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1

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

PubMed Central

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

2014-01-01

2

Teaching chest X-ray reading for child tuberculosis suspects.  

PubMed

SETTING Cape Town, South Africa. OBJECTIVE To improve the reading of chest X-rays (CXRs) in child tuberculosis (TB) suspects. DESIGN We designed a reporting and recording form to assist in the diagnosis of childhood TB from CXRs. We then developed an image bank of antero-posterior and lateral CXR pairs, with each image pair assigned to one of four diagnostic categories. Finally, we designed and carried out a 1-day training course to teach clinicians how to read paediatric CXRs, with pre- and post-course assessments. RESULTS Of the 27 participants included, 17 (63%) were women. The median age was 38 years (interquartile range [IQR] 32.5-43.5). The median pre-training score was 16.0/30 (IQR 13.0-18.0) and the median post-training score was 17.0 (IQR 13.5-21.0). Sensitivity (P = 0.09) and specificity (P = 0.06) to detect TB did not change as a result of the course; however, the Wilcoxon signed ranks paired-sample test indicated an increase in the participants' overall ability to read CXRs (P = 0.017). CONCLUSIONS Teaching clinicians with a 1-day training course using a systematic approach and a standardised form led to a limited improvement in CXR reading ability. PMID:24902549

Seddon, J A; Padayachee, T; Du Plessis, A-M; Goussard, P; Schaaf, H S; Lombard, C; Gie, R P

2014-07-01

3

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

PubMed

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

Lakshmipathy, Dhanurekha; Vetrivel, Umashankar; Irudayam, Lily Therese; Ramasubban, Gayathri; Madhavan, H N; Sridhar, R; Meenakshi, N

2014-01-01

4

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

PubMed Central

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

2012-01-01

5

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

PubMed Central

Background Little is known about the prevalence of tuberculosis (TB) and HIV among TB suspects in primary health care units in Ethiopia. Methods In the period of February to March, 2009, a cross sectional survey was done in 27 health centers of Addis Ababa to assess the prevalence of TB and HIV among TB suspects who have >?=?2 weeks symptoms of TB such as cough, fever and weight loss. Diagnosis of TB and HIV was based on the national guidelines. Information concerning socio-demographic variables and knowledge of the respondents about TB was collected using pretested questionnaire. Results Of the 545 TB suspects, 506 (92.7%) of them participated in the study. The prevalence of both pulmonary and extra pulmonary TB was 46.0% (233/506). The smear positivity rate among pulmonary TB suspect was 21.3%. Of the TB suspects, 298 (58.9%) of them were tested for HIV and 27.2% (81/298) were HIV seropositive. Fifty percent of the HIV positive TB suspects had TB. TB suspects who had a contact history with a TB patient in the family were 9 times more likely to have TB than those who did not have a contact history, [OR?=?9.1, (95%CI:4.0, 20.5)]. Individuals who had poor [OR?=?5.2, (95%CI: 2.3, 11.2)] and fair knowledge [OR?=?3.7, (95%CI: 1.3, 10.4)] about TB were more likely to have TB than individuals who had good knowledge. Conclusion In conclusion, the prevalence of TB among TB suspects with duration of 2 or more weeks is high. Fifty percent of the HIV positive TB suspects had TB. Case finding among TB suspects with duration of 2 or more weeks should be intensified particularly among those who have a contact history with a TB patient.

Deribew, Amare; Negussu, Nebiyu; Melaku, Zenebe; Deribe, Kebede

2011-01-01

6

Mycobacterium tuberculosis Prevents Inflammasome Activation  

PubMed Central

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

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

2013-01-01

7

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

PubMed Central

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

2014-01-01

8

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

PubMed Central

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

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

2010-01-01

9

Species spectrum of nontuberculous mycobacteria isolated from suspected tuberculosis patients, identification by multi locus sequence analysis.  

