional bacteriological or histological procedures. M. tuberculosis DNA was detected with the PCR technique in the peripheral blood mononuclear cells from 9 of 11 (82%) HIV-infected patients and in 7 of 21 (33%) HIV-negative patients (P < 0.01), while M. tuberculosis blood cultures were positive in 1 of 8 (12.5%) and 1 of 18 (5.5%) patients, respectively. PCR was positive in all cases with disseminated disease in both HIV-negative and HIV-positive patients and also in the HIV-positive patients with extrapulmonary tuberculosis. Seven samples from patients with documented illness other than tuberculosis and 12 specimens from healthy volunteers, including seven volunteers with a recent positive purified protein derivative test, were used as controls and had a negative PCR. These results suggest that detection of M. tuberculosis DNA in peripheral blood mononuclear cells may be a useful tool for rapid diagnosis of disseminated and extrapulmonary forms of tuberculosis, especially in an HIV-positive population. PMID:8904404

  12. Using Peer Helpers for Tuberculosis Prevention.

    ERIC Educational Resources Information Center

    McCue, Maureen; Afifi, Larry Anna

    1996-01-01

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

  13. Prime Suspect, Second Row Center

    ERIC Educational Resources Information Center

    Laird, Ellen A.

    2011-01-01

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

  14. A Clinical Algorithm to Identify HIV Patients at High Risk for Incident Active Tuberculosis: A Prospective 5-Year Cohort Study

    PubMed Central

    Lee, Susan Shin-Jung; Lin, Hsi-Hsun; Tsai, Hung-Chin; Su, Ih-Jen; Yang, Chin-Hui; Sun, Hsin-Yun; Hung, Chien-Chin; Sy, Cheng-Len; Wu, Kuan-Sheng; Chen, Jui-Kuang; Chen, Yao-Shen; Fang, Chi-Tai

    2015-01-01

    Background Predicting the risk of tuberculosis (TB) in people living with HIV (PLHIV) using a single test is currently not possible. We aimed to develop and validate a clinical algorithm, using baseline CD4 cell counts, HIV viral load (pVL), and interferon-gamma release assay (IGRA), to identify PLHIV who are at high risk for incident active TB in low-to-moderate TB burden settings where highly active antiretroviral therapy (HAART) is routinely provided. Materials and Methods A prospective, 5-year, cohort study of adult PLHIV was conducted from 2006 to 2012 in two hospitals in Taiwan. HAART was initiated based on contemporary guidelines (CD4 count < = 350/?L). Cox regression was used to identify the predictors of active TB and to construct the algorithm. The validation cohorts included 1455 HIV-infected individuals from previous published studies. Area under the receiver operating characteristic (ROC) curve was calculated. Results Seventeen of 772 participants developed active TB during a median follow-up period of 5.21 years. Baseline CD4 < 350/?L or pVL ? 100,000/mL was a predictor of active TB (adjusted HR 4.87, 95% CI 1.49–15.90, P = 0.009). A positive baseline IGRA predicted TB in patients with baseline CD4 ? 350/?L and pVL < 100,000/mL (adjusted HR 6.09, 95% CI 1.52–24.40, P = 0.01). Compared with an IGRA-alone strategy, the algorithm improved the sensitivity from 37.5% to 76.5%, the negative predictive value from 98.5% to 99.2%. Compared with an untargeted strategy, the algorithm spared 468 (60.6%) from unnecessary TB preventive treatment. Area under the ROC curve was 0.692 (95% CI: 0.587–0.798) for the study cohort and 0.792 (95% CI: 0.776–0.808) and 0.766 in the 2 validation cohorts. Conclusions A validated algorithm incorporating the baseline CD4 cell count, HIV viral load, and IGRA status can be used to guide targeted TB preventive treatment in PLHIV in low-to-moderate TB burden settings where HAART is routinely provided to all PLHIV. The implementation of this algorithm will avoid unnecessary exposure of low-risk patients to drug toxicity and simultaneously, reduce the burden of universal treatment on the healthcare system. PMID:26280669

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

    PubMed Central

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

    2001-01-01

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

  16. Mycobacterium tuberculosis MmsA, a novel immunostimulatory antigen, induces dendritic cell activation and promotes Th1 cell-type immune responses.

    PubMed

    Kim, Jong-Seok; Kim, Woo Sik; Choi, Hong-Hee; Kim, Hong Min; Kwon, Kee Woong; Han, Seung Jung; Cha, Seung Bin; Cho, Sang-Nae; Koh, Won-Jung; Shin, Sung Jae

    2015-01-01

    Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is an outstanding pathogen that modulates the host immune response. This inconvenient truth drives the continual identification of antigens that generate protective immunity, including Th1-type T cell immunity. Here, the contribution of methylmalonate semialdehyde dehydrogenase (MmsA, Rv0753c) of Mtb to immune responses was examined in the context of dendritic cell (DC) activation and T cell immunity both in vitro and in vivo. The results showed that MmsA induced DC activation by activating the MAPK and NF-?B signaling pathways. Additionally, MmsA-treated DCs activated naïve T cells, effectively polarized CD4(+) and CD8(+) T cells to secrete IFN-? and IL-2, and induced T cell proliferation. These results indicate that MmsA is a novel DC maturation-inducing antigen that drives the Th1 immune response. Thus, MmsA was found to potentially regulate immune responses via DC activation toward Th1-type T cell immunity, enhancing our understanding of Mtb pathogenesis. PMID:26507911

  17. Spinal Tuberculosis

    PubMed Central

    Ekinci, Safak; Tatar, Oner; Akpancar, Serkan; Bilgic, Serkan; Ersen, Omer

    2015-01-01

    Spinal tuberculosis (TB) is a significant form of TB, causing spinal deformity and paralysis. Early diagnosis and treatment are crucial for avoiding multivertebral destruction and are critical for improving outcomes in spinal TB. We believe that appropriate treatment method should be implemented at the early stage of this disease and that the Gulhane Askeri T?p Akademisi classification system can be considered a practical guide for spinal TB treatment planning in all countries. PMID:26609247

  18. Crystal structures, metal activation, and DNA-binding properties of two-domain IdeR from Mycobacterium tuberculosis.

    PubMed

    Wisedchaisri, Goragot; Chou, C James; Wu, Meiting; Roach, Claudia; Rice, Adrian E; Holmes, Randall K; Beeson, Craig; Hol, Wim G J

    2007-01-16

    The iron-dependent regulator IdeR is a key transcriptional regulator of iron uptake in Mycobacterium tuberculosis. In order to increase our insight into the role of the SH3-like third domain of this essential regulator, the metal-binding and DNA-binding properties of two-domain IdeR (2D-IdeR) whose SH3-like domain has been truncated were characterized. The equilibrium dissociation constants for Co2+ and Ni2+ activation of 2D-IdeR for binding to the fxbA operator and the DNA-binding affinities of 2D-IdeR in the presence of excess metal ions were estimated using fluorescence spectroscopy. 2D-IdeR binds to fxbA operator DNA with similar affinity as full-length IdeR in the presence of excess metal ion. However, the Ni2+ concentrations required to activate 2D-IdeR for DNA binding appear to be smaller than that for full-length IdeR while the concentration of Co2+ required for activation remains the same. We have determined the crystal structures of Ni2+-activated 2D-IdeR at 1.96 A resolution and its double dimer complex with the mbtA-mbtB operator DNA in two crystal forms at 2.4 A and 2.6 A, the highest resolutions for DNA complexes for any structures of iron-dependent regulator family members so far. The 2D-IdeR-DNA complex structures confirm the specificity of Ser37 and Pro39 for thymine bases and suggest preferential contacts of Gln43 to cytosine bases of the DNA. In addition, our 2D-IdeR structures reveal a remarkable property of the TEV cleavage sequence remaining after removal of the C-terminal His6. This C-terminal tail promotes crystal contacts by forming a beta-sheet with the corresponding tail of neighboring subunits in two unrelated structures of 2D-IdeR, one with and one without DNA. The contact-promoting properties of this C-terminal TEV cleavage sequence may be beneficial for crystallizing other proteins. PMID:17209554

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

    PubMed Central

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

    2015-01-01

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

  20. Science and social justice: the lessons of HIV/AIDS activism in the struggle to eradicate tuberculosis.

    PubMed

    Achmat, Z

    2006-12-01

    The global social, political and health emergency presented by the human immunodeficiency virus and the acquired immune-deficiency syndrome (HIV/AIDS) has also once again propelled tuberculosis (TB) into a global public health emergency. The examples I will use to show how activism and social mobilisation can assist in overcoming TB are primarily from my home country, South Africa. Despite significant differences in health systems, culture, politics and history, there are lessons that could be used to advocate for TB prevention, diagnosis, treatment and care globally. Our country experiences globally significant HIV and TB epidemics. I will return to the epidemiology of TB-HIV and the crisis of illness and death. Early in April 2005, one of my closest friends, Ronald Louw, a professor of law at the University of KwaZulu-Natal, a human rights lawyer and activist for more than 25 years, suffered a persistent fever and cough. While on sabbatical, he was taking care of his mother who had been diagnosed with cancer. He assumed his illness was stress-related and went to a doctor who diagnosed bronchitis. After 4 weeks' treatment with antibiotics, his illness was worse-he had a raging fever, night sweats and was becoming disoriented. He requested an HIV test. Within 24 hours Ronald Louw knew that he had been infected with HIV. His mother died on the same day. He also knew within 24 hours that his CD4 count was below 100. They could not diagnose his lung disease and concluded that it was Pneumocystis carinii pneumonia. Four weeks later his doctors diagnosed TB through a lung biopsy. Ronald Louw had been desperately sick under medical care with TB and HIV for more than 8 weeks. He died 3 days after receiving a definitive TB diagnosis, and a week after treatment for presumptive TB had commenced. PMID:17167946

  1. Nocardia Co-Infection in Patients With Pulmonary Tuberculosis

    PubMed Central

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

    2014-01-01

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

  2. Cutaneous tuberculosis overview and current treatment regimens.

    PubMed

    van Zyl, Lindi; du Plessis, Jeanetta; Viljoen, Joe

    2015-12-01

    Tuberculosis is one of the oldest diseases known to humankind and it is currently a worldwide threat with 8-9 million new active disease being reported every year. Among patients with co-infection of the human immunodeficiency virus (HIV), tuberculosis is ultimately responsible for the most deaths. Cutaneous tuberculosis (CTB) is uncommon, comprising 1-1.5% of all extra-pulmonary tuberculosis manifestations, which manifests only in 8.4-13.7% of all tuberculosis cases. A more accurate classification of CTB includes inoculation tuberculosis, tuberculosis from an endogenous source and haematogenous tuberculosis. There is furthermore a definite distinction between true CTB caused by Mycobacterium tuberculosis and CTB caused by atypical mycobacterium species. The lesions caused by mycobacterium species vary from small papules (e.g. primary inoculation tuberculosis) and warty lesions (e.g. tuberculosis verrucosa cutis) to massive ulcers (e.g. Buruli ulcer) and plaques (e.g. lupus vulgaris) that can be highly deformative. Treatment options for CTB are currently limited to conventional oral therapy and occasional surgical intervention in cases that require it. True CTB is treated with a combination of rifampicin, ethambutol, pyrazinamide, isoniazid and streptomycin that is tailored to individual needs. Atypical mycobacterium infections are mostly resistant to anti-tuberculous drugs and only respond to certain antibiotics. As in the case of pulmonary TB, various and relatively wide-ranging treatment regimens are available, although patient compliance is poor. The development of multi-drug and extremely drug-resistant strains has also threatened treatment outcomes. To date, no topical therapy for CTB has been identified and although conventional therapy has mostly shown positive results, there is a lack of other treatment regimens. PMID:26616847

  3. Brainstem tuberculosis.

    PubMed

    Demetriou, George A

    2013-01-01

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

  4. Ethnicity-tailored novel set of ESAT-6 peptides for differentiating active and latent tuberculosis.

    PubMed

    Singh, Salam Bhopen; Biswas, Debasis; Rawat, Jagdish; Sindhwani, Girish; Patras, Abhishek; Devrani, Suraj; Sarkar, Pronoti; Mitra, Soumik; Gupta, Shailendra K

    2013-11-01

    Differentiation between active and latent TB is a diagnostic challenge in TB-endemic regions. The commercially available IFN-?-release assays are unsuitable for achieving this discrimination. We, therefore, screened ESAT-6 and CFP-10 proteins through population coverage analysis to identify minimal sets of peptides that can discriminate between these two forms of TB in a North Indian population. Comparing the diagnostic performance of a set of 2 ESAT-6 peptides (positions: 16-36; 59-79) to that of the QuantiFERON(®)-TB Gold IT (QFTGIT) assay, we observed significant difference in IFN-? and TNF-? levels between patients (n = 15) and their age- and sex-matched healthy household contacts (n = 15). While the mean (±SD) IFN? titer was 241.8 (±219.24) IU/ml for patients, the same in controls was 564.2 (±334.82) IU/ml (p = 0.039). Similarly the TNF? response was significantly higher in patients, compared to controls (796.47 ± 175.21 IU/ml vs. 481.81 ± 378.72 IU/ml; p = 0.047). IL-4 response to these peptides was non- discriminatory between the two groups. The QFTGIT Assay, however, elicited no significant difference in IFN-?, TNF-? or IL-4 levels. Hence we conclude that IFN-? or TNF-? response to these ESAT-6 peptides has the potential to differentiate between active and latent TB in our population. PMID:24011630

  5. Lower cytotoxicity, high stability, and long-term antibacterial activity of a poly(methacrylic acid)/isoniazid/rifampin nanogel against multidrug-resistant intestinal Mycobacterium tuberculosis.

    PubMed

    Chen, Tao; Li, Qiang; Guo, Lina; Yu, Li; Li, Zhenyan; Guo, Huixin; Li, Haicheng; Zhao, Meigui; Chen, Liang; Chen, Xunxun; Zhong, Qiu; Zhou, Lin; Wu, Ting

    2016-01-01

    To overcome the undesirable side effects and reduce the cytotoxicity of isoniazid (INH) and rifampin (RMP) in the digestive tract, a poly(methacrylic acid) (PMAA) nanogel was developed as a carrier of INH and RMP. This PMAA/INH/RMP nanogel was prepared as a treatment for intestinal tuberculosis caused by multidrug-resistant Mycobacterium tuberculosis (MTB). The morphology, size, and in vitro release properties were evaluated in a simulated gastrointestinal medium, and long-term antibacterial performance, cytotoxicity, stability, and activity of this novel PMAA/INH/RMP nanogel against multidrug-resistant MTB in the intestine were investigated. Our results indicate that the PMAA/INH/RMP nanogel exhibited extended antibacterial activity by virtue of its long-term release of INH and RMP in the simulated gastrointestinal medium. Further, this PMAA/INH/RMP nanogel exhibited lower cytotoxicity than did INH or RMP alone, suggesting that this PMAA/INH/RMP nanogel could be a more useful dosage form than separate doses of INH and RMP for intestinal MTB. The novel aspects of this study include the cytotoxicity study and the three-phase release profile study, which might be useful for other researchers in this field. PMID:26478357

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

    SciTech Connect

    Fukuda, Hozumi Ibukuro, Kenji; Tsukiyama, Toshitaka; Ishii, Rei

    2004-09-15

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

  7. Nosocomial tuberculosis.

    PubMed

    Catanzaro, A

    1982-05-01

    Hospital employees are at risk of contracting tuberculosis from patients. The undiagnosed case with sputum-smear positive for acid-fast bacilli is the usual source case. However, even the smear-negative patient may pose a risk. This was documented by a high rate of skin test conversion in hospital staff exposed to a smear-negative, culture-positive patient in a respiratory intensive care unit. The patient required bronchoscopy, intubation, and assisted ventilation. Of susceptible hospital staff members who were exposed to the index case, 14 of 45 (31%) converted their PPD skin test. Ten of 13 (77%) susceptible hospital staff members present at the time of bronchoscopy converted, compared with 4 of 32 (12.5%) who were not present at bronchoscopy (Fischer's exact test p = 0.0006). Rough calculations suggest that during the bronchoscopy and intubation the index case generated at least 249 infectious units per hour. At the ventilation levels in this area, this resulted in 1 infectious unit of tuberculosis in each 68.9 cubic feet of air. Improved ventilation, high efficiency filters, and ultraviolet irradiation are effective recommended ways to clean the air of infectious particles. PMID:7081816

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

    PubMed Central

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

    2014-01-01

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

  9. Unusual presentation of renal tuberculosis.

    PubMed

    Chaudhari, Aunp P; Ranganath, Ravi; Pavan, Malleshappa

    2011-07-01

    Urogenital tuberculosis (TB) is a common late manifestation of an earlier symptomatic or asymptomatic pulmonary TB infection. A latency period ranging from 5 to 40 years between the time of the initial infection and the expression of urogenital TB frequently occurs. As one of the most common sites of involvement of extrapulmonary TB, urogenital TB accounts for 15% to 20% of the infections. We present a patient who had culture-negative active tubercular kidney disease due to silent tuberculous infection. Our case demonstrates the limitations of noninvasive testing in establishing the diagnosis of renal tuberculosis. PMID:21525583

  10. A serological test in tuberculosis

    PubMed Central

    Zykov, M. P.; Geser, A.; Egsmose, T.; Godovannyi, B. A.; Donets, I.; Ang'awa, J. A. W.; Patel, R. I.; Bløcher, C.; Poti, S. J.

    1966-01-01

    Takahashi reported in 1962 that his kaolin-agglutination test (KAT), using the phosphatide fraction of Mycobacterium tuberculosis as antigen, was capable of detecting specific antibodies in sera from patients with pulmonary tuberculosis, and that the test could differentiate between active and inactive disease. The present study was designed to investigate the diagnostic efficiency of the KAT under conditions that prevail in Africa. Blood specimens were obtained from various categories of people, ranging from presumably healthy tuberculin-negative persons to patients with far-advanced pulmonary tuberculosis, and these specimens were submitted ”blindly” for serological testing. The results showed that the KAT was less sensitive and also less specific in Kenya than it had been found in Japan by Takahashi. Some reasons for this discrepancy are discussed, but no final conclusion is reached. PMID:5335460

  11. Optimal intervention strategies for tuberculosis

    NASA Astrophysics Data System (ADS)

    Bowong, Samuel; Aziz Alaoui, A. M.

    2013-06-01

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

  12. The Prevalence Rate of Tuberculin Skin Test Positive by Contacts Group to Predict the Development of Active Tuberculosis After School Outbreaks

    PubMed Central

    Kim, Hee Jin; Chun, Byung Chul; Kwon, AmyM; Lee, Gyeong-Ho; Ryu, Sungweon; Oh, Soo Yeon; Lee, Jin Beom; Yoo, Se Hwa; Kim, Eui Sook; Kim, Je Hyeong; Shin, Chol

    2015-01-01

    Background The tuberculin skin test (TST) is the standard tool to diagnose latent tuberculosis infection (LTBI) in mass screening. The aim of this study is to find an optimal cut-off point of the TST+ rate within tuberculosis (TB) contacts to predict the active TB development among adolescents in school TB outbreaks. Methods The Korean National Health Insurance Review and Assessment database was used to identify active TB development in relation to the initial TST (cut-off, 10 mm). The 7,475 contacts in 89 schools were divided into two groups: Incident TB group (43 schools) and no incident TB group (46 schools). LTBI treatment was initiated in 607 of the 1,761 TST+ contacts. The association with active TB progression was examined at different cut-off points of the TST+ rate. Results The mean duration of follow-up was 3.9±0.9 years. Thirty-three contacts developed active TB during the 4,504 person-years among the TST+ contacts without LTBI treatment (n=1,154). The average TST+ rate for the incident TB group (n=43) and no incident TB group (n=46) were 31.0% and 15.5%, respectively. The TST+ rate per group was related with TB progression (odds ratio [OR], 1.025; 95% confidence interval [CI], 1.001-1.050; p=0.037). Based on the TST+ rate per group, active TB was best predicted at TST+ ? 16% (OR, 3.11; 95% CI, 1.29-7.51; area under curve, 0.64). Conclusion Sixteen percent of the TST+ rate per group within the same grade students can be suggested as an optimal cut-off to predict active TB development in middle and high schools TB outbreaks. PMID:26508922

  13. System and method for disrupting suspect objects

    DOEpatents

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

    2013-07-09

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

  14. Photometry of 50 suspected variable stars

    NASA Technical Reports Server (NTRS)

    Hooten, James T.; Hall, Douglas S.