PubMed

Identification of Mycobacterium species is difficult due to a complex and rapidly changing taxonomy, the failure of 16S rRNA to discriminate many closely related species and the unreliability of phenotypic testing. We investigated a collection of nontuberculous mycobacteria (NTM) strains isolated from suspected tuberculosis patients at Tuberculosis Reference Centre (Ahvaz, Iran) and Masoud Laboratory (Tehran, Iran) during 2008-2012 to evaluate the species spectrum of NTM isolates. Based on phenotypic tests, the isolates were identified up to species or complex level; however they were heterogonous by hsp65-PCR restriction fragment length polymorphism analysis (PRA) method. Representative isolates from each hsp65-PRA pattern, were subjected to identification using single locus and multi locus sequence analysis (MLSA) based on 16S rRNA, rpoB, hsp65 and 16S-23S internal transcribes spacer (ITS) fragments to determine their taxonomic affiliations. All 92 NTM isolates from different clinical specimens were considered as etiological agents causing disease according to American Thoracic Society (ATS) guideline. Phenotypic evaluation alone assigned 66 (72%) isolates to a species or complex level and consequently 76 (82%) isolates showed previously reported hsp65-PRA patterns. Although sequence base identification using single locus such as 16S rRNA, rpoB, hsp65 or ITS identified the isolates up to species level, MLSA correctly identified 16 different species of NTM from clinical isolates. In summary, four-locus MLSA is a reliable method for elucidating taxonomic data and reliable species identification of Mycobacterium isolates and therefore, would be more feasible for routine use in Tuberculosis (TB) reference laboratory. PMID:24070831

Hashemi-Shahraki, Abdolrazagh; Bostanabad, Saeed Zaker; Heidarieh, Parvin; Titov, Leonid Petrovich; Khosravi, Azar Dokht; Sheikhi, Nasrin; Ghalami, Mostafa; Nojoumi, Seyed Ali

2013-12-01

10

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

PubMed

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

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

2014-01-01

11

[Serum adenosine deaminase activity in pulmonary tuberculosis].  

PubMed

Adenosine deaminase (ADA) activity has been helpful for the diagnosis of tuberculous pleurisy. However, there are few studies about the role of ADA in the diagnosis and follow-up of pulmonary tuberculosis. In our study, serum ADA activity was determined in order to investigate the role of the enzyme in the diagnosis of pulmonary tuberculosis and monitoring the efficiency of therapy. The ADA activity was (mean +/- SD) 21.77 +/- 8.51 U/L in pulmonary tuberculosis patients (n= 44), 6.24 +/- 3.25 U/L in old tuberculosis patients (n= 24), 8.58 +/- 4.38 U/L in healthy control subjects (n= 20), whereas the mean for the patients with bronchial cancer (n= 20) was 18.51 +/- 7.85 U/L. There was no statistical difference between the results of pulmonary tuberculosis patients and the patients with bronchial cancer. On the contrary, the result of these two group were significantly different from both old tuberculosis patients and healthy control subjects (p< 0.001 for both). In 10 pulmonary tuberculosis patients, ADA activities were determined both before and after treatment and a significant decrease was observed in ADA activities after treatment (p< 0.001). In conclusion, serum ADA activity is increased in pulmonary tuberculosis patients, therefore it may be a helpful parameter for monitoring therapy. PMID:15143406

Alata?, Füsun; Uslu, Sema; Moral, Hale; Alata?, Ozkan; Metinta?, Muzaffer; Erginel, Sinan; Uçgun, Irfan

2003-01-01

12

Operational Implementation of LED Fluorescence Microscopy in Screening Tuberculosis Suspects in an Urban HIV Clinic in Uganda  

PubMed Central

Background Light emitting diode (LED) fluorescence microscopy (FM) is an affordable, technology targeted for use in resource-limited settings and recommended for widespread roll-out by the World Health Organization (WHO). We sought to compare the operational performance of three LED FM methods compared to light microscopy in a cohort of HIV-positive tuberculosis (TB) suspects at an urban clinic in a high TB burden country. Methods Two spot specimens collected from TB suspects were included in the study. Smears were stained using auramine O method and read after blinding by three LED-based FM methods by trained laboratory technicians in the Infectious Diseases Institutelaboratory. Leftover portions of the refrigerated sputum specimens were transported to the FIND Tuberculosis Research Laboratory for Ziehl Neelsen (ZN) smear preparation and reading by experienced technologist as well as liquid and solid culture. Results 174 of 627 (27.8%) specimens collected yielded one or more positive mycobacterial cultures. 94.3% (164/174) were M. tuberculosis complex. LED FM was between 7.3–11.0% more sensitive compared to ZN microscopy. Of the 592 specimens examined by all microscopy methods, there was no significant difference in sensitivity between the three LED FM methods. The specificity of the LED FM methods was between 6.1% and 7.7% lower than ZN microscopy (P<0.001), although exclusion of the single poor reader resulted in over 98% specificity for all FM methods. Conclusions Laboratory technicians in routine settings can be trained to use FM which is more sensitive than ZN microscopy. Despite rigorous proficiency testing, there were operator-dependent accuracy issues which highlight the critical need for intensive quality assurance procedures during LED FM implementation. The low sensitivity of FM for HIV-positive individuals particularly those with low CD4 T cell counts, will limit the number of additional patients found by LED FM in countries with high rates of HIV co-infection.