    1990-01-01

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

  15. 48 CFR 1303.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 1303.303 Reporting suspected antitrust violations. Suspected anti-competitive practices and antitrust law violations, as described in FAR...

  16. 48 CFR 1303.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 1303.303 Reporting suspected antitrust violations. Suspected anti-competitive practices and antitrust law violations, as described in FAR...

  17. 48 CFR 1303.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 1303.303 Reporting suspected antitrust violations. Suspected anti-competitive practices and antitrust law violations, as described in FAR...

  18. 48 CFR 1303.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 1303.303 Reporting suspected antitrust violations. Suspected anti-competitive practices and antitrust law violations, as described in FAR...

  19. 48 CFR 1303.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 1303.303 Reporting suspected antitrust violations. Suspected anti-competitive practices and antitrust law violations, as described in FAR...

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

    PubMed

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

    2011-01-01

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

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

    PubMed

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

    2015-03-01

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

  2. Tuberculosis in Blacks

    MedlinePLUS

    ... of Verified Case of Tuberculosis National Tuberculosis Indicators Project (NTIP): Frequently Asked Questions TB Genotyping TB Genotyping Information Management System (TB GIMS) Drug-Resistant TB Multidrug-Resistant ...

  3. Tuberculosis and Pregnancy

    MedlinePLUS

    ... of Verified Case of Tuberculosis National Tuberculosis Indicators Project (NTIP): Frequently Asked Questions TB Genotyping TB Genotyping Information Management System (TB GIMS) Drug-Resistant TB Multidrug-Resistant ...

  4. Tuberculosis (TB): Treatment

    MedlinePLUS

    ... 2/13 By Dr. Iseman Michael Iseman, MD Tuberculosis (TB): Treatment Given the many effective medications available ... Calendar Read the News View Daily Pollen Count Tuberculosis Program National Jewish Health is a world-renowned ...

  5. A DNA vaccine against tuberculosis based on the 65 kDa heat-shock protein differentially activates human macrophages and dendritic cells

    PubMed Central

    Franco, Luís H; Wowk, Pryscilla F; Silva, Célio L; Trombone, Ana PF; Coelho-Castelo, Arlete AM; Oliver, Constance; Jamur, Maria C; Moretto, Edson L; Bonato, Vânia LD

    2008-01-01

    Background A number of reports have demonstrated that rodents immunized with DNA vaccines can produce antibodies and cellular immune responses presenting a long-lasting protective immunity. These findings have attracted considerable interest in the field of DNA vaccination. We have previously described the prophylactic and therapeutic effects of a DNA vaccine encoding the Mycobacterium leprae 65 kDa heat shock protein (DNA-HSP65) in a murine model of tuberculosis. As DNA vaccines are often less effective in humans, we aimed to find out how the DNA-HSP65 stimulates human immune responses. Methods To address this question, we analysed the activation of both human macrophages and dendritic cells (DCs) cultured with DNA-HSP65. Then, these cells stimulated with the DNA vaccine were evaluated regarding the expression of surface markers, cytokine production and microbicidal activity. Results It was observed that DCs and macrophages presented different ability to uptake DNA vaccine. Under DNA stimulation, macrophages, characterized as CD11b+/CD86+/HLA-DR+, produced high levels of TNF-alpha, IL-6 (pro-inflammatory cytokines), and IL-10 (anti-inflammatory cytokine). Besides, they also presented a microbicidal activity higher than that observed in DCs after infection with M. tuberculosis. On the other hand, DCs, characterized as CD11c+/CD86+/CD123-/BDCA-4+/IFN-alpha-, produced high levels of IL-12 and low levels of TNF-alpha, IL-6 and IL-10. Finally, the DNA-HSP65 vaccine was able to induce proliferation of peripheral blood lymphocytes. Conclusion Our data suggest that the immune response is differently activated by the DNA-HSP65 vaccine in humans. These findings provide important clues to the design of new strategies for using DNA vaccines in human immunotherapy. PMID:18208592

  6. TUBERCULOSIS EXPOSURE CONTROL PLAN

    E-print Network

    Nicholson, Bruce J.

    TUBERCULOSIS EXPOSURE CONTROL PLAN THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO exposure to Mycobacterium tuberculosis. This plan should not be construed as a limitation on the use and employee procedures to minimize the exposure to Mycobacterium tuberculosis. This manual is intended

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

    PubMed Central

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

    2014-01-01

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

  8. Evaluation of the Diagnostic Potential of IP-10 and IL-2 as Biomarkers for the Diagnosis of Active and Latent Tuberculosis in a BCG-Vaccinated Population

    PubMed Central

    Wang, Sen; Diao, Ni; Lu, Chanyi; Wu, Jing; Gao, Yan; Chen, Jiazhen; Zhou, Zumo; Huang, Heqing; Shao, Lingyun; Jin, Jialin; Weng, Xinhua; Zhang, Ying; Zhang, Wenhong

    2012-01-01

    Background The Mycobacterium tuberculosis (Mtb)-specific T-cell interferon gamma release assays (IGRAs) are useful in detecting Mtb infection but perform poorly at distinguishing active tuberculosis disease (ATB) and latent tuberculosis infection (LTBI). This study is aimed at evaluating additional cytokines as biomarkers besides interferon-gamma (IFN-?) to improve the identification of ATB and LTBI. Methodology/Principal Findings Sixty-six patients with ATB, 73 household contacts (HHC) of ATB patients and 76 healthy controls (HC) were recruited to undergo QuantiFERON TB GOLD in-tube assay (QFT) and the enzyme-linked immunosorbent assay (ELISA) where the release of IFN-?, IFN-? inducible protein 10 (IP-10), Interleukin 2 (IL-2) and Tumor Necrosis Factor-? (TNF-?) was determined in the whole blood with or without antigen-stimulation. The positive rates of the QFT, IP-10 and IL-2 tests were 86.4%, 89.4% and 86.4% for the ATB group with no difference between them (p>0.05). However, QFT in combination with IP-10 and IL-2 significantly increased the detection rate to 95.5% in the ATB group (p?=?0.03) and the indeterminate rate of all samples decreased from 2.3% (5/215) to 0.4% (1/215). The un-stimulated level of IP-10 was significantly higher in the HHC than the ATB and HC groups. The IP-10 responses were strongly associated with extended Mtb exposure time and the degree of smear-positivity of the index cases. The IL-2/IFN-? ratio in the antigen-stimulated plasma could discriminate LTBI from ATB with a sensitivity of 77.2% and a specificity of 87.2%. Conclusion The increased Mtb-specific antigen-stimulated expression of IP-10 and IL-2 may be useful for detecting both ATB and LTBI. Combining the QFT with IP-10 and IL-2 could increase the detection accuracy of active TB over the QFT alone. PMID:23272100

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

    SciTech Connect

    Wubben, T.; Mesecar, A.D.

    2014-10-02

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

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

    SciTech Connect

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

    2010-07-20

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

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

    PubMed Central

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

    2014-01-01

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

  12. Virulence factors of the Mycobacterium tuberculosis complex

    PubMed Central

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

    2013-01-01

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

  13. Tuberculosis Facts - Exposure to TB

    MedlinePLUS

    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 ... Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination

  14. Tuberculosis in the lung (image)

    MedlinePLUS

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

  15. Tuberculosis Facts - Testing for TB

    MedlinePLUS

    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 ... Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination

  16. Health Care Workers and Tuberculosis

    MedlinePLUS

    MENU Return to Web version Health Care Workers and Tuberculosis How can I protect myself from tuberculosis infection? It's important to know which ... care worker, you should have a tuberculosis skin test once or twice a year. The test determines ...

  17. Guidelines for identifying suspect/counterfeit material

    SciTech Connect

    1995-09-01

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

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

    PubMed

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

    2013-02-01

    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

  19. CTIOPI: Fingerprinting Nearby Star Suspects

    NASA Astrophysics Data System (ADS)

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

    2001-02-01

    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.

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

    PubMed Central

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

    2013-01-01

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

  1. [A case of pulmonary Mycobacterium kansasii infection with pleural effusion, distinguished from pulmonary tuberculosis].

    PubMed

    Kimura, Yosuke; Kurosawa, Takayuki; Hosaka, Kiminori

    2014-09-01

    A case of pulmonary Mycobacterium kansasii infection with pleural effusion is very rare. We report a case of pulmonary Mycobacterium kansasii infection with pleural effusion, distinguished from pulmonary tuberculosis. A 44-year-old man presented to a clinic with a productive cough, sputum, and loss of appetite for several months. Chest X-ray and chest computed tomography (CT) showed right pleural effusion, centrilobular nodules and infiltrative shadows with cavities in the bilateral lung fields. The direct smear examination showed positive acid-fast bacilli (Gaffky 5). He was referred to our hospital for suspected recurrent pulmonary tuberculosis. We started anti-tuberculosis drugs because pulmonary tuberculosis complicated with pleurisy was first suspected from the findings of high ADA level (78.6 IU/l) of the effusion and positive result of interferon-gamma release assay (QuantiFERON TB-2G). But Mycobacterium tuberculosis and M. avium complex was not identified by the polymerase chain reaction method and the culture of the sputum was negative. At a later date, Mycobacterium kansasii was detected by sputum culture. The patient was diagnosed as pulmonary Mycobacterium kansasii infection and treatment with anti-tuberculosis drugs including RFP resulted in a good clinical response. This case was a rare case of pulmonary Mycobacterium kansasii infection with pleural effusion, distinguished from pulmonary tuberculosis. PMID:25730945

  2. Tuberculosis: Medico-Legal Aspects

    PubMed Central

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

    2014-01-01

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

  3. 38 CFR 3.372 - Initial grant following inactivity of tuberculosis.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... inactivity of tuberculosis. 3.372 Section 3.372 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF... Considerations Relative to Specific Diseases § 3.372 Initial grant following inactivity of tuberculosis. When... tuberculosis and there is satisfactory evidence that the condition was active previously but is now...

  4. 38 CFR 3.372 - Initial grant following inactivity of tuberculosis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... inactivity of tuberculosis. 3.372 Section 3.372 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF... Considerations Relative to Specific Diseases § 3.372 Initial grant following inactivity of tuberculosis. When... tuberculosis and there is satisfactory evidence that the condition was active previously but is now...

  5. 38 CFR 3.372 - Initial grant following inactivity of tuberculosis.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... inactivity of tuberculosis. 3.372 Section 3.372 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF... Considerations Relative to Specific Diseases § 3.372 Initial grant following inactivity of tuberculosis. When... tuberculosis and there is satisfactory evidence that the condition was active previously but is now...

  6. 38 CFR 3.372 - Initial grant following inactivity of tuberculosis.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... inactivity of tuberculosis. 3.372 Section 3.372 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF... Considerations Relative to Specific Diseases § 3.372 Initial grant following inactivity of tuberculosis. When... tuberculosis and there is satisfactory evidence that the condition was active previously but is now...

  7. SINGLE MOLECULE DETECTION OF TUBERCULOSIS NUCLEIC ACID USING DARK FIELD TETHERED PARTICLE MOTION

    E-print Network

    Rieger, Bernd

    SINGLE MOLECULE DETECTION OF TUBERCULOSIS NUCLEIC ACID USING DARK FIELD TETHERED PARTICLE MOTION for tuberculosis nucleic acid detection re- quire amplification and labeling before detection is possible. We of a range of infections (for example active tuberculosis) a nucleic acid Corresponding author: s

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

    E-print Network

    Yeh, Syun-Ru

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

  9. 38 CFR 3.372 - Initial grant following inactivity of tuberculosis.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... inactivity of tuberculosis. 3.372 Section 3.372 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF... Considerations Relative to Specific Diseases § 3.372 Initial grant following inactivity of tuberculosis. When... tuberculosis and there is satisfactory evidence that the condition was active previously but is now...

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

    E-print Network

    Stroud, Robert

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

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

    PubMed Central

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

    2013-01-01

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

  12. Bilateral Parotid Tuberculosis

    PubMed Central

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

    2011-01-01

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

  13. TUBERCULOSIS COMO ENFERMEDAD OCUPACIONAL

    PubMed Central

    Mendoza-Ticona, Alberto

    2014-01-01

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

  14. EXPERIMENTAL EPIDEMIOLOGY OF TUBERCULOSIS

    PubMed Central

    Perla, David

    1927-01-01

    1. Normal guinea pigs exposed to tuberculous cage mates infected intraperitoneally and with no cutaneous ulceration readily contract spontaneous tuberculosis. 2. The incidence of spontaneous tuberculosis increases with the intensity and with the duration of exposure. 3. Spontaneous tuberculosis acquired from infected cage mates has with few exceptions the characters of an infection which has entered by way of the digestive tract, disease of mesenteric and cervical lymph nodes being conspicuous. 4. Guinea pigs exposed to tuberculous animals in the same room but not in the same cage may acquire tuberculosis which has the characters of a bronchiogenic infection associated with lesions of the lungs and tracheobronchial lymph nodes. PMID:19869247

  15. 45 CFR 96.127 - Requirements regarding tuberculosis.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... confidentiality requirements, including 42 CFR part 2; and (4) will conduct case management activities to ensure... 45 Public Welfare 1 2010-10-01 2010-10-01 false Requirements regarding tuberculosis. 96.127... Substance Abuse Prevention and Treatment Block Grant § 96.127 Requirements regarding tuberculosis....

  16. 45 CFR 96.127 - Requirements regarding tuberculosis.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... confidentiality requirements, including 42 CFR part 2; and (4) will conduct case management activities to ensure... 45 Public Welfare 1 2013-10-01 2013-10-01 false Requirements regarding tuberculosis. 96.127... Substance Abuse Prevention and Treatment Block Grant § 96.127 Requirements regarding tuberculosis....

  17. 45 CFR 96.127 - Requirements regarding tuberculosis.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... confidentiality requirements, including 42 CFR part 2; and (4) will conduct case management activities to ensure... 45 Public Welfare 1 2014-10-01 2014-10-01 false Requirements regarding tuberculosis. 96.127... Substance Abuse Prevention and Treatment Block Grant § 96.127 Requirements regarding tuberculosis....

  18. 45 CFR 96.127 - Requirements regarding tuberculosis.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... confidentiality requirements, including 42 CFR part 2; and (4) will conduct case management activities to ensure... 45 Public Welfare 1 2011-10-01 2011-10-01 false Requirements regarding tuberculosis. 96.127... Substance Abuse Prevention and Treatment Block Grant § 96.127 Requirements regarding tuberculosis....

  19. 45 CFR 96.127 - Requirements regarding tuberculosis.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... confidentiality requirements, including 42 CFR part 2; and (4) will conduct case management activities to ensure... 45 Public Welfare 1 2012-10-01 2012-10-01 false Requirements regarding tuberculosis. 96.127... Substance Abuse Prevention and Treatment Block Grant § 96.127 Requirements regarding tuberculosis....

  20. [Tuberculosis in Asia].

    PubMed

    2002-10-01

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

  1. Acute Hypercalcaemia and Hypervitaminosis D in an Infant with Extra Pulmonary Tuberculosis.

    PubMed

    Dayal, Devi; Didel, Siya Ram; Agarwal, Sikha; Sachdeva, Naresh; Singh, Meenu

    2015-10-01

    In patients with tuberculosis, abnormal extrarenal production of 1,25-dihydroxyvitamin D3 by activated macrophages in granulomatous tissues may result in hypercalcaemia. More commonly reported in adults with active pulmonary tuberculosis, this complication may rarely occur in extrapulmonary tuberculosis, and children. The hypercalcaemia may be precipitated by usually recommended vitamin D and calcium supplementation in patients with tuberculosis. We report here an infant with tubercular meningitis who developed hypercalcaemia 12 days after starting routine vitamin D and calcium supplementation. This communication highlights the importance of close monitoring of calcium levels in patients with tuberculosis, especially if started on vitamin D and calcium replacement before anti-tubercular therapy. PMID:26557587

  2. Acute Hypercalcaemia and Hypervitaminosis D in an Infant with Extra Pulmonary Tuberculosis

    PubMed Central

    Didel, Siya Ram; Agarwal, Sikha; Sachdeva, Naresh; Singh, Meenu

    2015-01-01

    In patients with tuberculosis, abnormal extrarenal production of 1,25-dihydroxyvitamin D3 by activated macrophages in granulomatous tissues may result in hypercalcaemia. More commonly reported in adults with active pulmonary tuberculosis, this complication may rarely occur in extrapulmonary tuberculosis, and children. The hypercalcaemia may be precipitated by usually recommended vitamin D and calcium supplementation in patients with tuberculosis. We report here an infant with tubercular meningitis who developed hypercalcaemia 12 days after starting routine vitamin D and calcium supplementation. This communication highlights the importance of close monitoring of calcium levels in patients with tuberculosis, especially if started on vitamin D and calcium replacement before anti-tubercular therapy. PMID:26557587

  3. Structure and inhibition of subunit I of the anthranilate synthase complex of Mycobacterium tuberculosis and expression of the active complex.

    PubMed

    Bashiri, Ghader; Johnston, Jodie M; Evans, Genevieve L; Bulloch, Esther M M; Goldstone, David C; Jirgis, Ehab N M; Kleinboelting, Silke; Castell, Alina; Ramsay, Rochelle J; Manos-Turvey, Alexandra; Payne, Richard J; Lott, J Shaun; Baker, Edward N

    2015-11-01

    The tryptophan-biosynthesis pathway is essential for Mycobacterium tuberculosis (Mtb) to cause disease, but not all of the enzymes that catalyse this pathway in this organism have been identified. The structure and function of the enzyme complex that catalyses the first committed step in the pathway, the anthranilate synthase (AS) complex, have been analysed. It is shown that the open reading frames Rv1609 (trpE) and Rv0013 (trpG) encode the chorismate-utilizing (AS-I) and glutamine amidotransferase (AS-II) subunits of the AS complex, respectively. Biochemical assays show that when these subunits are co-expressed a bifunctional AS complex is obtained. Crystallization trials on Mtb-AS unexpectedly gave crystals containing only AS-I, presumably owing to its selective crystallization from solutions containing a mixture of the AS complex and free AS-I. The three-dimensional structure reveals that Mtb-AS-I dimerizes via an interface that has not previously been seen in AS complexes. As is the case in other bacteria, it is demonstrated that Mtb-AS shows cooperative allosteric inhibition by tryptophan, which can be rationalized based on interactions at this interface. Comparative inhibition studies on Mtb-AS-I and related enzymes highlight the potential for single inhibitory compounds to target multiple chorismate-utilizing enzymes for TB drug discovery. PMID:26527146

  4. [Tuberculosis microepidemic in a commuter bus].

    PubMed

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

    1999-06-01

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

  5. Breath-based biomarkers for tuberculosis

    NASA Astrophysics Data System (ADS)

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

    2012-06-01

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

  6. Synthetic Long Peptide Derived from Mycobacterium tuberculosis Latency Antigen Rv1733c Protects against Tuberculosis.

    PubMed

    Coppola, Mariateresa; van den Eeden, Susan J F; Wilson, Louis; Franken, Kees L M C; Ottenhoff, Tom H M; Geluk, Annemieke

    2015-09-01

    Responsible for 9 million new cases of active disease and nearly 2 million deaths each year, tuberculosis (TB) remains a global health threat of overwhelming dimensions. Mycobacterium bovis BCG, the only licensed vaccine available, fails to confer lifelong protection and to prevent reactivation of latent infection. Although 15 new vaccine candidates are now in clinical trials, an effective vaccine against TB remains elusive, and new strategies for vaccination are vital. BCG vaccination fails to induce immunity against Mycobacterium tuberculosis latency antigens. Synthetic long peptides (SLPs) combined with adjuvants have been studied mostly for therapeutic cancer vaccines, yet not for TB, and proved to induce efficient antitumor immunity. This study investigated an SLP derived from Rv1733c, a major M. tuberculosis latency antigen which is highly expressed by "dormant" M. tuberculosis and well recognized by T cells from latently M. tuberculosis-infected individuals. In order to assess its in vivo immunogenicity and protective capacity, Rv1733c SLP in CpG was administered to HLA-DR3 transgenic mice. Immunization with Rv1733c SLP elicited gamma interferon-positive/tumor necrosis factor-positive (IFN-?(+)/TNF(+)) and IFN-?(+) CD4(+) T cells and Rv1733c-specific antibodies and led to a significant reduction in the bacterial load in the lungs of M. tuberculosis-challenged mice. This was observed both in a pre- and in a post-M. tuberculosis challenge setting. Moreover, Rv1733c SLP immunization significantly boosted the protective efficacy of BCG, demonstrating the potential of M. tuberculosis latency antigens to improve BCG efficacy. These data suggest a promising role for M. tuberculosis latency antigen Rv1733c-derived SLPs as a novel TB vaccine approach, both in a prophylactic and in a postinfection setting. PMID:26202436

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

    PubMed Central

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

    2014-01-01

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

  8. Mycobacterium bovis (Bovine Tuberculosis) in Humans

    MedlinePLUS

    Mycobacterium bovis (Bovine Tuberculosis) in Humans What is Mycobacterium bovis ? In the United States, the majority of tuberculosis (TB) cases in people are caused by Mycobacterium tuberculosis ( ...

  9. 78 FR 36698 - Microbiology Devices; Reclassification of Nucleic Acid-Based Systems for Mycobacterium tuberculosis

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-19

    ...nucleic acid-based in vitro diagnostic devices for...of rapid detection of infection in patients with suspected...nucleic acid- based in vitro diagnostic devices for...transmission of tuberculosis infection to health care workers...nucleic acid-based in vitro diagnostic devices...

  10. 77 FR 16126 - Microbiology Devices; Reclassification of Nucleic Acid-Based Systems for Mycobacterium tuberculosis

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-19

    ...transmission of tuberculosis infection to healthcare workers...nucleic acid-based in vitro diagnostic devices for...nucleic acid-based in vitro diagnostic devices for...of rapid detection of infection in patients with suspected...nucleic acid- based in vitro diagnostic devices...

  11. 48 CFR 403.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 403.303 Reporting suspected antitrust violations. Contracting officers shall...circumstances of suspected violations of antitrust laws to the Office of Inspector General in...

  12. 48 CFR 403.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 403.303 Reporting suspected antitrust violations. Contracting officers shall...circumstances of suspected violations of antitrust laws to the Office of Inspector General in...

  13. 48 CFR 403.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 403.303 Reporting suspected antitrust violations. Contracting officers shall...circumstances of suspected violations of antitrust laws to the Office of Inspector General in...

  14. 48 CFR 1403.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...PERSONAL CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 1403.303 Reporting suspected antitrust violations. (a) Reports on suspected violations of antitrust laws as required by FAR 3.303 shall be prepared by...

  15. 48 CFR 403.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 403.303 Reporting suspected antitrust violations. Contracting officers shall...circumstances of suspected violations of antitrust laws to the Office of Inspector General in...

  16. 48 CFR 403.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 403.303 Reporting suspected antitrust violations. Contracting officers shall...circumstances of suspected violations of antitrust laws to the Office of Inspector General in...

  17. 48 CFR 1403.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ...PERSONAL CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 1403.303 Reporting suspected antitrust violations. (a) Reports on suspected violations of antitrust laws as required by FAR 3.303 shall be prepared by...

  18. 48 CFR 1403.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...PERSONAL CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 1403.303 Reporting suspected antitrust violations. (a) Reports on suspected violations of antitrust laws as required by FAR 3.303 shall be prepared by...

  19. Pulmonary tuberculosis

    MedlinePLUS

    ... risk of active TB or reactivation of TB: Elderly Infants People with weakened immune systems, for example due to HIV/AIDS , chemotherapy , diabetes, or medicines that weaken the immune system Your ...

  20. Spinal tuberculosis: a review.

    PubMed

    Garg, Ravindra Kumar; Somvanshi, Dilip Singh

    2011-01-01

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

  1. "Tuberculosis Case Management" Training.

    ERIC Educational Resources Information Center

    Knebel, Elisa; Kolodner, Jennifer

    2001-01-01

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

  2. Primary tuberculosis of thyroid.

    PubMed

    Varghese, Ashish; Suneha, Swati; Shaha, Ashok

    2015-01-01

    Tuberculosis (TB) of the thyroid gland, either in its primary or secondary form, is an extremely rare occurrence. It is infrequent even in countries with high incidence and prevalence of pulmonary and extrapulmonary TB. We report here a case of primary tuberculosis of thyroid presenting to us with sudden onset thyroid swelling since 20 days. PMID:26545476

  3. Tuberculosis and nature's pharmacy of putative anti-tuberculosis agents.

    PubMed

    Chinsembu, Kazhila C

    2016-01-01

    Due to the growing problem of drug resistant Mycobacterium tuberculosis strains, coupled with the twinning of tuberculosis (TB) to human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), the burden of TB is now difficult to manage. Therefore, new antimycobacterial agents are being sought from natural sources. This review focuses on natural antimycobacterial agents from endophytes and medicinal plants of Africa, Europe, Asia, South America and Canada. In the countries mentioned in this review, numerous plant species display putative anti-TB activity. Several antimycobacterial chemical compounds have also been isolated, including: ellagitannin punicalagin, allicin, anthraquinone glycosides, iridoids, phenylpropanoids, beta-sitosterol, galanthimine, crinine, friedelin, gallic acid, ellagic acids, anthocyanidin, taraxerol, termilignan B, arjunic acid, glucopyranosides, 1-epicatechol, leucopelargonidol, hydroxybenzoic acids, benzophenanthridine alkaloids, neolignans, and decarine. These compounds may provide leads to novel and more efficacious drugs to lessen the global burden of TB and drug-resistant M. tuberculosis strains. If there is a long-term remedy for TB, it must lie in nature's pharmacy of putative antimycobacterial agents. PMID:26464047

  4. Acceptability of sputum specimens for diagnosing pulmonary tuberculosis.

    PubMed

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

    2015-06-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-09-01

    Doubly end-on azido-bridged mixed-valence trinuclear cobalt complex, [Co3(L)2(N3)6(CH3OH)2] (1) is afforded by employing a potential monoanionic tetradentate-N2O2 Schiff base precursor (2-[{[2-(dimethylamino)ethyl]imino}methyl]-6-methoxyphenol; HL). Single crystal X-ray structure reveals that in 1, the adjacent CoII and CoIII ions are linked by double end-on azido bridges and thus the full molecule is generated by the site symmetry of a crystallographic twofold rotation axis. Complex 1 is subjected on different spectral analysis such as IR, UV-vis, emission and EPR spectroscopy. On variable temperature magnetic study, we observe that during cooling, the ?MT values decrease smoothly until 15 K and then reaches to the value 1.56 cm3 K mol-1 at 2 K. Complex 1 inhibits the cell growth on human lung carcinoma (A549 cells), human colorectal (COLO 205 and HT-29 cells), and human heptacellular (PLC5 cells) carcinoma cells. Complex 1 exhibits anti-mycobacterial activity and considerable efficacy on Mycobacterium tuberculosis H37Rv ATCC 27294 and H37Ra ATCC 25177 strains.

  6. Phytochemical analyses and activity of herbal medicinal plants of North- East India for anti-diabetic, anti-cancer and anti-tuberculosis and their docking studies.

    PubMed

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

    2015-01-01

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

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

    SciTech Connect

    Pal, Kuntal; Kumar, Shiva; Sharma, Shikha; Garg, Saurabh Kumar; Alam, Mohammad Suhail; Xu, H. Eric; Agrawal, Pushpa; Swaminathan, Kunchithapadam

    2010-07-13

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

  8. Soluble Markers of the Toll-Like Receptor 4 Pathway Differentiate between Active and Latent Tuberculosis and Are Associated with Treatment Responses

    PubMed Central

    Feruglio, Siri L.; Trøseid, Marius; Damås, Jan Kristian; Kvale, Dag; Dyrhol-Riise, Anne Ma

    2013-01-01

    Background Biomarkers to differentiate between active tuberculosis (TB) and latent TB infection (LTBI) and to monitor treatment responses are requested to complement TB diagnostics and control, particularly in patients with multi-drug resistant TB. We have studied soluble markers of the Toll-like-receptor 4 (TLR-4) pathway in various stages of TB disease and during anti-TB treatment. Methods Plasma samples from patients with culture confirmed drug-sensitive TB (n?=?19) were collected before and after 2, 8 and 24 weeks of efficient anti-TB treatment and in a LTBI group (n?=?6). Soluble (s) CD14 and myeloid differentiation-2 (MD-2) were analyzed by the Enzyme-linked immunosorbent assay (ELISA). Lipopolysaccharide (LPS) was analyzed by the Limulus Amebocyte Lysate colorimetric assay. Nonparametric statistics were applied. Results Plasma levels of sCD14 (p<0.001), MD-2 (p?=?0.036) and LPS (p?=?0.069) were elevated at baseline in patients with untreated active TB compared to the LTBI group. MD-2 concentrations decreased after 2 weeks of treatment (p?=?0.011), while LPS levels decreased after 8 weeks (p?=?0.005). In contrast, sCD14 levels increased after 2 weeks (p?=?0.047) with a subsequent modest decrease throughout the treatment period. There was no significant difference in concentrations of any of these markers between patients with pulmonary and extrapulmonary TB or between patients with or without symptoms. Conclusion Our data suggest that plasma levels of LPS, MD-2 and sCD14 can discriminate between active TB and LTBI. A decline in LPS and MD-2 concentrations was associated with response to anti-TB treatment. The clinical potential of these soluble TLR-4 pathway proteins needs to be further explored. PMID:23875007

  9. Ocular tuberculosis: current perspectives

    PubMed Central

    Shakarchi, Faiz I

    2015-01-01

    The World Health Organization currently estimates that nearly two billion people, or one-third of the world’s population, are infected by tuberculosis, and that roughly 10% of the infected people are symptomatic. Tuberculosis affects the lungs in 80% of patients, while in the remaining 20% the disease may affect other organs, including the eye. Uveitis can be seen concurrently with tuberculosis, but a direct association is difficult to prove. Ocular tuberculosis is usually not associated with clinical evidence of pulmonary tuberculosis, as up to 60% of extrapulmonary tuberculosis patients may not have pulmonary disease. The diagnosis of tuberculous uveitis is often problematic and in nearly all reported cases, the diagnosis was only presumptive. Tuberculous uveitis is a great mimicker of various uveitis entities and it can be considered in the differential diagnosis of any type of intraocular inflammation. It is still unknown if ocular manifestations result from a direct mycobacterium infection or hypersensitivity reaction and this is reflected on the management of tuberculous uveitis. Prevalence of tuberculosis as an etiology of uveitis may reach up to 10% in endemic areas. Tuberculous uveitis is a vision-threatening disease that inevitably leads to blindness if not properly diagnosed and treated. The aim of this review is to illustrate the various clinical features and management of presumed tuberculous uveitis. The current review focuses on the diagnostic criteria, significance of tuberculin skin test, and use of systemic corticosteroids in the management of tuberculous uveitis as recommended in recent publications. PMID:26648690

  10. Transforming the Fight Against Tuberculosis: Targeting Catalysts of Transmission

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  12. Atypical spinal tuberculosis.

    PubMed

    Pande, Ketan C; Babhulkar, Sudhir S

    2002-05-01

    Typical spinal tuberculosis is readily diagnosed and treated. Certain atypical clinical and radiologic presentations of spinal tuberculosis are described. Failure to recognize these presentations may lead to delay in diagnosis and initiation of treatment. In some atypical forms of the disease, this may have disastrous consequences. The current authors present a new classification for atypical spinal tuberculosis and describe the various presentations. The role of advanced imaging studies such as computed tomography scanning and magnetic resonance imaging and imaging-guided aspiration cytology is discussed. PMID:11964633

  13. Suspected poisoning of domestic animals by pesticides.

    PubMed

    Caloni, Francesca; Cortinovis, Cristina; Rivolta, Marina; Davanzo, Franca

    2016-01-01

    A retrospective study was carried out by reviewing all suspected cases of domestic animal poisoning attributed to pesticides, reported to the Milan Poison Control Centre (MPCC) between January 2011 and December 2013. During this period, pesticides were found to be responsible for 37.3% of all suspected poisoning enquiries received (815). The most commonly species involved was the dog (71.1% of calls) followed by the cat (15.8%), while a limited number of cases involved horses, goats and sheep. Most cases of exposure (47.1%) resulted in mild to moderate clinical signs. The outcome was reported in 59.9% of these cases, with death occurring in 10.4% of them. Insecticides (40.8%) proved to be the most common group of pesticides involved and exposure to pyrethrins-pyrethroids accounted for the majority of calls. According to the MPCC data, there has been a decrease in the number of suspected poisonings cases attributed to pesticides that have been banned by the EU, including aldicarb, carbofuran, endosulfan and paraquat. In contrast, there has been an increase of suspected poisoning cases attributed to the neonicotinoids, imidacloprid and acetamiprid, probably due to their widespread use in recent years. Cases of suspected poisoning that involved exposure to rodenticides accounted for 27.6% of calls received by the MPCC and anticoagulant rodenticides were the primary cause of calls, with many cases involving brodifacoum and bromadiolone. Herbicides were involved in 14.2% of calls related to pesticides and glyphosate was the main culprit in cases involving dogs, cats, horses, goats and sheep. As far as exposure to molluscicides (11.5%) and fungicides (5.9%), most of the cases involved dogs and the suspected poisoning agents were metaldehyde and copper compounds respectively. The data collected are useful in determining trends in poisoning episodes and identifying newly emerging toxicants, thus demonstrating the prevalence of pesticides as causative agents in animal poisonings. PMID:26367188

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

    PubMed Central

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

    2014-01-01

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

  15. Asymptomatic Helminth Infection in Active Tuberculosis Is Associated with Increased Regulatory and Th-2 Responses and a Lower Sputum Smear Positivity

    PubMed Central

    Abate, Ebba; Belayneh, Meseret; Idh, Jonna; Diro, Ermias; Elias, Daniel; Britton, Sven; Aseffa, Abraham; Stendahl, Olle; Schön, Thomas

    2015-01-01

    Background The impact of intestinal helminth infection on the clinical presentation and immune response during active tuberculosis (TB) infection is not well characterized. Our aim was to investigate whether asymptomatic intestinal helminth infection alters the clinical signs and symptoms as well as the cell mediated immune responses in patients with active TB. Methodology Consecutive, newly diagnosed TB patients and healthy community controls (CCs) were recruited in North-west Ethiopia. TB-score, body mass index and stool samples were analyzed. Cells from HIV-negative TB patients (HIV-/TB) and from CCs were analyzed for regulatory T-cells (Tregs) and cytokine responses using flow cytometry and ELISPOT, respectively. Results A significantly higher ratio of helminth co-infection was observed in TB patients without HIV (Helm+/HIV-/TB) compared to HIV negative CCs, (40% (121/306) versus 28% (85/306), p = 0.003). Helm+/HIV-/TB patients showed significantly increased IL-5 secreting cells compared to Helm-/HIV-/TB (37 SFU (IQR:13–103) versus 2 SFU (1–50); p = 0.02, n = 30). Likewise, levels of absolute Tregs (9.4 (3.2–16.7) cells/?l versus 2.4 (1.1–4.0) cells/?l; p = 0.041) and IL-10 secreting cells (65 SFU (7–196) versus 1 SFU (0–31); p = 0.014) were significantly higher in Helm+/HIV-/TB patients compared to Helm-/HIV-/TB patients. In a multivariate analysis, a lower rate of sputum smear positivity for acid fast bacilli, lower body temperature, and eosinophilia were independently associated with helminth infection in TB patients. Conclusions Asymptomatic helminth infection is associated with increased regulatory T-cell and Th2-type responses and a lower rate of sputum smear positivity. Further studies are warranted to investigate the clinical and immunological impact of helminth infection in TB patients. PMID:26248316

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

    PubMed Central

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

    2015-01-01

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

  17. Challenges from Tuberculosis Diagnosis to Care in Community-Based Active Case Finding among the Urban Poor in Cambodia: A Mixed-Methods Study

    PubMed Central

    Malhotra, Shelly; Koeut, Pichenda; Thai, Sopheak; Khun, Kim Eam; Colebunders, Robert; Lynen, Lut

    2015-01-01

    Background While community-based active case finding (ACF) for tuberculosis (TB) holds promise for increasing early case detection among hard-to-reach populations, limited data exist on the acceptability of active screening. We aimed to identify barriers and explore facilitators on the pathway from diagnosis to care among TB patients and health providers. Methods Mixed-methods study. We administered a survey questionnaire to, and performed in-depth interviews with, TB patients identified through ACF from poor urban settlements in Phnom Penh, Cambodia. Additionally, we conducted focus group discussions and in-depth interviews with community and public health providers involved in ACF, respectively. Results Acceptance of home TB screening was strong among key stakeholders due to perceived reductions in access barriers and in direct and indirect patient costs. Privacy and stigma were not an issue. To build trust and facilitate communication, the participation of community representatives alongside health workers was preferred. Most health providers saw ACF as complementary to existing TB services; however, additional workload as a result of ACF was perceived as straining operating capacity at public sector sites. Proximity to a health facility and disease severity were the strongest determinants of prompt care-seeking. The main reasons reported for delays in treatment-seeking were non-acceptance of diagnosis, high indirect costs related to lost income/productivity and transportation expenses, and anticipated side-effects from TB drugs. Conclusions TB patients and health providers considered home-based ACF complementary to facility-based TB screening. Strong engagement with community representatives was believed critical in gaining access to high risk communities. The main barriers to prompt treatment uptake in ACF were refusal of diagnosis, high indirect costs, and anticipated treatment side-effects. A patient-centred approach and community involvement were essential in mitigating barriers to care in marginalised communities. PMID:26222545

  18. Risk Factors for Tuberculosis

    PubMed Central

    Narasimhan, Padmanesan; Wood, James; MacIntyre, Chandini Raina; Mathai, Dilip

    2013-01-01

    The risk of progression from exposure to the tuberculosis bacilli to the development of active disease is a two-stage process governed by both exogenous and endogenous risk factors. Exogenous factors play a key role in accentuating the progression from exposure to infection among which the bacillary load in the sputum and the proximity of an individual to an infectious TB case are key factors. Similarly endogenous factors lead in progression from infection to active TB disease. Along with well-established risk factors (such as human immunodeficiency virus (HIV), malnutrition, and young age), emerging variables such as diabetes, indoor air pollution, alcohol, use of immunosuppressive drugs, and tobacco smoke play a significant role at both the individual and population level. Socioeconomic and behavioral factors are also shown to increase the susceptibility to infection. Specific groups such as health care workers and indigenous population are also at an increased risk of TB infection and disease. This paper summarizes these factors along with health system issues such as the effects of delay in diagnosis of TB in the transmission of the bacilli. PMID:23476764

  19. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... nonpulmonary tuberculosis initially entitled after August 19, 1968. 4.88c Section 4.88c Pensions, Bonuses, and... tuberculosis initially entitled after August 19, 1968. Rating For 1 year after date of inactivity, following active tuberculosis 100 Thereafter: Rate residuals under the specific body system or systems...