Albert, Heidi; Nakiyingi, Lydia; Sempa, Joseph; Mbabazi, Olive; Mukkada, Sheena; Nyesiga, Barnabas; Perkins, Mark D.; Manabe, Yukari C.

2013-01-01

13

Validation of Mycobacterium tuberculosis Rv1681 protein as a diagnostic marker of active pulmonary tuberculosis.  

PubMed

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

Pollock, Nira R; 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; Campos-Neto, Antonio

2013-05-01

14

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

PubMed Central

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

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

2011-01-01

15

Adrenal function in patients with active tuberculosis.  

PubMed Central

Although tuberculosis is a recognised cause of adrenal insufficiency, little is known about adrenal function in patients with active tuberculosis. Ninety Melanesian adults with active tuberculosis (30 pulmonary, 30 miliary, 30 extrapulmonary) had adrenal function assessed prospectively before and three to four weeks after starting antituberculous chemotherapy. Basal serum cortisol concentrations were normal in 55 (61%) and raised in 35 (39%) of the subjects. No patient had a low basal cortisol concentration. After Synacthen stimulation, cortisol responses were normal in 81 (92%) of the patients and subnormal in seven (8%). After antituberculous chemotherapy the response to Synacthen stimulation was normal in all but one patient. It is concluded that adrenal dysfunction is an uncommon problem in patients with active tuberculosis, and that, contrary to recent reports, antituberculous chemotherapy regimens that include rifampicin do not have an adverse effect on adrenal function.

Barnes, D J; Naraqi, S; Temu, P; Turtle, J R

1989-01-01

16

T-Cell Immunophenotyping Distinguishes Active From Latent Tuberculosis  

PubMed Central

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.

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

17

Detection of mycobacterial lipoarabinomannan with an antigen-capture ELISA in unprocessed urine of Tanzanian patients with suspected tuberculosis.  

PubMed

A direct antigen-capture ELISA based on the detection of mycobacterial lipoarabinomannan (LAM) in unprocessed urine was evaluated for its usefulness in clinical practice. In Tanzania, 231 patients with suspected pulmonary tuberculosis (TB) and 103 healthy volunteers were screened with standard TB tests and with the new LAM-ELISA. Of 132 patients with confirmed pulmonary mycobacterial disease (positive sputum culture), 106 were positive using the LAM-ELISA (sensitivity 80.3%). In comparison, the sensitivity of acid-fast bacilli (AFB) sputum microscopy was 62.1% (82 of 132 confirmed cases). Of the 231 patients, 17 were both culture- and AFB-negative, but had typical radiographic signs of pulmonary mycobacterial infection and did not respond to antibiotic treatment. Of these 17 patients, 13 (76.5%) had positive LAM-ELISA test results. To define the specificity of the assay, urine samples from 103 healthy volunteers were also screened using LAM-ELISA. All but one had an optical density below the cut-off (specificity 99%). Of interest was a significant correlation between level of microscopic density of mycobacteria in sputum and LAM antigen concentration in urine (chi2=8.44). The LAM-ELISA is a field-adapted tool that can improve screening standards in countries with a high incidence of TB. PMID:16139316

Boehme, C; Molokova, E; Minja, F; Geis, S; Loscher, T; Maboko, L; Koulchin, V; Hoelscher, M

2005-12-01

18

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

PubMed Central

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

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

2014-01-01

19

Discriminating between latent and active tuberculosis with multiple biomarker responses  

PubMed Central

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.

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

2011-01-01

20

Discriminating between latent and active tuberculosis with multiple biomarker responses.  

PubMed

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

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

2011-05-01

21

Risk of Progression to Active Tuberculosis Following Reinfection With Mycobacterium tuberculosis  

PubMed Central

(See the Editorial Commentary by Vernon and Villarino, on pages 792–3.) Background.?The risk of progression to active tuberculosis is greatest in the several years following initial infection. The extent to which latent tuberculosis infection reduces the risk of progressive disease following reexposure and reinfection is not known. Indirect estimates from population models have been highly variable. Methods.?We reviewed prospective cohort studies of persons exposed to individuals with infectious tuberculosis that were published prior to the widespread treatment of latent tuberculosis to estimate the incidence of tuberculosis among individuals with latent tuberculosis infection (LTBI group) and without latent tuberculosis (uninfected; UI group). We calculated the incidence rate ratio (IRR) of tuberculosis disease following infection between these 2 groups. We then adjusted incidence for expected reactivation, proportion of each group that was infected, and median time of observation following infection during the study. Results.?We identified 18 publications reporting tuberculosis incidence among 23 paired cohorts of individuals with and without latent infection (total N = 19 886). The weighted mean adjusted incidence rate of tuberculosis in the LTBI and UI groups attributable to reinfection was 13.5 per 1000 person-years (95% confidence interval [CI]: 5.0–26.2 per 1000 person-years) and that attributable to primary infection was 60.1 per 1000 person-years (95% CI: 38.6–87.4 per 1000 person-years). The adjusted IRR for tuberculosis in the LTBI group compared with the UI group was 0.21 (95% CI: .14–.30). Conclusions.?Individuals with latent tuberculosis had 79% lower risk of progressive tuberculosis after reinfection than uninfected individuals. The risk reduction estimated in this study is greater than most previous estimates made through population models.