  20. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... nonpulmonary tuberculosis initially entitled after August 19, 1968. 4.88c Section 4.88c Pensions, Bonuses, and... tuberculosis initially entitled after August 19, 1968. Rating For 1 year after date of inactivity, following active tuberculosis 100 Thereafter: Rate residuals under the specific body system or systems...

  1. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... nonpulmonary tuberculosis initially entitled after August 19, 1968. 4.88c Section 4.88c Pensions, Bonuses, and... tuberculosis initially entitled after August 19, 1968. Rating For 1 year after date of inactivity, following active tuberculosis 100 Thereafter: Rate residuals under the specific body system or systems...

  2. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... nonpulmonary tuberculosis initially entitled after August 19, 1968. 4.88c Section 4.88c Pensions, Bonuses, and... tuberculosis initially entitled after August 19, 1968. Rating For 1 year after date of inactivity, following active tuberculosis 100 Thereafter: Rate residuals under the specific body system or systems...

  3. 38 CFR 4.88c - Ratings for inactive nonpulmonary tuberculosis initially entitled after August 19, 1968.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... nonpulmonary tuberculosis initially entitled after August 19, 1968. 4.88c Section 4.88c Pensions, Bonuses, and... tuberculosis initially entitled after August 19, 1968. Rating For 1 year after date of inactivity, following active tuberculosis 100 Thereafter: Rate residuals under the specific body system or systems...

  4. Comprehensive Tuberculosis Testing for the Dermatologist

    PubMed Central

    Jordan, Laura

    2015-01-01

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

  5. A Model for Tuberculosis with Exogeneous Reinfection

    E-print Network

    Feng, Z., et al.

    2000-05-16

    T=rI&_;cT. I. N. &+T,. N=S+E+I+T. 4 is the constant recruitment rate; ; and _; are the average ..... experience ``nontypical'' contact patterns (e.g., enterprise zones at the ..... models for the economic allocation of tuberculosis control activities.

  6. Renal tuberculosis in infancy

    PubMed Central

    Dhua, A. K.; Borkar, N.; Ghosh, V.; Aggarwal, S. K.

    2011-01-01

    We report a case of congenital renal tuberculosis in a 34-day-old child presenting as severe hematuria. Adequate antitubercular treatment may provide protection to fetus in subsequent pregnancies. PMID:21731237

  7. Update on cutaneous tuberculosis*

    PubMed Central

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

    2014-01-01

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

  8. Tuberculosis in tropical Africa

    PubMed Central

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

    1964-01-01

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

  9. Endobronchial tuberculosis mimicking malignancy

    PubMed Central

    Patel, Shahid M; Iyer, Aparna; Jayalakshmi, TK; Nair, Girija

    2015-01-01

    Endobronchial tuberculosis has a very varied presentation. Diagnosis is often very challenging as typical radiological features are absent and sputum smear for acid-fast bacilli is often negative. However, detection is essential as it may lead to long-term sequelae such as bronchial stenosis. Bronchoscopy is a very useful investigation in such cases. Our case is a rare manifestation of endobronchial tuberculosis as it mimicked malignancy.

  10. Suspected Child Maltreatment: Recognize and Respond

    ERIC Educational Resources Information Center

    Kemple, Kristen Mary; Kim, Hae Kyoung

    2011-01-01

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

  11. The history of tuberculosis.

    PubMed

    Daniel, Thomas M

    2006-11-01

    Tuberculosis has claimed its victims throughout much of known human history. It reached epidemic proportions in Europe and North America during the 18th and 19th centuries, earning the sobriquet, "Captain Among these Men of Death." Then it began to decline. Understanding of the pathogenesis of tuberculosis began with the work of Théophile Laennec at the beginning of the 19th century and was further advanced by the demonstration of the transmissibility of Mycobacterium tuberculosis infection by Jean-Antoine Villemin in 1865 and the identification of the tubercle bacillus as the etiologic agent by Robert Koch in 1882. Clemens von Pirquet developed the tuberculin skin test in 1907 and 3 years later used it to demonstrate latent tuberculous infection in asymptomatic children. In the late 19th and early 20th centuries sanatoria developed for the treatment of patients with tuberculosis. The rest provided there was supplemented with pulmonary collapse procedures designed to rest infected parts of lungs and to close cavities. Public Health measures to combat the spread of tuberculosis emerged following the discovery of its bacterial cause. BCG vaccination was widely employed following World War I. The modern era of tuberculosis treatment and control was heralded by the discovery of streptomycin in 1944 and isoniazid in 1952. PMID:16949809

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

    PubMed Central

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

    2015-01-01

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

  13. Incidence of active mycobacterial infections in Brazilian patients with chronic inflammatory arthritis and negative evaluation for latent tuberculosis infection at baseline - A longitudinal analysis after using TNFa blockers.

    PubMed

    Gomes, Carina Mori Frade; Terreri, Maria Teresa; Moraes-Pinto, Maria Isabel de; Barbosa, Cássia; Machado, Natália Pereira; Melo, Maria Roberta; Pinheiro, Marcelo Medeiros

    2015-11-01

    Several studies point to the increased risk of reactivation of latent tuberculosis infection (LTBI) in patients with chronic inflammatory arthritis (CIAs) after using tumour necrosis factor (TNF)a blockers. To study the incidence of active mycobacterial infections (aMI) in patients starting TNFa blockers, 262 patients were included in this study: 109 with rheumatoid arthritis (RA), 93 with ankylosing spondylitis (AS), 44 with juvenile idiopathic arthritis (JIA) and 16 with psoriatic arthritis (PsA). All patients had indication for anti-TNFatherapy. Epidemiologic and clinical data were evaluated and a simple X-ray and tuberculin skin test (TST) were performed. The control group included 215 healthy individuals. The follow-up was 48 months to identify cases of aMI. TST positivity was higher in patients with AS (37.6%) than in RA (12.8%), PsA (18.8%) and JIA (6.8%) (p < 0.001). In the control group, TST positivity was 32.7%. Nine (3.43%) patients were diagnosed with aMI. The overall incidence rate of aMI was 86.93/100,000 person-years [95% confidence interval (CI) 23.6-217.9] for patients and 35.79/100,000 person-years (95% CI 12.4-69.6) for control group (p < 0.001). All patients who developed aMI had no evidence of LTBI at the baseline evaluation. Patients with CIA starting TNFa blockers and no evidence of LTBI at baseline, particularly with nonreactive TST, may have higher risk of aMI. PMID:26560983

  14. Incidence of active mycobacterial infections in Brazilian patients with chronic inflammatory arthritis and negative evaluation for latent tuberculosis infection at baseline - A longitudinal analysis after using TNF? blockers

    PubMed Central

    Gomes, Carina Mori Frade; Terreri, Maria Teresa; de Moraes-Pinto, Maria Isabel; Barbosa, Cássia; Machado, Natália Pereira; Melo, Maria Roberta; Pinheiro, Marcelo Medeiros

    2015-01-01

    Several studies point to the increased risk of reactivation of latent tuberculosis infection (LTBI) in patients with chronic inflammatory arthritis (CIAs) after using tumour necrosis factor (TNF)? blockers. To study the incidence of active mycobacterial infections (aMI) in patients starting TNF ? blockers, 262 patients were included in this study: 109 with rheumatoid arthritis (RA), 93 with ankylosing spondylitis (AS), 44 with juvenile idiopathic arthritis (JIA) and 16 with psoriatic arthritis (PsA). All patients had indication for anti-TNF ? therapy. Epidemiologic and clinical data were evaluated and a simple X-ray and tuberculin skin test (TST) were performed. The control group included 215 healthy individuals. The follow-up was 48 months to identify cases of aMI. TST positivity was higher in patients with AS (37.6%) than in RA (12.8%), PsA (18.8%) and JIA (6.8%) (p < 0.001). In the control group, TST positivity was 32.7%. Nine (3.43%) patients were diagnosed with aMI. The overall incidence rate of aMI was 86.93/100,000 person-years [95% confidence interval (CI) 23.6-217.9] for patients and 35.79/100,000 person-years (95% CI 12.4-69.6) for control group (p < 0.001). All patients who developed aMI had no evidence of LTBI at the baseline evaluation. Patients with CIA starting TNF ? blockers and no evidence of LTBI at baseline, particularly with nonreactive TST, may have higher risk of aMI. PMID:26560983

  15. Tuberculosis Information for International Travelers

    MedlinePLUS

    ... of Verified Case of Tuberculosis National Tuberculosis Indicators Project (NTIP): Frequently Asked Questions TB Genotyping TB Genotyping Information Management System (TB GIMS) Drug-Resistant TB Multidrug-Resistant ...

  16. Tuberculosis in Hispanics/Latinos

    MedlinePLUS

    ... of Verified Case of Tuberculosis National Tuberculosis Indicators Project (NTIP): Frequently Asked Questions TB Genotyping TB Genotyping Information Management System (TB GIMS) Drug-Resistant TB Multidrug-Resistant ...

  17. Tuberculosis: Getting Healthy, Staying Healthy

    MedlinePLUS

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

  18. Update on Veterinary Tuberculosis Vaccines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Educational Objective: At the conclusion of this presentation, the participant will know the current status of veterinary tuberculosis vaccine research and development, and understand the challenges which remain for the future introduction of tuberculosis vaccines intended for wildlife and livestock...

  19. National tuberculosis control programme.

    PubMed

    Khatri, G R

    1996-10-01

    In 1962, the government of India launched a National Tuberculosis Control Program to detect as many tuberculosis cases as possible, provide effective treatment, establish district tuberculosis centers, extend short-course chemotherapy, and strengthen existing state tuberculosis training and demonstration centers. To date, district tuberculosis centers have been established in 454 of India's 496 districts and a total of 330 tuberculosis clinics are in operation. The tuberculosis mortality rate dropped from 80/100,000 population in 1970 to 53/100,000 in 1993. However, a 1992 review of the national program revealed inadequate budgetary outlays and drug shortages, an overemphasis on clinical and radiologic diagnosis, insufficient utilization of sputum microscopy facilities, an emphasis on case detection rather than cure, and a lack of consensus on treatment regimens. On the basis of these findings, the national strategy has been revised to achieve an 85% cure rate through administration of short-course (6-8 months) chemotherapy and to detect 70% of estimated cases. Strategies for achieving these objectives include use of sputum testing as the primary diagnostic method among self-referred cases, a standardized treatment regimen, an uninterrupted supply of drugs at all levels of the health system, increased budgetary outlays, creation of a sub-district supervisory unit, and greater emphasis on training and operations research. A pilot project testing this approach in five areas in 1993 resulted in significant improvements in the pulmonary smear positive to negative ratios and cure rates. As a result, the government of India will expand the project strategy to 17 sites covering a population of 15.83 million. PMID:9141875

  20. Childhood Tuberculosis, Still with Us...

    ERIC Educational Resources Information Center

    Chaulet, Pierre; And Others

    1992-01-01

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

  1. Tuberculosis: A Problem for Lifeguards?

    ERIC Educational Resources Information Center

    Skaros, Susan

    1996-01-01

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

  2. Comparative Genomics of Mycobacterium Tuberculosis

    E-print Network

    Brutlag, Doug

    Comparative Genomics of Mycobacterium Tuberculosis #12;My Questions · What is TB ­ What;Papers of interest · The Epidemiology of Tuberculosis in San Francisco, Peter M. Small et. Al · Deciphering the biology of Mycobacterium Tuberculosis from the complete genome sequence, Stuart Cole et al

  3. Tuberculosis-resistant transgenic cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tuberculosis is a devastating disease that affects humans and many animal species. In humans, tuberculosis (TB) is mainly caused by Mycobacterium tuberculosis, while most cases in cattle are caused by Mycobacterium bovis. However, Mb can also cause, albeit rarely, human TB. In this issue, Wu et al. ...

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

    E-print Network

    Cohen, Ted

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  6. Suspect burial excavation procedure: a cautionary tale.

    PubMed

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

    2009-01-10

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

  7. The evaluation of suspected child physical abuse.

    PubMed

    Christian, Cindy W

    2015-05-01

    Child physical abuse is an important cause of pediatric morbidity and mortality and is associated with major physical and mental health problems that can extend into adulthood. Pediatricians are in a unique position to identify and prevent child abuse, and this clinical report provides guidance to the practitioner regarding indicators and evaluation of suspected physical abuse of children. The role of the physician may include identifying abused children with suspicious injuries who present for care, reporting suspected abuse to the child protection agency for investigation, supporting families who are affected by child abuse, coordinating with other professionals and community agencies to provide immediate and long-term treatment to victimized children, providing court testimony when necessary, providing preventive care and anticipatory guidance in the office, and advocating for policies and programs that support families and protect vulnerable children. PMID:25917988

  8. [Lessons learned from tuberculosis outbreak cases].

    PubMed

    Kato, Seiya; Kuwabara, Katsuhiro

    2014-02-01

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

  9. PICTURES OF A SUSPECT-TRU RETRIEVAL

    SciTech Connect

    GADD, R.R.

    2007-05-24

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

  10. New approaches in the diagnosis and treatment of latent tuberculosis infection

    PubMed Central

    2010-01-01

    With nearly 9 million new active disease cases and 2 million deaths occurring worldwide every year, tuberculosis continues to remain a major public health problem. Exposure to Mycobacterium tuberculosis leads to active disease in only ~10% people. An effective immune response in remaining individuals stops M. tuberculosis multiplication. However, the pathogen is completely eradicated in ~10% people while others only succeed in containment of infection as some bacilli escape killing and remain in non-replicating (dormant) state (latent tuberculosis infection) in old lesions. The dormant bacilli can resuscitate and cause active disease if a disruption of immune response occurs. Nearly one-third of world population is latently infected with M. tuberculosis and 5%-10% of infected individuals will develop active disease during their life time. However, the risk of developing active disease is greatly increased (5%-15% every year and ~50% over lifetime) by human immunodeficiency virus-coinfection. While active transmission is a significant contributor of active disease cases in high tuberculosis burden countries, most active disease cases in low tuberculosis incidence countries arise from this pool of latently infected individuals. A positive tuberculin skin test or a more recent and specific interferon-gamma release assay in a person without overt signs of active disease indicates latent tuberculosis infection. Two commercial interferon-gamma release assays, QFT-G-IT and T-SPOT.TB have been developed. The standard treatment for latent tuberculosis infection is daily therapy with isoniazid for nine months. Other options include therapy with rifampicin for 4 months or isoniazid + rifampicin for 3 months or rifampicin + pyrazinamide for 2 months or isoniazid + rifapentine for 3 months. Identification of latently infected individuals and their treatment has lowered tuberculosis incidence in rich, advanced countries. Similar approaches also hold great promise for other countries with low-intermediate rates of tuberculosis incidence. PMID:21126375

  11. [Urogenital tuberculosis today].

    PubMed

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

    2013-01-01

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

  12. [Intestinal tuberculosis--a rare differential diagnosis of Crohn's disease in an ethnic Danish woman].

    PubMed

    Alexandraki, Maria Joanna; Wejse, Christian; Esbjørn, Mette; Kristensen, Lena Hagelskjær

    2015-06-29

    We report a case of intestinal tuberculosis in a 42-year-old Danish woman with stomach pain, weight loss and diarrhoea for months suspective of Crohn's disease. She underwent hysterectomy where white, small nodules were found on the small intestine. Biopsies showed non-necrotizing granulomatous inflammation. Gastroscopy and colonoscopy were normal. Capsule endoscopy revealed small intestine ulcers and a stenosis. A CT scan of the abdomen confirmed stenosis and inflammation of terminal ileum. QuantiFERON-TB Gold Test was positive and Mycobacterium tuberculosis was detected in faeces cultures. PMID:26239740

  13. Role of QuantiFERON-TB Gold antigen-specific IL-1? in diagnosis of active tuberculosis.

    PubMed

    Prabhavathi, Maddineni; Kabeer, Basirudeen Syed Ahamed; Deenadayalan, Anbarasu; Raja, Alamelu

    2015-10-01

    The main objective of the study was to evaluate whether in vitro QuantiFERON-TB Gold In-Tube (QFT-GIT) assay antigen-specific IL-1?, TNF-?, IL-2, IL-6, IL-8 and IL-12 (p40) production is associated with active TB. In a cohort of 77 pulmonary TB patients (PTB), 67 healthy household contacts (HHC) and 83 healthy control subjects (HCS), the antigen-specific cytokines levels were determined in supernatants generated from QFT-GIT tubes. Antigen-specific IL-1? levels were significantly higher in PTB than HHC and HCS. At a fixed cutoff point (1,108 pg/ml), IL-1? showed positivity of 62.33% in PTB, 22.38% in HHC and 22.89% in HCS. Moreover, antigen-specific IL-1? assay can differentiate PTB and HHC (believed to be latently infected) (p < 0.0001). Like IL-1?, significantly higher levels of antigen-specific TNF-? were associated with PTB and displayed 43.63% positivity in PTB. The antigen-specific IL-2 levels were associated both with PTB (54.54%) and HHC (48.14%). Other cytokines levels did not differ among the groups. Our results suggest that antigen-specific IL-1? can be used as a biomarker for active TB diagnosis as well as for differential diagnosis of PTB and LTBI. PMID:25504009

  14. 78 FR 40481 - Agency Information Collection Activities; Proposals, Submissions, and Approvals

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-05

    ... Tuberculosis Prevention (NCHHSTP), Centers for Disease Control and Prevention (CDC). Background and Brief... tuberculosis (TB), as well as for community-based HIV prevention activities, syphilis, and TB...

  15. Efficacy of Nitazoxanide against Clinical Isolates of Mycobacterium tuberculosis

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2013-06-01

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

  17. 48 CFR 1403.806 - Processing suspected violations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

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

  18. 48 CFR 1403.806 - Processing suspected violations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

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

  19. 48 CFR 903.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 903.303 Reporting suspected antitrust violations. (a) Potential anti-competitive...such as described in 48 CFR 3.301, and antitrust law violations as described in 48...

  20. 48 CFR 903.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 903.303 Reporting suspected antitrust violations. (a) Potential anti-competitive...such as described in FAR 3.301, and antitrust law violations as described in FAR...

  1. 48 CFR 903.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 903.303 Reporting suspected antitrust violations. (a) Potential anti-competitive...such as described in 48 CFR 3.301, and antitrust law violations as described in 48...

  2. 48 CFR 903.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 903.303 Reporting suspected antitrust violations. (a) Potential anti-competitive...such as described in 48 CFR 3.301, and antitrust law violations as described in 48...

  3. 48 CFR 903.303 - Reporting suspected antitrust violations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...CONFLICTS OF INTEREST Reports of Suspected Antitrust Violations 903.303 Reporting suspected antitrust violations. (a) Potential anti-competitive...such as described in 48 CFR 3.301, and antitrust law violations as described in 48...

  4. Recent advances in the diagnosis of childhood tuberculosis

    PubMed Central

    Marais, Ben J; Pai, Madhukar

    2007-01-01

    Children account for a major proportion of the global tuberculosis disease burden, especially in endemic areas. However, the accurate diagnosis of childhood tuberculosis remains a major challenge. This review provides an overview of the most important recent advances in the diagnosis of intrathoracic childhood tuberculosis: (1) symptom?based approaches, including symptom?based screening of exposed children and symptom?based diagnosis of active disease; (2) novel immune?based approaches, including T cell assays and novel antigen?based tests; and (3) bacteriological and molecular methods that are more rapid and/or less expensive than conventional culture techniques for tuberculosis diagnosis and/or drug?resistance testing. Recent advances have improved our ability to diagnose latent infection and active tuberculosis in children, but establishing a diagnosis of either latent infection or active disease in HIV?infected children remains a major challenge, particularly in high?burden settings. Although improved access to diagnosis and treatment is essential, ultimately the burden of childhood tuberculosis is determined by the level of epidemic control achieved in a particular community. Several recent initiatives, in particular the United Nations Millennium Developmental Goals, deal with the problem of poverty and disease in a holistic fashion, but global political commitment is required to support these key initiatives. PMID:17449528

  5. [Molecuar epidemiology of tuberculosis].

    PubMed

    Hyncicová, I

    1998-04-01

    Tuberculosis is a serious disease, killing many people every year. After decades of progressive decrease this disease, boosted by the appearance of HIV, reemerges showing a marked upward tendency and most afflicting populations in developing countries. At present, many researchers have been involved in molecular epidemiology of tuberculosis using DNA fingerprinting to determine restriction profiles of different strains. This method has also proved useful in detecting outbreaks of the disease in populations. That is very important for determining primary infection sources and their subsequent elimination from the environment to prevent recurrent infections. PMID:9611895

  6. Demonstration of Mycobacterium Tuberculosis in Sputum and Saliva Smears of Tuberculosis Patients Using Ziehl Neelsen and Flurochrome Staining- A Comparative Study

    PubMed Central

    Ganvir, Sindhu M; Shah, Nishat N; Bansode, Shriram C; Shende, Ishali; Jawade, Rashmi; Bijjargi, Shobha C

    2014-01-01

    Background: Early detection of tuberculosis is important for reducing its morbidity and mortality especially in the patients with non-productive cough. To overcome the cumbersome process involved in collection and processing of the sputum specimen, the time consumed for reporting of sputum by Ziehl Neelsen (ZN) method and to introduce a routine screening test in suspected, symptomless tuberculosis patients, the present study was designed using saliva as diagnostic medium and Auramine Rhodamine (AR) as staining method. On review of literature, there was no study which has tried diagnosing tuberculosis using saliva with flurochrome stain; hence the present study was designed. Aim: To introduce a routine screening test for tuberculosis patient using saliva and to determine the diagnostic efficacy of routine ZN staining method and AR fluorescent staining method in sputum and saliva smears of pulmonary tuberculosis patients. Settings and Design: Laboratory settings and Experimental design. Materials and Method: Fifty smears samples of sputum and saliva of known cases of pulmonary tuberculosis were stained with routine ZN stain and other with AR fluorescent stain. All the specimens were inoculated into Lowenstein-Jensen culture media. The smears were subjected for scanning of Mycobacterium tuberculous bacilli under X 1000 magnification for ZN stain and X 400 magnification for AR stain by grid pattern proposed by National tuberculosis institute and graded by RNTCP grading system. Results: All 50 sputum samples showed 100% positivity by ZN and AR stain while only 76% positivity was seen by culture. Of the 50 saliva samples 10% cases were positive by ZN, 76% were positive by AR & 70% by culture method. Statistical analysis using chi square test was done, and the value was found to be statistically highly significant for AR staining technique. (p<0.001) Conclusion: Saliva can prove to be an important tool for the diagnosis as well as screening of the patients with pulmonary tuberculosis when aided with flurochrome staining method. PMID:25177636

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  10. HIV and tuberculosis coinfection: inextricably linked liaison.

    PubMed Central

    Idemyor, Vincent

    2007-01-01

    In sub-Saharan Africa, human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (TB) are among the leading causes of morbidity and mortality. Sub-Saharan Africa has seen the woeful failure of World Health Organization (WHO) targets of detecting 70% of the infectious cases of tuberculosis and curing > or =85%. Current treatment of Mycobacterium tuberculosis in most resource limited settings is comprised of a four-drug initial antituberculosis regimen for two months, followed by either a two-drug continuation phase of antituberculosis regimen for four months or six months depending on the medications. Many countries in sub-Saharan Africa are scaling up with highly active antiretroviral therapy (HAART), using one of the first-line regimens that consist of two nucleoside reverse transcriptase inhibitors (NRTI) and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Our current HAART regimen and antituberculosis drugs continue to give us a therapeutic challenge in terms of adverse effects, drug-drug interactions and immune reconstitution inflammatory syndromes. Scientific research is needed in the areas of diagnosis, treatment and prevention of tuberculosis in sub-Saharan Africa. Such research could be facilitated due to greater availability of funding than a decade ago. PMID:18229780

  11. New weapons in the war on tuberculosis.

    PubMed

    Sharma, Sujata; Yoder, Mark A

    2011-07-01

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

  12. Reactive thrombocytosis in pulmonary tuberculosis.

    PubMed Central

    Baynes, R D; Bothwell, T H; Flax, H; McDonald, T P; Atkinson, P; Chetty, N; Bezwoda, W R; Mendelow, B V

    1987-01-01

    The incidence of reactive thrombocytosis in active pulmonary tuberculosis was studied in 122 patients. Thrombocytosis was common, platelet counts often exceeding 1 X 10(12)/1. A significant inverse correlation was noted between the mean platelet volume and the platelet count (r = -0.54, p less than 0.0001). Interval estimation suggested that this relation was non-linear. Further studies were done in a small group of six patients. Platelet survival was considerably shortened, the platelets aggregated excessively in vitro, serum concentrations of thrombopoiesis stimulating activity were raised, and serotonin uptake and release were within normal limits. The degree of thrombocytosis correlated significantly with the degree of inflammation measured by the erythrocyte sedimentation rate (r = 0.40, p less than 0.003) and serum C-reactive protein concentration (r = 0.35, p less than 0.008). PMID:3611396

  13. Protective efficacy of piperine against Mycobacterium tuberculosis.

    PubMed

    Sharma, Sandeep; Kalia, Nitin Pal; Suden, Pankaj; Chauhan, Prashant Singh; Kumar, Manoj; Ram, Anshu Beulah; Khajuria, Anamika; Bani, Sarang; Khan, Inshad Ali

    2014-07-01

    Piperine a trans-trans isomer of 1-piperoyl-piperidine was evaluated for its immunomodulatory activity to enhance the efficacy of rifampicin in a murine model of Mycobacterium tuberculosis infection. In-vitro immunomodulation of piperine was tested on mouse splenocytes for lymphocyte proliferation, cytokine production and macrophage activation. Protective efficacy of piperine was tested in a mice infection model of M. tuberculosis for the activation of Th-1 response and synergistic combination efficacy with rifampicin. Murine splenocytes exposed to piperine exhibited proliferation of T and B cell, increased Th-1 cytokines and enhanced macrophage activation. Piperine (1 mg/kg) in mice infected with M. tuberculosis activated the differentiation of T cells into Th-1 sub-population (CD4+ / CD8+ subsets). There was an increase in secretion of Th-1 cytokines (IFN-? and IL-2) by these cells. The qRT-PCR studies revealed corresponding increases in the mRNA transcripts of IFN-? and IL-2 in the infected lung tissues. Combination of piperine and rifampicin (1 mg/kg) exhibited better efficacy of and resulted in additional 1.4 to 0.8 log reduction in lung cfu as compared to rifampicin alone. The up-regulation of Th1 immunity by piperine can be synergistically combined with rifampicin to improve its therapeutic efficacy in immune-compromised TB patients. PMID:24880706

  14. Proteomic analysis of extracellular vesicles derived from Mycobacterium tuberculosis.

    PubMed

    Lee, Jaewook; Kim, Si-Hyun; Choi, Dong-Sic; Lee, Jong Seok; Kim, Dae-Kyum; Go, Gyeongyun; Park, Seon-Min; Kim, Si Hyun; Shin, Jeong Hwan; Chang, Chulhun L; Gho, Yong Song

    2015-10-01

    The release of extracellular vesicles, also known as outer membrane vesicles, membrane vesicles, exosomes, and microvesicles, is an evolutionarily conserved phenomenon from bacteria to eukaryotes. It has been reported that Mycobacterium tuberculosis releases extracellular vesicles harboring immunologically active molecules, and these extracellular vesicles have been suggested to be applicable in vaccine development and biomarker discovery. However, the comprehensive proteomic analysis has not been performed for M. tuberculosis extracellular vesicles. In this study, we identified a total of 287 vesicular proteins by four LC-MS/MS analyses with high confidence. In addition, we identified several vesicular proteins associated with the virulence of M. tuberculosis. This comprehensive proteome profile will help elucidate the pathogenic mechanism of M. tuberculosis. The data have been deposited to the ProteomeXchange with identifier PXD001160 (http://proteomecentral.proteomexchange.org/dataset/PXD001160). PMID:26201501

  15. UNCORRECTEDPROOF Comparing epidemic tuberculosis in demographically

    E-print Network

    Kirschner, Denise

    UNCORRECTEDPROOF Comparing epidemic tuberculosis in demographically distinct heterogeneous variation in endemic tuberculosis (TB) levels between countries and we seek to identify 10 possible causes of these differences. In this study we present an epidemiological model of Mycobacterium 11 tuberculosis infection

  16. Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children: An Update.

    PubMed

    Graham, Stephen M; Cuevas, Luis E; Jean-Philippe, Patrick; Browning, Renee; Casenghi, Martina; Detjen, Anne K; Gnanashanmugam, Devasena; Hesseling, Anneke C; Kampmann, Beate; Mandalakas, Anna; Marais, Ben J; Schito, Marco; Spiegel, Hans M L; Starke, Jeffrey R; Worrell, Carol; Zar, Heather J

    2015-10-15

    Consensus case definitions for childhood tuberculosis have been proposed by an international expert panel, aiming to standardize the reporting of cases in research focusing on the diagnosis of intrathoracic tuberculosis in children. These definitions are intended for tuberculosis diagnostic evaluation studies of symptomatic children with clinical suspicion of intrathoracic tuberculosis, and were not intended to predefine inclusion criteria into such studies. Feedback from researchers suggested that further clarification was required and that these case definitions could be further improved. Particular concerns were the perceived complexity and overlap of some case definitions, as well as the potential exclusion of children with acute onset of symptoms or less severe disease. The updated case definitions proposed here incorporate a number of key changes that aim to reduce complexity and improve research performance, while maintaining the original focus on symptomatic children suspected of having intrathoracic tuberculosis. The changes proposed should enhance harmonized classification for intrathoracic tuberculosis disease in children across studies, resulting in greater comparability and the much-needed ability to pool study results. PMID:26409281

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

    PubMed Central

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

    2013-01-01

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

  18. Global Tuberculosis (TB)

    MedlinePLUS

    ... Global Tuberculosis (TB) TB is one of the world’s deadliest diseases: One third of the world’s population are infected with TB. In 2013, 9 ... health problem in many other parts of the world. In 2013, 65% of all TB cases and ...

  19. TUBERCULOSIS EXPOSURE CONTROL PLAN

    E-print Network

    Nicholson, Bruce J.

    TUBERCULOSIS EXPOSURE CONTROL PLAN THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO Provided by: Environmental Health &Safety Department June 2015 #12;TB Exposure Control Plan Environmental, patient care, and research. In the pursuit of these endeavors, occupational exposure to potentially

  20. B in TB: B Cells as Mediators of Clinically Relevant Immune Responses in Tuberculosis

    PubMed Central

    Rao, Martin; Valentini, Davide; Poiret, Thomas; Dodoo, Ernest; Parida, Shreemanta; Zumla, Alimuddin; Brighenti, Susanna; Maeurer, Markus

    2015-01-01

    The protective role of B cells and humoral immune responses in tuberculosis infection has been regarded as inferior to cellular immunity directed to the intracellular pathogen Mycobacterium tuberculosis. However, B-cell–mediated immune responses in tuberculosis have recently been revisited in the context of B-cell physiology and antigen presentation. We discuss in this review the diverse functions of B cells in tuberculosis, with a focus on their biological and clinical relevance to progression of active disease. We also present the peptide microarray platform as a promising strategy to discover unknown antigenic targets of M. tuberculosis that could contribute to the better understanding of epitope focus of the humoral immune system against M. tuberculosis. PMID:26409285

  1. Structures of the Michaelis Complex (1.2A) and the Covalent Acyl Intermediate (2.0A ) of Cefamandole Bound in the Active Sites of the Mycobacterium tuberculosis beta-Lactamase K72A and E166A Mutants

    SciTech Connect

    L Tremblay; h Xu; J Blanchard

    2011-12-31

    The genome of Mycobacterium tuberculosis (TB) contains a gene that encodes a highly active {beta}-lactamase, BlaC, that imparts TB with resistance to {beta}-lactam chemotherapy. The structure of covalent BlaC-{beta}-lactam complexes suggests that active site residues K73 and E166 are essential for acylation and deacylation, respectively. We have prepared the K73A and E166A mutant forms of BlaC and have determined the structures of the Michaelis complex of cefamandole and the covalently bound acyl intermediate of cefamandole at resolutions of 1.2 and 2.0 {angstrom}, respectively. These structures provide insight into the details of the catalytic mechanism.

  2. The tuberculosis hospital in Hohenkrug, Stettin. Department of Genitourinary Tuberculosis.

    PubMed

    Zajaczkowski, Tadeusz

    2012-01-01

    Towards the end of the 19th century, Europe turned particular attention to the problem of tuberculosis, at that time the most serious social disease. In the majority of cases, pulmonary tuberculosis had a fatal outcome owing to the lack of effective drugs and methods of treatment. Due to poor sanitary conditions, particularly as regards dwellings, pulmonary tuberculosis was able to spread rapidly. Hospital departments were reluctant to admit patients suffering from tuberculosis. It was only after the discoveries of Robert Koch (bacillus tubercle in 1882) that the cause of the disease became understood and methods of treatment began to be developed. A modern sanatorium and hospital with 270 beds was erected in Hohenkrug (today Szczecin-Zdunowo) between 1915 and 1930. Patients could now be treated with modern methods, surgically in most cases. After the Second World War, pulmonary tuberculosis was still an enormous epidemiologic problem. In 1949, the Polish authorities opened a 400-bed sanatoriumin Zdunowo. The methods of treatment were not much different from pre-war practice and it was only the routine introduction of antituberculotic drugs during the fifties of the past century that brought about a radical change in the fight against tuberculosis. The growing numbers of patients with tuberculosis of the genitourinary system led to the opening in 1958 of a 40-bed specialist ward at the Tuberculosis Sanatorium in Zdunowo. It should be emphasized that the Department of Genitourinary Tuberculosis in Szczecin-Zdunowo was a historical necessity and a salvation for thousands of patients from Northern Poland. The Department totally fulfilled its social duties thanks to the commitment of many outstanding persons dedicated to helping the patients. This unit was finally closed in 1987 because the demand for surgical treatment of tuberculosis was declining concurrently with the advent of new and potent antituberculotics and falling number of new cases of genitourinary tuberculosis. Today, the decision to close the Department of Genitourinary Tuberculosis is deeply regretted by urologists in Stettin. PMID:23767185

  3. Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection.

    PubMed

    Kimmey, Jacqueline M; Huynh, Jeremy P; Weiss, Leslie A; Park, Sunmin; Kambal, Amal; Debnath, Jayanta; Virgin, Herbert W; Stallings, Christina L

    2015-12-24

    Mycobacterium tuberculosis, a major global health threat, replicates in macrophages in part by inhibiting phagosome-lysosome fusion, until interferon-? (IFN?) activates the macrophage to traffic M. tuberculosis to the lysosome. How IFN? elicits this effect is unknown, but many studies suggest a role for macroautophagy (herein termed autophagy), a process by which cytoplasmic contents are targeted for lysosomal degradation. The involvement of autophagy has been defined based on studies in cultured cells where M. tuberculosis co-localizes with autophagy factors ATG5, ATG12, ATG16L1, p62, NDP52, BECN1 and LC3 (refs 2, 3, 4, 5, 6), stimulation of autophagy increases bacterial killing, and inhibition of autophagy increases bacterial survival. Notably, these studies reveal modest (~1.5-3-fold change) effects on M. tuberculosis replication. By contrast, mice lacking ATG5 in monocyte-derived cells and neutrophils (polymorponuclear cells, PMNs) succumb to M. tuberculosis within 30 days, an extremely severe phenotype similar to mice lacking IFN? signalling. Importantly, ATG5 is the only autophagy factor that has been studied during M. tuberculosis infection in vivo and autophagy-independent functions of ATG5 have been described. For this reason, we used a genetic approach to elucidate the role for multiple autophagy-related genes and the requirement for autophagy in resistance to M. tuberculosis infection in vivo. Here we show that, contrary to expectation, autophagic capacity does not correlate with the outcome of M. tuberculosis infection. Instead, ATG5 plays a unique role in protection against M. tuberculosis by preventing PMN-mediated immunopathology. Furthermore, while Atg5 is dispensable in alveolar macrophages during M. tuberculosis infection, loss of Atg5 in PMNs can sensitize mice to M. tuberculosis. These findings shift our understanding of the role of ATG5 during M. tuberculosis infection, reveal new outcomes of ATG5 activity, and shed light on early events in innate immunity that are required to regulate disease pathology and bacterial replication. PMID:26649827

  4. Interferon Gamma Release Assays for Diagnosis of Pleural Tuberculosis: a Systematic Review and Meta-Analysis.

    PubMed

    Aggarwal, Ashutosh N; Agarwal, Ritesh; Gupta, Dheeraj; Dhooria, Sahajal; Behera, Digambar

    2015-08-01

    The role of interferon gamma release assays (IGRAs), although established for identifying latent tuberculosis, is still evolving in the diagnosis of active extrapulmonary tuberculosis. We systematically evaluated the diagnostic performance of blood- and pleural fluid-based IGRAs in tuberculous pleural effusion (TPE). We searched the PubMed and Embase databases for studies evaluating the use of commercially available IGRAs on blood and/or pleural fluid samples for diagnosing TPE. The quality of the studies included was assessed through the QUADAS-2 tool. The pooled estimates of sensitivity and specificity with 95% confidence intervals (95% CI) were generated using a bivariate random-effects model and examined using forest plots and hierarchical summary receiver operating characteristic (HSROC) curves. Indeterminate IGRA results were included for sensitivity calculations. Heterogeneity was explored through subgroup analysis and meta-regression based on prespecified covariates. We identified 19 studies assessing the T.SPOT.TB and/or QuantiFERON assays. There were 20 and 14 evaluations, respectively, of whole-blood and pleural fluid assays, involving 1,085 and 727 subjects, respectively. There was only one good-quality study, and five studies used nonstandard assay thresholds. The pooled sensitivity and specificity for the blood assays were 0.77 (95% CI, 0.71 to 0.83) and 0.71 (95% CI, 0.65 to 0.76), respectively. The pooled sensitivity and specificity for the pleural fluid assays were 0.72 (95% CI, 0.55 to 0.84) and 0.78 (95% CI, 0.65 to 0.87), respectively. There was considerable heterogeneity; however, multivariate meta-regression did not identify any covariate with significant influence. There was no publication bias for blood assays. We conclude that commercial IGRAs, performed either on whole-blood or pleural fluid samples, have poor diagnostic accuracy in patients suspected to have TPE. PMID:25994163

  5. Magnetic Resonance Imaging of the Lung as an Alternative for a Pregnant Woman with Pulmonary Tuberculosis

    PubMed Central

    Schloß, Manuel; Heckrodt, Jan; Schneider, Christian; Discher, Thomas; Krombach, Gabriele Anja

    2015-01-01

    We report a case of a pregnant 21-year-old woman with pulmonary tuberculosis in which magnetic resonance imaging of the lung was used to assess the extent and characteristics of the pathological changes. Although the lung has been mostly ignored in magnetic resonance imaging for many decades, today technical development enables detailed examinations of the lung. The technique is now entering the clinical arena and its indications are increasing. Magnetic resonance imaging of the lung is not only an alternative method without radiation exposure, it can provide additional information in pulmonary imaging compared to other modalities including computed tomography. We describe a successful application of magnetic resonance imaging of the lung and the imaging appearance of post-primary tuberculosis. This case report indicates that magnetic resonance imaging of the lung can potentially be the first choice imaging technique in pregnant women with suspected pulmonary tuberculosis. PMID:26622928

  6. Oral tuberculosis involving maxillary gingiva

    PubMed Central

    Jaiswal, Rohit; Singh, Anil; Badni, Manjunath; Singh, Priyanka

    2011-01-01

    Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis, which is transmitted by aerosolized saliva droplets among individuals in close contact with expelled sputum of a diseased patient. However, TB lesions of the oral cavity are often overlooked in the differential diagnosis. We report here a case of tuberculosis of oral cavity affecting the gingiva of a 24-year-old male. PMID:22639508

  7. [Treatment of tuberculosis : Current standards].