Noubary, Farzad; Walensky, Rochelle P.; Cerda, Rodrigo; Losina, Elena; Horsburgh, C. Robert

2012-01-01

22

[Spontaneous pneumothorax associated to active pulmonary tuberculosis].  

PubMed

This paper reviewed 8 cases of spontaneous pneumothorax, associated to pulmonary tuberculosis during a period of time of two years at the A.L.M. General Hospital of Toluca, Mex. The diagnosis was confirmed by clinical picture, radiology and bacteriology studies. Six males and two females proceding of the low class; farmers all of them. Their age ranged between 18 and 35 years. Two of the patients showed cavitary lesions, five had difusse fibrosis of the lung. We analized the clinical manifestations and reviewed the pathogenic mechanisms as well the medical and surgical treatment. No deaths ocurred en this series. We concluded that the direct relation between active pulmonary tuberculosis and spontaneous pneumothorax is not clear, but their association in this serie suggested further studies to stablished this. We emphasized the importance of this complication rare in the world literature. PMID:119959

Díaz Rojas, F; Córdova Gutiérrez, H; Aguirre Gas, H

1978-01-01

23

38 CFR 3.374 - Effect of diagnosis of active tuberculosis.  

Code of Federal Regulations, 2013 CFR

...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...

2013-07-01

24

38 CFR 3.374 - Effect of diagnosis of active tuberculosis.  

Code of Federal Regulations, 2010 CFR

...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...

2010-07-01

25

38 CFR 3.374 - Effect of diagnosis of active tuberculosis.  

Code of Federal Regulations, 2012 CFR

...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...

2012-07-01

26

38 CFR 3.374 - Effect of diagnosis of active tuberculosis.  

Code of Federal Regulations, 2011 CFR

...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...

2011-07-01

27

Enzyme-linked immunosorbent assay (ELISA) with mycobacterial crude antigens for the sero-epidemiological diagnosis of active tuberculosis.  

PubMed

In search for reliable, nonexpensive procedures for tuberculosis diagnosis suitable for seroepidemiological studies in leprosy-endemic areas, enzyme-linked immunosorbent assays (ELISAs) with whole intact bacilli, whole lipid-free bacilli and protein-enriched soluble extracts from the H37Rv Mycobacterium tuberculosis strain were evaluated. Sera tested came from 47 active, pulmonary tuberculosis adult cases, 60 household contacts of active tuberculosis cases, 20 lepromatous leprosy adult patients, and 67 healthy adult controls obtained from low and high leprosy and tuberculosis endemicity areas. There was no influence of such endemicity levels in the number of positive results in control sera. Antibody levels obtained with each of the antigens in ELISAs were significantly different in tuberculosis patients and the control groups. Ten percent of tuberculosis contacts were positive with some of the antigens and three of them showed suggestive chest radiographs. The best combination for a high number of positive results with tuberculosis sera and low positive results with leprosy sera was the BCG soluble extract (91% and 15%, respectively). This preparation also yielded excellent sensitivity and specificity values for tuberculosis (91.5% and 92.5%, respectively). These data suggest that BCG soluble extract ELISAs could provide helpful information to estimate tuberculosis prevalence only in leprosy-free areas, under a situation of unavailability of purified antigens. In pulmonary cases, sputum microscopic examination and culture have higher sensibility than serodiagnosis; therefore, the utilization of BCG soluble extract ELISAs as a diagnostic aid in individual patients with suspected active tuberculosis only can be useful in extrapulmonary cases. PMID:9030108

Escobar-Gutierrez, A; Amezcua-Chavarria, M E; Pasten-Sanchez, S; Ramirez-Casanova, E; Cazares, J V; Granados, G; Loo-Mendez, E; Cicero, R

1996-12-01

28

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

Code of Federal Regulations, 2010 CFR

... 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...

2010-07-01

29

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

Code of Federal Regulations, 2012 CFR

... 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...