    PubMed

    Schaberg, T

    2015-12-01

    The treatment of drug-sensitive tuberculosis consists of 2 months of isoniazid, rifampin, pyrazinamide and ethambutol, followed by 4 months of isoniazid and rifampin. These drugs are well tolerated and cure rate are above 95?%. In contrast the treatment of drug-resistent tuberculosis is difficult, mostly due to side effects of the drugs used under these circumstances. Therefore, any treatment of drug-resistant tuberculosis has to be done by experts. PMID:26631087

  8. Novel inhibitors of Mycobacterium tuberculosis growth based on modified pyrimidine nucleosides and their analogues

    NASA Astrophysics Data System (ADS)

    Shmalenyuk, E. R.; Kochetkov, S. N.; Alexandrova, L. A.

    2013-09-01

    The review summarizes data on the synthesis and antituberculosis activity of pyrimidine nucleoside derivatives and their analogues. Enzymes from M. tuberculosis as promising targets for prototypes of new-generation drugs are considered. Nucleosides as inhibitors of drug-resistant M. tuberculosis strains are characterized. The bibliography includes 101 references.

  9. [Acute miliary tuberculosis or Isambert disease: a case report].

    PubMed

    Ziad, T; Nouri, H; Adny, A; Rochdi, Y; Aderdour, L; Raji, A

    2013-01-01

    Pharynx tuberculosis consists in a set of active lesions in granulomatous-type mucosa, resulting from Mycobacterium tuberculosis infection. In an endemic context, this diagnosis should be raised in cases of head and neck disease. A recent observation of a case of acute miliary tuberculosis gave us the opportunity to conduct a literature review of this disorder. This 9-year-old girl presented with dysphagia associated with pharyngeal discomfort, snoring, and hoarseness lasting for 8 months. This pharyngeal syndrome occurred in the context of an impaired general condition. Clinical examination found a diffuse mucosal granulation aspect in the oropharynx. The workup showed an inflammatory syndrome with a strong positive intradermal tuberculin reaction. The biopsy found an aspect of giant cell granuloma with caseous necrosis. The course was favorable on antituberculous chemotherapy. Tuberculosis is a chronic bacterial infection caused by a bacterium belonging to the M. tuberculosis complex. Pharyngeal tuberculosis remains a rare disease, but several epidemiological parameters show an upsurge of this disease, prompting us to report this observation. PMID:23266174

  10. Diagnostic approach to patients with suspected vasculitis

    PubMed Central

    Suresh, E

    2006-01-01

    Vasculitis presents several diagnostic challenges. Firstly, patients could present with protean clinical manifestations with a wide spectrum ranging from isolated cutaneous vasculitis to multisystem involvement. Secondly, there are several medical conditions that could mimic the presentation of vasculitis. The range of differential diagnosis is therefore broad. Thirdly, vasculitis could occur as a primary disorder or be secondary to various medical conditions. It becomes important to differentiate them, as treatment of some forms of vasculitis such as those that are secondary to infection or drugs, is different from that of primary vasculitis. Fourthly, there are several different forms of vasculitis. Some are benign and self limiting, while others have the potential to threaten vital organ function and life. It follows that a rational approach is required during evaluation of patients with suspected vasculitis. PMID:16891436

  11. Exome Sequencing in Suspected Monogenic Dyslipidemias

    PubMed Central

    Stitziel, Nathan O.; Peloso, Gina M.; Abifadel, Marianne; Cefalu, Angelo B.; Fouchier, Sigrid; Motazacker, M. Mahdi; Tada, Hayato; Larach, Daniel B.; Awan, Zuhier; Haller, Jorge F.; Pullinger, Clive R.; Varret, Mathilde; Rabès, Jean-Pierre; Noto, Davide; Tarugi, Patrizia; Kawashiri, Masa-aki; Nohara, Atsushi; Yamagishi, Masakazu; Risman, Marjorie; Deo, Rahul; Ruel, Isabelle; Shendure, Jay; Nickerson, Deborah A.; Wilson, James G.; Rich, Stephen S.; Gupta, Namrata; Farlow, Deborah N.; Neale, Benjamin M.; Daly, Mark J.; Kane, John P.; Freeman, Mason W.; Genest, Jacques; Rader, Daniel J.; Mabuchi, Hiroshi; Kastelein, John J.P.; Hovingh, G. Kees; Averna, Maurizio R.; Gabriel, Stacey; Boileau, Catherine; Kathiresan, Sekar

    2015-01-01

    Background Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We utilized this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. Methods and Results We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein (LDL) cholesterol (after candidate gene sequencing excluded known genetic causes for high LDL cholesterol families) or high-density lipoprotein (HDL) cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual in order to account for their burden of common genetic variants known to influence lipid levels. In nine families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families despite follow-up analyses. We identified three factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. Conclusions We identified the genetic basis of disease in nine of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies. PMID:25632026

  12. Suboptimal Antigen Presentation Contributes to Virulence of Mycobacterium tuberculosis In Vivo.

    PubMed

    Grace, Patricia S; Ernst, Joel D

    2016-01-01

    Mycobacterium tuberculosis commonly causes persistent or chronic infection, despite the development of Ag-specific CD4 T cell responses. We hypothesized that M. tuberculosis evades elimination by CD4 T cell responses by manipulating MHC class II Ag presentation and CD4 T cell activation and tested this hypothesis by comparing activation of Ag85B-specific CD4 T cell responses to M. tuberculosis and M. bovis bacillus Calmette-Guérin (BCG) Pasteur in vivo and in vitro. We found that, although M. tuberculosis persists in lungs of immunocompetent mice, M. bovis BCG is cleared, and clearance is T cell dependent. We further discovered that M. tuberculosis-infected macrophages and dendritic cells activate Ag85B-specific CD4 T cells less efficiently and less effectively than do BCG-infected cells, in vivo and in vitro, despite higher production and secretion of Ag85B by M. tuberculosis. During BCG infection, activation of Ag85B-specific CD4 T cells requires fewer infected dendritic cells and fewer Ag-producing bacteria than during M. tuberculosis infection. When dendritic cells containing equivalent numbers of M. tuberculosis or BCG were transferred to mice, BCG-infected cells activated proliferation of more Ag85B-specific CD4 T cells than did M. tuberculosis-infected cells. Differences in Ag85B-specific CD4 T cell activation were attributable to differential Ag presentation rather than differential expression of costimulatory or inhibitory molecules. These data indicate that suboptimal Ag presentation contributes to persistent infection and that limiting Ag presentation is a virulence property of M. tuberculosis. PMID:26573837

  13. Intestinal/Peritoneal Tuberculosis in Children: An Analysis of Autopsy Cases

    PubMed Central

    Ridaura-Sanz, Cecilia; López-Corella, Eduardo; Lopez-Ridaura, Ruy

    2012-01-01

    Infection by Mycobacterium bovis is not infrequently identified in Mexico. Its relation to nonpasteurized milk products ingestion is well recognized with primary infection usually in the intestinal tract. The term “abdominal tuberculosis” includes peritoneal as well as primary and secondary intestinal tuberculosis. The clinical differentiation of these conditions is difficult. In this work, we reviewed the clinical and pathological features of 24 cases of children dying with tuberculosis in whom autopsy revealed abdominal disease in a referral hospital in Mexico City. We identified 8 cases of primary intestinal tuberculosis, with documentation of M. bovis in 6 of them, and 9 cases of secondary intestinal tuberculosis (primary pulmonary disease), all negative to M. bovis. Seven patients had peritoneal tuberculosis without intestinal lesions and with active pulmonary disease in 4 of them, and of the remaining three, two had mesenteric lymph node involvement suggesting healed intestinal disease. In this approach to abdominal tuberculosis, postmortem analysis was able to differentiate primary from secondary intestinal tuberculosis and to define the nature of peritoneal involvement. This discrimination gives rise to different diagnostic approaches and epidemiological and preventive actions, particularly in countries where tuberculosis is endemic and infection by M. bovis continues to be identified. PMID:23320161

  14. Endotracheal tuberculosis with obstruction.

    PubMed

    Uçar, Yildiz; Sözener, Zeynep Celebi; Karnak, Demet

    2010-05-01

    Endotracheal involvement of tuberculosis (TB), a type of endobronchial TB, is defined as granulomatous infection of the tracheobronchial tree. We present the case of a 33 year-old female agriculture engineer with endotracheal tuberculosis (ETTB). It was treated successfully with prompt long-course antituberculous medication without complications or need for endotracheal intervention. This unusual case of ETTB, diagnosed promptly by fiberoptic bronchoscopy, and microbiological studies, is presented to emphasize the importance of macroscopic recognition to start anti-TB therapy in cases with significant airway obstruction. This case is important for countries where the various presentations of TB are encountered as well as in countries where TB is not endemic. PMID:20578548

  15. TUBERCULOSIS 1 Tuberculosis in Aboriginal Populations in Canada

    E-print Network

    Saskatchewan, University of

    TUBERCULOSIS 1 Tuberculosis in Aboriginal Populations in Canada: The Role of Health Care.3 Aboriginal Health Issues College of Nursing, University of Saskatchewan Submitted to Arlene Kent-Wilkinson RN affected include children, youth and the elderly (Health Canada, 2012). Control programs in the past

  16. Synthesis, crystal, computational study and in vitro anti-tuberculosis activity of N-(furan-2-yl-methyl)- N-(phenyl(quinolin-3-yl)methyl) acetamide derivatives

    NASA Astrophysics Data System (ADS)

    Bai, Yuefei; Wang, Lijuan; Chen, Yu; Yuan, Lei; Xu, Wei; Sun, Tiemin

    2011-11-01

    A one-pot synthesis of N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methyl)- N-(furan-2-yl-methyl)-2-morpholinoacetamide ( 1) and N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methyl)- N-(furan-2-yl-methyl)-2-adamantylacetamide ( 2) was achieved in good yield for the first time. Compounds 1 and 2·H 2O were characterized by single crystal X-ray diffraction in solid state. The structures of two new derivatives have been confirmed by typical spectroscopic techniques, namely IR, 1H and 13C NMR. The optimized geometric bond lengths and bond angles obtained by using density functional theory (DFT) have been compared with X-ray diffraction values. The experimental molecular structures are well reproduced by the computation. The geometrical parameters of the title compounds are similar to those of some reported derivatives. In addition, in vitro anti-tuberculosis activities of derivatives 1 and 2 were also investigated.

  17. Function prediction and analysis of mycobacterium tuberculosis hypothetical proteins.

    PubMed

    Mazandu, Gaston K; Mulder, Nicola J

    2012-01-01

    High-throughput biology technologies have yielded complete genome sequences and functional genomics data for several organisms, including crucial microbial pathogens of humans, animals and plants. However, up to 50% of genes within a genome are often labeled "unknown", "uncharacterized" or "hypothetical", limiting our understanding of virulence and pathogenicity of these organisms. Even though biological functions of proteins encoded by these genes are not known, many of them have been predicted to be involved in key processes in these organisms. In particular, for Mycobacterium tuberculosis, some of these "hypothetical" proteins, for example those belonging to the Pro-Glu or Pro-Pro-Glu (PE/PPE) family, have been suspected to play a crucial role in the intracellular lifestyle of this pathogen, and may contribute to its survival in different environments. We have generated a functional interaction network for Mycobacterium tuberculosis proteins and used this to predict functions for many of its hypothetical proteins. Here we performed functional enrichment analysis of these proteins based on their predicted biological functions to identify annotations that are statistically relevant, and analysed and compared network properties of hypothetical proteins to the known proteins. From the statistically significant annotations and network information, we have tried to derive biologically meaningful annotations related to infection and disease. This quantitative analysis provides an overview of the functional contributions of Mycobacterium tuberculosis "hypothetical" proteins to many basic cellular functions, including its adaptability in the host system and its ability to evade the host immune response. PMID:22837694

  18. Cutaneous tuberculosis: a rare presentation in an immigrant.

    PubMed

    Gulisano, G; Mariani, L

    1998-09-01

    The increased incidence of tubercular diseases in industrialized countries appears to be due to several factors, including development of resistance to the most commonly used specific chemotherapeutic substances, unsuitable control programmes, HIV infection, the increased influx of immigrants, and homelessness. Different forms of cutaneous tuberculosis are caused by different species of mycobacteria (e.g., Mycobacterium tuberculosis, M. bovis, M. avium). Determining the species of mycobacteria is relevant when disease is suspected to be linked to the type of employment of the patient, mainly because the clinical features do not always indicate which species is the cause of the infection. Mycobacterium tuberculosis (MT) usually infects through the lung, but in rare cases can penetrate the skin or mucous membranes. Skin transmission can be exogenous by inoculation, or endogenous by diffusion (lymphatic or hematic) or by contiguity. The immunologic status of the patient is a crucial factor which influences the clinical variants and the course of disease itself. Here we report a case of an illegal immigrant who presented with a bilateral, symmetrical ulcer on the neck. PMID:9772331

  19. Treatment of childhood tuberculosis in India.

    PubMed

    Swaminathan, S; Sachdeva, K S

    2015-12-01

    With a quarter of the global burden of tuberculosis (TB) occurring in India, children in this country are at high risk of tuberculous infection and TB disease. India's Revised National Tuberculosis Control Programme provides free diagnosis and treatment for children with TB using quality assured, weight-based individual drug boxes. Guidelines have recently been revised, updating both the diagnostic algorithm and shifting to a daily regimen with World Health Organization recommended dosages using child-friendly, fixed-dose combination pills. Active case finding is practised in households of TB patients as well as among human immunodeficiency virus infected and malnourished children. More attention needs to be paid to the provision of preventive therapy for household contacts aged <6 years as well as to the detection of multidrug-resistant TB among children. Case notification and the use of the Standards of TB Care in India are being strengthened in the private sector. PMID:26564540

  20. Tuberculosis Immunity: Opportunities from Studies with Cattle

    PubMed Central

    Waters, W. Ray; Palmer, Mitchell V.; Thacker, Tyler C.; Davis, William C.; Sreevatsan, Srinand; Coussens, Paul; Meade, Kieran G.; Hope, Jayne C.; Estes, D. Mark

    2011-01-01

    Mycobacterium tuberculosis and M. bovis share >99% genetic identity and induce similar host responses and disease profiles upon infection. There is a rich history of codiscovery in the development of control measures applicable to both human and bovine tuberculosis (TB) including skin-testing procedures, M. bovis BCG vaccination, and interferon-? release assays. The calf TB infection model offers several opportunities to further our understanding of TB immunopathogenesis. Recent observations include correlation of central memory immune responses with TB vaccine efficacy, association of SIRP?+ cells in ESAT-6:CFP10-elicited multinucleate giant cell formation, early ?? T cell responses to TB, antimycobacterial activity of memory CD4+ T cells via granulysin production, association of specific antibody with antigen burden, and suppression of innate immune gene expression in infected animals. Partnerships teaming researchers with veterinary and medical perspectives will continue to provide mutual benefit to TB research in man and animals. PMID:21197095

  1. Cyclic GMP-AMP Synthase Is an Innate Immune DNA Sensor for Mycobacterium tuberculosis.

    PubMed

    Collins, Angela C; Cai, Haocheng; Li, Tuo; Franco, Luis H; Li, Xiao-Dong; Nair, Vidhya R; Scharn, Caitlyn R; Stamm, Chelsea E; Levine, Beth; Chen, Zhijian J; Shiloh, Michael U

    2015-06-10

    Activation of the DNA-dependent cytosolic surveillance pathway in response to Mycobacterium tuberculosis infection stimulates ubiquitin-dependent autophagy and inflammatory cytokine production, and plays an important role in host defense against M. tuberculosis. However, the identity of the host sensor for M. tuberculosis DNA is unknown. Here we show that M. tuberculosis activated cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) in macrophages to produce cGAMP, a second messenger that activates the adaptor protein stimulator of interferon genes (STING) to induce type I interferons and other cytokines. cGAS localized with M. tuberculosis in mouse and human cells and in human tuberculosis lesions. Knockdown or knockout of cGAS in human or mouse macrophages blocked cytokine production and induction of autophagy. Mice deficient in cGAS were more susceptible to lethality caused by infection with M. tuberculosis. These results demonstrate that cGAS is a vital innate immune sensor of M. tuberculosis infection. PMID:26048137

  2. 21 CFR 866.3370 - Mycobacterium tuberculosis immunofluorescent reagents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...2013-04-01 false Mycobacterium tuberculosis immunofluorescent reagents... § 866.3370 Mycobacterium tuberculosis immunofluorescent reagents...Identification. Mycobacterium tuberculosis immunofluorescent...

  3. 21 CFR 866.3370 - Mycobacterium tuberculosis immunofluorescent reagents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...2010-04-01 false Mycobacterium tuberculosis immunofluorescent reagents... § 866.3370 Mycobacterium tuberculosis immunofluorescent reagents...Identification. Mycobacterium tuberculosis immunofluorescent...

  4. 21 CFR 866.3370 - Mycobacterium tuberculosis immunofluorescent reagents.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...2012-04-01 false Mycobacterium tuberculosis immunofluorescent reagents... § 866.3370 Mycobacterium tuberculosis immunofluorescent reagents...Identification. Mycobacterium tuberculosis immunofluorescent...

  5. 21 CFR 866.3370 - Mycobacterium tuberculosis immunofluorescent reagents.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...2011-04-01 false Mycobacterium tuberculosis immunofluorescent reagents... § 866.3370 Mycobacterium tuberculosis immunofluorescent reagents...Identification. Mycobacterium tuberculosis immunofluorescent...

  6. 21 CFR 866.3370 - Mycobacterium tuberculosis immunofluorescent reagents.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...2014-04-01 false Mycobacterium tuberculosis immunofluorescent reagents... § 866.3370 Mycobacterium tuberculosis immunofluorescent reagents...Identification. Mycobacterium tuberculosis immunofluorescent...

  7. AcpM, the meromycolate extension acyl carrier protein of Mycobacterium tuberculosis, is activated by the 4'-phosphopantetheinyl transferase PptT, a potential target of the multistep mycolic acid biosynthesis.

    PubMed

    Zimhony, Oren; Schwarz, Alon; Raitses-Gurevich, Maria; Peleg, Yoav; Dym, Orly; Albeck, Shira; Burstein, Yigal; Shakked, Zippora

    2015-04-14

    Modification of acyl carrier proteins (ACP) or domains by the covalent binding of a 4'-phosphopantetheine (4'-PP) moiety is a fundamental condition for activation of fatty acid synthases (FASes) and polyketide synthases (PKSes). Binding of 4'-PP is mediated by 4' phosphopantetheinyl transfersases (PPTases). Mycobacterium tuberculosis (Mtb) possesses two essential PPTases: acyl carrier protein synthase (Mtb AcpS), which activates the multidomain fatty acid synthase I (FAS I), and Mtb PptT, an Sfp-type broad spectrum PPTase that activates PKSes. To date, it has not been determined which of the two Mtb PPTases, AcpS or PptT, activates the meromycolate extension ACP, Mtb AcpM, en route to the production of mycolic acids, the main components of the mycobacterial cell wall. In this study, we tested the enzymatic activation of a highly purified Mtb apo-AcpM to Mtb holo-AcpM by either Mtb PptT or Mtb AcpS. By using SDS-PAGE band shift assay and mass spectrometry analysis, we found that Mtb PptT is the PPTase that activates Mtb AcpM. We measured the catalytic activity of Mtb PptT toward CoA, using an activation assay of a blue pigment synthase, BpsA (a nonribosomal peptide synthase, NRPS). BpsA activation by Mtb PptT was inhibited by Mtb apo-AcpM through competition for CoA, in accord with Mtb AcpM activation. A structural model of the putative interaction between Mtb PptT and Mtb AcpM suggests that both hydrophobic and electrostatic interactions stabilize this complex. To conclude, activation of Mtb AcpM by Mtb PptT reveals a potential target of the multistep mycolic acid biosynthesis. PMID:25785780

  8. Transformative tools for tackling tuberculosis.

    PubMed

    Gardiner, Jennifer L; Karp, Christopher L

    2015-10-19

    The world is in need of more effective approaches to controlling tuberculosis. The development of improved control strategies has been hampered by deficiencies in the tools available for detecting Mycobacterium tuberculosis and defining the dynamic consequences of the interaction of M. tuberculosis with its human host. Key needs include a highly sensitive, specific nonsputum diagnostic; biomarkers predictive of responses to therapy; correlates of risk for disease development; and host response-independent markers of M. tuberculosis infection. Tools able to sensitively detect and quantify total body M. tuberculosis burden might well be transformative across many needed use cases. Here, we review the current state of the field, paying particular attention to needed changes in experimental paradigms that would facilitate the discovery, validation, and development of such tools. PMID:26458772

  9. Non-human sources of Mycobacterium tuberculosis.

    PubMed

    Ghodbane, Ramzi; Drancourt, Michel

    2013-11-01

    Mycobacterium tuberculosis is a successful pathogen responsible for the vast majority of deadly tuberculosis cases in humans. It rests in a dormant form in contaminated people who constitute the reservoir with airborne interhuman transmission during pulmonary tuberculosis. M. tuberculosis is therefore regarded majoritary as a human pathogen. Here, we review the evidence for anthroponotic M. tuberculosis infection in non-human primates, other mammals and psittacines. Some infected animals may be sources for zoonotic tuberculosis caused by M. tuberculosis, with wild life trade and zoos being amplifying factors. Moreover, living animals and cadavers can scatter M. tuberculosis in the environment where it could survive for extended periods of time in soil where amoebae could play a role. Although marginal in the epidemiology of human tuberculosis, these data indicate that M. tuberculosis is not uniquely adapted to humans. PMID:24119770

  10. Nitazoxanide Stimulates Autophagy and Inhibits mTORC1 Signaling and Intracellular Proliferation of Mycobacterium tuberculosis

    PubMed Central

    Lam, Karen K. Y.; Zheng, Xingji; Forestieri, Roberto; Balgi, Aruna D.; Nodwell, Matt; Vollett, Sarah; Anderson, Hilary J.; Andersen, Raymond J.; Av-Gay, Yossef; Roberge, Michel

    2012-01-01

    Tuberculosis, caused by Mycobacterium tuberculosis infection, is a major cause of morbidity and mortality in the world today. M. tuberculosis hijacks the phagosome-lysosome trafficking pathway to escape clearance from infected macrophages. There is increasing evidence that manipulation of autophagy, a regulated catabolic trafficking pathway, can enhance killing of M. tuberculosis. Therefore, pharmacological agents that induce autophagy could be important in combating tuberculosis. We report that the antiprotozoal drug nitazoxanide and its active metabolite tizoxanide strongly stimulate autophagy and inhibit signaling by mTORC1, a major negative regulator of autophagy. Analysis of 16 nitazoxanide analogues reveals similar strict structural requirements for activity in autophagosome induction, EGFP-LC3 processing and mTORC1 inhibition. Nitazoxanide can inhibit M. tuberculosis proliferation in vitro. Here we show that it inhibits M. tuberculosis proliferation more potently in infected human THP-1 cells and peripheral monocytes. We identify the human quinone oxidoreductase NQO1 as a nitazoxanide target and propose, based on experiments with cells expressing NQO1 or not, that NQO1 inhibition is partly responsible for mTORC1 inhibition and enhanced autophagy. The dual action of nitazoxanide on both the bacterium and the host cell response to infection may lead to improved tuberculosis treatment. PMID:22589723

  11. Reversal of Mycobacterium tuberculosis Phenotypic Drug Resistance by 2-Aminoimidazole Based Small Molecules

    PubMed Central

    Ackart, David F.; Lindsey, Erick A.; Podell, Brendan K.; Melander, Roberta J.; Basaraba, Randall J.; Melander, Christian

    2014-01-01

    The expression of phenotypic drug resistance or drug tolerance serves as a strategy for Mycobacterium tuberculosis to survive in vivo antimicrobial drug treatment; however the mechanisms are poorly understood. Progress toward a more in depth understanding of in vivo drug tolerance and the discovery of new therapeutic strategies designed specifically to treat drug-tolerant M. tuberculosis are hampered by the lack of appropriate in vitro assays. A library of 2-aminoimidazole based small molecules combined with the anti-tuberculosis drug isoniazid were screened against M. tuberculosis expressing in vitro drug-tolerance as microbial communities attached to an extracellular matrix derived from lysed leukocytes. Based on the ability of nine of ten 2-aminoimidazole compounds to inhibit M. smegmatis biofilm formation and three of ten molecules capable of dispersing established biofilms, two active candidates and one inactive control were tested against drug tolerant M. tuberculosis. The two active compounds restored isoniazid susceptibility as well as reduced the in vitro minimum inhibitory concentrations of isoniazid in a dose-dependent manner. The dispersion of drug tolerant M. tuberculosis with 2-aminoimidazole based small molecules as an adjunct to antimicrobial treatment has the potential to be an effective anti-tuberculosis treatment strategy designed specifically to eradicate drug-tolerant M. tuberculosis. PMID:24478046

  12. Esophageal tuberculosis presenting with an appearance similar to that of carcinoma of the esophagus.

    PubMed

    Fujiwara, Yushi; Osugi, Harushi; Takada, Nobuyasu; Takemura, Masashi; Lee, Shigeru; Ueno, Masakatsu; Fukuhara, Kenichiro; Tanaka, Yoshinori; Nishizawa, Satoshi; Kinoshita, Hiroaki

    2003-01-01

    A case of esophageal tuberculosis presenting with an appearance similar to that of esophageal cancer is reported. The patient was an 82-year-old man with progressive dysphagia. Barium swallow and esophagoscopy revealed an elevated lesion with deep ulceration in the middle thoracic esophagus. Esophageal carcinoma, in particular, an undermining type of undifferentiated carcinoma, was suspected fluoroscopically and endoscopically. Histological examination of biopsy specimens revealed no malignancy, but there were epithelioid granulomas and a few Langhans' type multinucleated giant cells. Endoscopic ultrasonography clearly demonstrated an extramural lesion with calcification and direct infiltration of enlarged subcarinal lymph nodes into the esophageal wall. Ultrasonographic and histological findings indicated the possibility of esophageal tuberculosis. Although no bacteriological evidence was obtained, a therapeutic trial for tuberculosis, using antituberculous drugs, was started. After 2 weeks, the enlarged subcarinal lymph nodes were markedly reduced in size. The patient's symptoms improved gradually and had disappeared 8 weeks after he started treatment, when tubercle bacilli were isolated from sputum. A connection between the esophageal wall and its adjacent structures was clearly demonstrated by endoscopic ultrasonography. For patients with findings indicative of esophageal tuberculosis on endoscopic ultrasonography, a therapeutic trial for tuberculosis should be considered, even if polymerase chain reaction assay or culture is negative. PMID:12768391

  13. Understanding and intervening in HIV-associated tuberculosis.

    PubMed

    Rockwood, Neesha; Wilkinson, Robert John

    2015-12-01

    HIV-associated tuberculosis can present as extremes, ranging from acute life-threatening disseminated disease to occult asymptomatic infection. Both ends of this spectrum have distinct pathological correlates and require specific diagnostic and treatment approaches. Novel therapeutics, targeting both pathogen and host, are needed to augment pathogen clearance. In latent tuberculosis infection, enhancement of immune activation could be desirable. Antiretroviral therapy augments the beneficial effects of antitubercular therapy. However, in the context of high bacillary burden, antiretroviral therapy can also result in pathology (tuberculosis immune reconstitution inflammatory syndrome). In the immune reconstituting patient, modulation of immune activation controls tissue destruction. Interventions should also be appropriate and sustainable within the programmatic setting. PMID:26634681

  14. Structural and functional characterization of Mycobacterium tuberculosis triosephosphate isomerase

    SciTech Connect

    Connor, Sean E.; Capodagli, Glenn C.; Deaton, Michelle K.; Pegan, Scott D.

    2012-04-18

    Tuberculosis (TB) is a major infectious disease that accounts for over 1.7 million deaths every year. Mycobacterium tuberculosis, the causative agent of tuberculosis, enters the human host by the inhalation of infectious aerosols. Additionally, one third of the world's population is likely to be infected with latent TB. The incidence of TB is on the rise owing in part to the emergence of multidrug-resistant strains. As a result, there is a growing need to focus on novel M. tuberculosis enzyme targets. M. tuberculosis triosephosphate isomerase (MtTPI) is an essential enzyme for gluconeogenetic pathways, making it a potential target for future therapeutics. In order to determine its structure, the X-ray crystal structure of MtTPI has been determined, as well as that of MtTPI bound with a reaction-intermediate analog. As a result, two forms of the active site were revealed. In conjunction with the kinetic parameters obtained for the MtTPI-facilitated conversion of dihydroxyacetone phosphate (DHAP) to D-glyceraldehyde-3-phosphate (D-GAP), this provides a greater structural and biochemical understanding of this enzyme. Additionally, isothermal titration calorimetry was used to determine the binding constant for a reaction-intermediate analog bound to the active site of MtTPI.

  15. Early Events in Mycobacterium tuberculosis Infection in Cynomolgus Macaques†

    PubMed Central

    Lin, Philana Ling; Pawar, Santosh; Myers, Amy; Pegu, Amarenda; Fuhrman, Carl; Reinhart, Todd A.; Capuano, Saverio V.; Klein, Edwin; Flynn, JoAnne L.

    2006-01-01

    Little is known regarding the early events of infection of humans with Mycobacterium tuberculosis. The cynomolgus macaque is a useful model of tuberculosis, with strong similarities to human tuberculosis. In this study, eight cynomolgus macaques were infected bronchoscopically with low-dose M. tuberculosis; clinical, immunologic, microbiologic, and pathologic events were assessed 3 to 6 weeks postinfection. Gross pathological abnormalities were observed as early as 3 weeks, including Ghon complex formation by 5 weeks postinfection. Caseous granulomas were observed in the lung as early as 4 weeks postinfection. Only caseous granulomas were observed in the lungs at these early time points, reflecting a rigorous initial response. T-cell activation (CD29 and CD69) and chemokine receptor (CXCR3 and CCR5) expression appeared localized to different anatomic sites. Activation markers were increased on cells from airways and only at modest levels on cells in peripheral blood. The priming of mycobacterium-specific T cells, characterized by the production of gamma interferon occurred slowly, with responses seen only after 4 weeks of infection. These responses were observed from T lymphocytes in blood, airways, and hilar lymph node, with responses predominantly localized to the site of infection. From these studies, we conclude that immune responses to M. tuberculosis are relatively slow in the local and peripheral compartments and that necrosis occurs surprisingly quickly during granuloma formation. PMID:16790751

  16. DevR (DosR) mimetic peptides impair transcriptional regulation and survival of Mycobacterium tuberculosis under hypoxia by inhibiting the autokinase activity of DevS sensor kinase

    PubMed Central

    2014-01-01

    Background Two-component systems have emerged as compelling targets for antibacterial drug design for a number of reasons including the distinct histidine phosphorylation property of their constituent sensor kinases. The DevR-DevS/DosT two component system of Mycobacterium tuberculosis (M. tb) is essential for survival under hypoxia, a stress associated with dormancy development in vivo. In the present study a combinatorial peptide phage display library was screened for DevS histidine kinase interacting peptides with the aim of isolating inhibitors of DevR-DevS signaling. Results DevS binding peptides were identified from a phage display library after three rounds of panning using DevS as bait. The peptides showed sequence similarity with conserved residues in the N-terminal domain of DevR and suggested that they may represent interacting surfaces between DevS and DevR. Two DevR mimetic peptides were found to specifically inhibit DevR-dependent transcriptional activity and restrict the hypoxic survival of M. tb. The mechanism of peptide action is majorly attributed to an inhibition of DevS autokinase activity. Conclusions These findings demonstrate that DevR mimetic peptides impede DevS activation and that intercepting DevS activation at an early step in the signaling cascade impairs M. tb survival in a hypoxia persistence model. PMID:25048654

  17. Some Nigerian Anti-Tuberculosis Ethnomedicines: A Preliminary Efficacy Assessment

    PubMed Central

    Ibekwe, Nneka N.; Nvau, John B.; Oladosu, Peters O.; Usman, Auwal M.; Ibrahim, Kolo; Boshoff, Helena I.; Dowd, Cynthia S.; Orisadipe, Abayomi T.; Aiyelaagbe, Olapeju; Adesomoju, Akinbo A.; Barry, Clifton E.; Okogun, Joseph I.

    2014-01-01

    Ethnopharmacological significance Nigerian herbalists possess indigenous ethnomedicinal recipes for the management of tuberculosis and related ailments. Aim of the study To carry out a collaborative preliminary modern scientific evaluation of the efficacy of some Nigerian ethnomedicines used by traditional medicine practitioners (TMPs) in the management of tuberculosis and related ailments Materials and methods Ethnomedicinal recipes (ETMs) were collected from TMPs from locations in various ecological zones of Nigeria under a collaborative understanding. The aqueous methanolic extracts of the ETMs were screened against Mycobacterium bovis, BCG and Mycobacterium tuberculosis (M. tb.) strain H37Rv using the broth microdilution method. Results Extracts of ETMs screened against BCG showed 69% activity against the organism. The activities varied from weak, ? 2500?g /mL to highly active, 33?g /mL 64% of the extracts were active against M. tb. The activities of the extracts against M.tb. varied from weak, ? 2500?g /mL to highly active, 128?g/mL. There was 77% agreement in results obtained using BCG or M. tb. as test organisms Conclusion The results show clear evidence for the efficacy of the majority of indigenous Nigerian herbal recipes in the ethnomedicinal management of tuberculosis and related ailments. BCG may be effectively used, to a great extent, as the organism for screening for potential anti-M. tb. agents. A set of prioritization criteria for the selection of plants for initial further studies for the purpose of antituberculsis drug discovery research is proposed. PMID:24911338

  18. Report of Suspected Identity Theft Page 1 of 3

    E-print Network

    Report of Suspected Identity Theft Page 1 of 3 University of Connecticut Health Center Report of Suspected Identity Theft Part I-Initial Report Background Information: Your Name: ____________________ Incident Description: Include all indicators that signal possible identity theft or other fraudulent

  19. Guidelines for Investigating Suspected Financial Fraud November 26, 2013

    E-print Network

    Guidelines for Investigating Suspected Financial Fraud November 26, 2013 Introduction Safeguarding to a manager or employee who suspects fraud is being committed. Overview of Fraud Occupational fraud is defined or misapplication of the employing organization's resources or assets." In general terms a fraud takes place when

  20. REPORTING SUSPECTED CHILD ABUSE AND NEGLECT Policy Statement

    E-print Network

    Ottino, Julio M.

    Page 1 REPORTING SUSPECTED CHILD ABUSE AND NEGLECT Policy Statement Northwestern University places with the provisions of this policy. Furthermore, the Illinois Abused and Neglected Child Reporting Act specifies that all University employees are mandated reporters of suspected cases of child abuse and/or neglect

  1. Highly structured genetic diversity of the Mycobacterium tuberculosis population in

    E-print Network

    Choisy, Marc

    Highly structured genetic diversity of the Mycobacterium tuberculosis population in Djibouti S, Djibouti Ville, Djibouti Abstract Djibouti is an East African country with a high tuberculosis incidence with pulmonary tuberculosis (TB) were included. Genetic characterization of Mycobacterium tuberculosis, using

  2. Bone marrow mesenchymal stem cells provide an antibiotic-protective niche for persistent viable Mycobacterium tuberculosis that survive antibiotic treatment.

    PubMed

    Beamer, Gillian; Major, Samuel; Das, Bikul; Campos-Neto, Antonio

    2014-12-01

    During tuberculosis (TB), some Mycobacterium tuberculosis bacilli persist in the presence of an active immunity and antibiotics that are used to treat the disease. Herein, by using the Cornell model of TB persistence, we further explored our recent finding that suggested that M. tuberculosis can escape therapy by residing in the bone marrow (BM) mesenchymal stem cells. We initially showed that M. tuberculosis rapidly disseminates to the mouse BM after aerosol exposure and maintained a stable burden for at least 220 days. In contrast, in the lungs, the M. tuberculosis burden peaked at 28 days and subsequently declined approximately 10-fold. More important, treatment of the mice with the antibiotics rifampicin and isoniazid, as expected, resulted in effective clearance of M. tuberculosis from the lungs and spleen. In contrast, M. tuberculosis persisted, albeit at low numbers, in the BM of antibiotic-treated mice. Moreover, most viable M. tuberculosis was recovered from the bone marrow CD271(+)CD45(-)-enriched cell fraction, and only few viable bacteria could be isolated from the CD271(-)CD45(+) cell fraction. These results clearly show that BM mesenchymal stem cells provide an antibiotic-protective niche for M. tuberculosis and suggest that unraveling the mechanisms underlying this phenomenon will enhance our understanding of M. tuberculosis persistence in treated TB patients. PMID:25451154

  3. Tuberculosis mimicking lung cancer

    PubMed Central

    Hammen, I.

    2015-01-01

    Tuberculosis (TB) is well known as a diagnostic chameleon and can resemble malignancy. In thorax TB can be manifested as pulmonary infiltrates and/or mediastinal lymphadenopathy. In low incident countries with high incidence of lung cancer and varying clinical presentations, TB often gets misdiagnosed with the result of delayed treatment start and unnecessary diagnostic procedures. Our case report presents two patients, who were referred to the Thorax diagnostic centre at the Department of Respiratory Medicine, Odense University Hospital, with presumptive diagnosis of neoplasm and had proved lung TB with no evidence of malignancy instead. In the first case diagnosis was confirmed after thoracotomy, in the second case after bronchoscopy.

  4. Fish mycobacteriosis (Tuberculosis)

    USGS Publications Warehouse

    Parisot, T.J.; Wood, J.W.

    1959-01-01

    The etiologic agent for the bacterial disease, "fish tuberculosis" (more correctly "mycobacteriosis"), was first observed in carp in 189& from a pond in France. Subsequently similar agents have been isolated from or observed in fish in fresh water, salt water, and brackish water, in fish in aquaria, hatcheries, and natural habitat~ (wild populations of fish). The disease has been recognized as an important infection among hatchery reared salmonid fishes on the West Coast of the United States, and in aquarium fishes such as the neon tetra, the Siamese fighting fish, and in salt water fish held in zoological displays.

  5. Tuberculosis in the AIDS era.

    PubMed Central

    Sepkowitz, K A; Raffalli, J; Riley, L; Kiehn, T E; Armstrong, D

    1995-01-01

    A resurgence of tuberculosis has occurred in recent years in the United States and abroad. Deteriorating public health services, increasing numbers of immigrants from countries of endemicity, and coinfection with the human immunodeficiency virus (HIV) have contributed to the rise in the number of cases diagnosed in the United States. Outbreaks of resistant tuberculosis, which responds poorly to therapy, have occurred in hospitals and other settings, affecting patients and health care workers. This review covers the pathogenesis, epidemiology, clinical presentation, laboratory diagnosis, and treatment of Mycobacterium tuberculosis infection and disease. In addition, public health and hospital infection control strategies are detailed. Newer approaches to epidemiologic investigation, including use of restriction fragment length polymorphism analysis, are discussed. Detailed consideration of the interaction between HIV infection and tuberculosis is given. We also review the latest techniques in laboratory evaluation, including the radiometric culture system, DNA probes, and PCR. Current recommendations for therapy of tuberculosis, including multidrug-resistant tuberculosis, are given. Finally, the special problem of prophylaxis of persons exposed to multidrug-resistant tuberculosis is considered. PMID:7621399

  6. Management of multidrug resistant tuberculosis.

    PubMed

    Daley, Charles L; Caminero, Jose A

    2013-02-01

    Drug-resistant strains of Mycobacterium tuberculosis have emerged as a major threat to global tuberculosis control. Despite the availability of curative antituberculosis therapy for nearly half a century, inappropriate and inadequate treatment has allowed M. tuberculosis to acquire resistance to our most important antituberculosis drugs. The epidemic of drug-resistant tuberculosis has spread quickly in some areas due to the convergence of resistant strains of M. tuberculosis in high-risk patients (e.g., those with human immunodeficiency virus/acquired immunodeficiency syndrome) and high-risk environments (e.g., hospitals and prisons). The World Health Organization (WHO) estimates that there were 650,000 cases of multidrug resistant tuberculosis (MDR-TB) in 2010, defined as strains that are resistant to at least isoniazid (INH) and rifampicin (RIF). Globally, WHO estimates that 3.7% of new tuberculosis cases and 20% of re-treatment cases have MDR-TB. By the end of 2012, 84 countries had reported at least one case of extensively drug resistant strains (XDR-TB), which are MDR-TB strains that have acquired additional resistance to fluoroquinolones and at least one second-line injectable. Recently, cases of "totally drug resistant" tuberculosis have been reported. It is estimated that only 10% of all MDR-TB cases are currently receiving therapy and only 2% are receiving quality-assured drugs. This article reviews the management of MDR and XDR-TB and highlights the updated 2011 WHO guidelines on the programmatic management of drug-resistant tuberculosis. PMID:23460005

  7. Fistula Formation between Right Upper Bronchus and Bronchus Intermedius Caused by Endobronchial Tuberculosis: A Case Report

    PubMed Central

    Kim, Mikyoung; Kang, Eun Seok; Park, Jin Yong; Kang, Hwa Rim; Kim, Jee Hyun; Chang, YouJin; Choi, Kang Hyeon; Lee, Ki Man; Kim, Yook

    2015-01-01

    Endobronchial tuberculosis is defined as a tuberculous infection of the tracheobronchial tree and has a prevalence of up to 50% in active pulmonary tuberculosis cases. The most common complication of endobronchial tuberculosis is bronchial stenosis; benign fistula formation by endobronchial tuberculosis is rare, especially inter-bronchial fistula formation. We reported a rare case of a 73-year-old woman with a fistula between the right upper bronchus and bronchus intermedius. A diagnosis of inter-bronchial fistula caused by endobronchial tuberculosis was based on the results of chest computed tomography scans, bronchoscopy, and microbiological and pathological tests. The patient was treated with anti-tuberculous medication, and her symptoms gradually improved. PMID:26175787

  8. RePORT International: Advancing Tuberculosis Biomarker Research Through Global Collaboration.

    PubMed

    Hamilton, Carol D; Swaminathan, Soumya; Christopher, Devasahayam J; Ellner, Jerrold; Gupta, Amita; Sterling, Timothy R; Rolla, Valeria; Srinivasan, Sudha; Karyana, Muhammad; Siddiqui, Sophia; Stoszek, Sonia K; Kim, Peter

    2015-10-15

    Progress in tuberculosis clinical research is hampered by a lack of reliable biomarkers that predict progression from latent to active tuberculosis, and subsequent cure, relapse, or failure. Regional Prospective Observational Research in Tuberculosis (RePORT) International represents a consortium of regional cohorts (RePORT India, RePORT Brazil, and RePORT Indonesia) that are linked through the implementation of a Common Protocol for data and specimen collection, and are poised to address this critical research need. Each RePORT network is designed to support local, in-country tuberculosis-specific data and specimen biorepositories, and associated research. Taken together, the expected results include greater global clinical research capacity in high-burden settings, and increased local access to quality data and specimens for members of each network and their domestic and international collaborators. Additional networks are expected to be added, helping to spur tuberculosis treatment and prevention research around the world. PMID:26409277

  9. PCR colorimetric dot-blot assay and clinical pretest probability for diagnosis of Pulmonary Tuberculosis in Smear-Negative patients

    PubMed Central

    Scherer, Luciene Cardoso; Sperhacke, Rosa Dea; Jarczewski, Carla; Cafrune, Patrícia I; Minghelli, Simone; Ribeiro, Marta Osório; Mello, Fernanda CQ; Ruffino-Netto, Antonio; Rossetti, Maria LR; Kritski, Afrânio L

    2007-01-01

    Background Smear-negative pulmonary tuberculosis (SNPTB) accounts for 30% of Pulmonary Tuberculosis (PTB) cases reported annually in developing nations. Polymerase chain reaction (PCR) may provide an alternative for the rapid detection of Mycobacterium tuberculosis (MTB); however little data are available regarding the clinical utility of PCR in SNPTB, in a setting with a high burden of TB/HIV co-infection. Methods To evaluate the performance of the PCR dot-blot in parallel with pretest probability (Clinical Suspicion) in patients suspected of having SNPTB, a prospective study of 213 individuals with clinical and radiological suspicion of SNPTB was carried out from May 2003 to May 2004, in a TB/HIV reference hospital. Respiratory specialists estimated the pretest probability of active disease into high, intermediate, low categories. Expectorated sputum was examined by direct microscopy (Ziehl-Neelsen staining), culture (Lowenstein Jensen) and PCR dot-blot. Gold standard was based on culture positivity combined with the clinical definition of PTB. Results In smear-negative and HIV subjects, active PTB was diagnosed in 28.4% (43/151) and 42.2% (19/45), respectively. In the high, intermediate and low pretest probability categories active PTB was diagnosed in 67.4% (31/46), 24% (6/25), 7.5% (6/80), respectively. PCR had sensitivity of 65% (CI 95%: 50%–78%) and specificity of 83% (CI 95%: 75%–89%). There was no difference in the sensitivity of PCR in relation to HIV status. PCR sensitivity and specificity among non-previously TB treated and those treated in the past were, respectively: 69%, 43%, 85% and 80%. The high pretest probability, when used as a diagnostic test, had sensitivity of 72% (CI 95%:57%–84%) and specificity of 86% (CI 95%:78%–92%). Using the PCR dot-blot in parallel with high pretest probability as a diagnostic test, sensitivity, specificity, positive and negative predictive values were: 90%, 71%, 75%, and 88%, respectively. Among non-previously TB treated and HIV subjects, this approach had sensitivity, specificity, positive and negative predictive values of 91%, 79%, 81%, 90%, and 90%, 65%, 72%, 88%, respectively. Conclusion PCR dot-blot associated with a high clinical suspicion may provide an important contribution to the diagnosis of SNPTB mainly in patients that have not been previously treated attended at a TB/HIV reference hospital. PMID:18096069

  10. 9 CFR 309.2 - Livestock suspected of being diseased or affected with certain conditions; identifying suspects...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 2 2012-01-01 2012-01-01 false Livestock suspected of being diseased or affected with certain conditions; identifying suspects; disposition on post-mortem inspection or otherwise. 309.2 Section 309.2 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY ORGANIZATION...

  11. A Prospective Study of Tuberculosis Drug Susceptibility in Sabah, Malaysia, and an Algorithm for Management of Isoniazid Resistance

    PubMed Central

    Rashid Ali, Muhammad Redzwan S.; Parameswaran, Uma; William, Timothy; Bird, Elspeth; Wilkes, Christopher S.; Lee, Wai Khew; Yeo, Tsin Wen; Anstey, Nicholas M.; Ralph, Anna P.

    2015-01-01

    Introduction. The burden of tuberculosis is high in eastern Malaysia, and rates of Mycobacterium tuberculosis drug resistance are poorly defined. Our objectives were to determine M. tuberculosis susceptibility and document management after receipt of susceptibility results. Methods. Prospective study of adult outpatients with smear-positive pulmonary tuberculosis (PTB) in Sabah, Malaysia. Additionally, hospital clinicians accessed the reference laboratory for clinical purposes during the study. Results. 176 outpatients were enrolled; 173 provided sputum samples. Mycobacterial culture yielded M. tuberculosis in 159 (91.9%) and nontuberculous Mycobacterium (NTM) in three (1.7%). Among outpatients there were no instances of multidrug resistant M. tuberculosis (MDR-TB). Seven people (4.5%) had isoniazid resistance (INH-R); all were switched to an appropriate second-line regimen for varying durations (4.5–9 months). Median delay to commencement of the second-line regimen was 13 weeks. Among 15 inpatients with suspected TB, 2 had multidrug resistant TB (one extensively drug resistant), 2 had INH-R, and 4 had NTM. Conclusions. Current community rates of MDR-TB in Sabah are low. However, INH-resistance poses challenges, and NTM is an important differential diagnosis in this setting, where smear microscopy is the usual diagnostic modality. To address INH-R management issues in our setting, we propose an algorithm for the treatment of isoniazid-resistant PTB. PMID:25838829

  12. Immunology of Tuberculosis

    PubMed Central

    Bozzano, Federica; Marras, Francesco; De Maria, Andrea

    2014-01-01

    MTB ranks as the first worldwide pathogen latently infecting one third of the population and the second leading cause of death from a single infectious agent, after the human immunodeficiency virus (HIV). The development of vigorous and apparently appropriate immune response upon infection with M. tuberculosis in humans and experimental animals conflict with failure to eradicate the pathogen itself and with its ability to undergo clinical latency from which it may exit. From a clinical standpoint, our views on MTB infection may take advantage from updating the overall perspective, that has quite changed over the last decade, following remarkable advances in our understanding of the manipulation of the immune system by M. tuberculosis and of the role of innate components of the immune response, including macrophages, neutrophils, dendritic cells and NK cells in the initial spread of MTB and its exit from latency. Scope of this review is to highlight the major mechanisms of MTB escape from immune control and to provide a supplementary translational perspective for the interpretation of innate immune mechanisms with particular impact on clinical aspects. PMID:24804000

  13. Tuberculosis: Epidemiology and Control

    PubMed Central

    Sulis, Giorgia; Roggi, Alberto; Matteelli, Alberto; Raviglione, Mario C.

    2014-01-01

    Tuberculosis (TB) is a major public health concern worldwide: despite a regular, although slow, decline in incidence over the last decade, as many as 8.6 million new cases and 1.3 million deaths were estimated to have occurred in 2012. TB is by all means a poverty-related disease, mainly affecting the most vulnerable populations in the poorest countries. The presence of multidrug-resistant strains of M. tuberculosis in most countries, with somewhere prevalence is high, is among the major challenges for TB control, which may hinder recent achievements especially in some settings. Early TB case detection especially in resource-constrained settings and in marginalized groups remains a challenge, and about 3 million people are estimated to remain undiagnosed or not notified and untreated. The World Health Organization (WHO) has recently launched a new global TB strategy for the “post-2015 era” aimed at “ending the global TB epidemic” by 2035. This strategy is based on the three pillars that emphasize patient-centred TB care and prevention, bold policies and supportive systems, and intensified research and innovation. This paper aims to provide an overview of the global TB epidemiology as well as of the main challenges that must be faced to eliminate the disease as a public health problem everywhere. PMID:25408856

  14. Social and cultural factors in the successful control of tuberculosis.

    PubMed Central

    Rubel, A J; Garro, L C

    1992-01-01

    The burden of tuberculosis on the public health is staggering. Worldwide, annual incidence of new cases is estimated to be about 8 million. Almost 3 million deaths occur yearly. Early case identification and adherence to treatment regimens are the remaining barriers to successful control. In many nations, however, fewer than half those with active disease receive a diagnosis, and fewer than half those beginning treatment complete it. The twin problems of delay in seeking treatment and abandonment of a prescribed regimen derive from complex factors. People's confusion as to the implications of the tuberculosis symptoms, costs of transportation to clinic services, the social stigma that attaches to tuberculosis, the high cost of medication, organizational problems in providing adequate followup services, and patients' perception of clinic facilities as inhospitable all contribute to the complexity. Sociocultural factors are emphasized in this report because hitherto they have not been adequately explored. Salient among those sociocultural factors is the health culture of the patients. That is, the understanding and information people have from family, friends, and neighbors as to the nature of a health problem, its cause, and its implications. A knowledge of the health culture of their patients has become a critical tool if tuberculosis control programs are to be successful. Several anthropological procedures are recommended to help uncover the health culture of people served by tuberculosis clinics. PMID:1454974

  15. Immunologic Cerebral Vasculitis and Extrapulmonary Tuberculosis: An Uncommon Association

    PubMed Central

    Wang, Yiyi; Li, Qian; Zhen, Xiaohan; Liu, Yuan

    2015-01-01

    Infection can cause cerebral vasculitis not only by direct invasion of the vessel wall, but by immune complex deposition, or through secondary cryoglobulineamia. There are also two types of cerebral vasculitis associated with tuberculosis (TB). In TB treatment, cerebral vasculitis caused by immunologic injury received little attention than vasculitis due to direct invasion of TB infection. We report a case in a young woman who presented with fever, generalized lymphadenopathy, stroke-like events, movement disorder and coma, which was found to be active, lymph node TB with immunologic cerebral vacuities without tuberculosis meningitis. PMID:26500938

  16. Immunologic Cerebral Vasculitis and Extrapulmonary Tuberculosis: An Uncommon Association.

    PubMed

    Wang, Yiyi; Li, Qian; Zhen, Xiaohan; Liu, Yuan; Wu, Qi

    2015-09-01

    Infection can cause cerebral vasculitis not only by direct invasion of the vessel wall, but by immune complex deposition, or through secondary cryoglobulineamia. There are also two types of cerebral vasculitis associated with tuberculosis (TB). In TB treatment, cerebral vasculitis caused by immunologic injury received little attention than vasculitis due to direct invasion of TB infection. We report a case in a young woman who presented with fever, generalized lymphadenopathy, stroke-like events, movement disorder and coma, which was found to be active, lymph node TB with immunologic cerebral vacuities without tuberculosis meningitis. PMID:26500938

  17. Multiple Toxin-Antitoxin Systems in Mycobacterium tuberculosis

    PubMed Central

    Sala, Ambre; Bordes, Patricia; Genevaux, Pierre

    2014-01-01

    The hallmark of Mycobacterium tuberculosis is its ability to persist for a long-term in host granulomas, in a non-replicating and drug-tolerant state, and later awaken to cause disease. To date, the cellular factors and the molecular mechanisms that mediate entry into the persistence phase are poorly understood. Remarkably, M. tuberculosis possesses a very high number of toxin-antitoxin (TA) systems in its chromosome, 79 in total, regrouping both well-known (68) and novel (11) families, with some of them being strongly induced in drug-tolerant persisters. In agreement with the capacity of stress-responsive TA systems to generate persisters in other bacteria, it has been proposed that activation of TA systems in M. tuberculosis could contribute to its pathogenesis. Herein, we review the current knowledge on the multiple TA families present in this bacterium, their mechanism, and their potential role in physiology and virulence. PMID:24662523

  18. Multiple toxin-antitoxin systems in Mycobacterium tuberculosis.

    PubMed

    Sala, Ambre; Bordes, Patricia; Genevaux, Pierre

    2014-03-01

    The hallmark of Mycobacterium tuberculosis is its ability to persist for a long-term in host granulomas, in a non-replicating and drug-tolerant state, and later awaken to cause disease. To date, the cellular factors and the molecular mechanisms that mediate entry into the persistence phase are poorly understood. Remarkably, M. tuberculosis possesses a very high number of toxin-antitoxin (TA) systems in its chromosome, 79 in total, regrouping both well-known (68) and novel (11) families, with some of them being strongly induced in drug-tolerant persisters. In agreement with the capacity of stress-responsive TA systems to generate persisters in other bacteria, it has been proposed that activation of TA systems in M. tuberculosis could contribute to its pathogenesis. Herein, we review the current knowledge on the multiple TA families present in this bacterium, their mechanism, and their potential role in physiology and virulence. PMID:24662523

  19. Tuberculosis Drug Resistance Mutation Database

    E-print Network

    Church, George M.

    Tuberculosis (TB) remains the leading cause of death from a largely preventable and curable infectious disease, with an estimated 1.7 million deaths in 2006. Global prospects for TB control are challenged by the emergence ...

  20. Peritonitis due to genital tuberculosis.

    PubMed

    Svendsen, J H; Mikkelsen, A L; Siemssen, O J

    1985-01-01

    A case of genital tuberculosis is presented. The diagnosis was made by laparotomy and histological examination of biopsies from peritoneum and the Fallopian tube. The literature is reviewed and the diagnostic approach and treatment discussed. PMID:4083779