2012-07-01

30

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

Code of Federal Regulations, 2011 CFR

... 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...

2011-07-01

31

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

Microsoft Academic Search

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

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

2010-01-01

32

Isoxyl Activation Is Required for Bacteriostatic Activity against Mycobacterium tuberculosis?  

PubMed Central

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

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

2007-01-01

33

Tuberculosis  

MedlinePLUS

Tuberculosis (TB) is one of the oldest human diseases. Mummies from ancient Egypt show signs of tubercular ... his discovery that a microbe he called Mycobacterium tuberculosis (Mtb) causes TB. He also demonstrated that TB ...

34

Does Neutralization of Gastric Aspirates from Children with Suspected Intrathoracic Tuberculosis Affect Mycobacterial Yields on MGIT Culture?  

PubMed Central

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

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

2013-01-01

35

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

PubMed

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

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

2013-06-01

36

Evaluation of two line probe assays for rapid detection of Mycobacterium tuberculosis, tuberculosis (TB) drug resistance, and non-TB Mycobacteria in HIV-infected individuals with suspected TB.  

PubMed

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

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

2014-04-01

37

Association between Tobacco Smoking and Active Tuberculosis in Taiwan  

Microsoft Academic Search

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

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

2009-01-01

38

Factors associated with bovine tuberculosis confirmation rates in suspect lesions found in cattle at routine slaughter in Great Britain, 2003-2008.  

PubMed

Bovine tuberculosis (bTB) is one of the most complex and intractable animal health problems facing the British cattle industry today. The inspection of carcasses from cattle sent to slaughter is part of routine surveillance for bTB in Great Britain (GB). Tissue with suspect lesions from cattle from herds previously considered uninfected with bTB is sent to the Animal Health and Veterinary Laboratories Agency (AHVLA) for culture and histopathological examination for Mycobacterium bovis infection. In this study, risk factors for confirmation of infection in suspect bTB lesions found at routine slaughter of cattle from officially bTB-free (OTF) herds in GB were investigated. The study sample included the first record of a suspect lesion in a bovine from any OTF herd identified during post-mortem inspection between 2003 and 2008. There were 3663 submissions from 151 slaughterhouses of which 2470 (67.4%) were confirmed as culture positive for M. bovis. Logistic regression analysis with a random intercept for slaughterhouse was used to investigate relationships between bTB confirmation and animal and herd-level risk factors. Slaughterhouse of post mortem and the following factors related to bTB prevalence were significant predictors of confirmation probability: region of farm of origin of the animal, the testing interval for routine field surveillance for bTB on the farm, number of reactors in the last bTB incident on the farm within the last 4 years, if applicable, the animal's date of birth and the year of animal's slaughter. The modelled predicted population averaged probabilities for confirmation varied from 0.14 to 0.90 between slaughterhouses. Differences in the detection of cattle with bTB between British slaughterhouses warrant further study. PMID:23540447

Shittu, A; Clifton-Hadley, R S; Ely, E R; Upton, P U; Downs, S H

2013-07-01

39

Spooky Suspects  

ERIC Educational Resources Information Center

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

Pacifici, Lara

2011-01-01

40

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

PubMed Central

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

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

2013-01-01

41

Programmatic approaches to screening for active tuberculosis.  

PubMed

Passive case finding, the detection of tuberculosis (TB) cases among persons presenting to health facilities with symptoms suggestive of TB, has remained the principal public health approach for TB diagnosis. While this approach, in combination with improved treatment, has led to substantial global progress, the overall epidemiological impact has been inadequate. Stagnating case notifications and sluggish decline in incidence prompt the pursuit of a more active approach to TB case detection. Screening among contacts of TB patients and people living with human immunodeficiency virus infection, long recommended, needs scaling up. Screening in other risk groups may also be considered, depending on the epidemiological situation. The World Health Organization (WHO) has recently produced recommendations on systematic screening for active TB, which set out principles and provide guidance on the prioritisation of risk groups for screening and choice of screening and diagnostic algorithms. With a view to help translate WHO recommendations into practice, this concluding article of the State of the Art series discusses programmatic approaches. Published literature is scanty. However, considerable field experience exists to draw important lessons. Cautioning against a hasty pursuit of active case finding, the article stresses that programmatic implementation of TB screening requires a systematic approach. Important considerations should include setting clear goals and objectives based on a thorough assessment of the situation; considering the place of TB screening in the overall approach to enhancing TB detection; identifying and prioritising risk groups; choosing appropriate screening and diagnostic algorithms; and pursuing setting-specific implementation strategies with engagement of relevant partners, due attention to ethical considerations and built-in monitoring and evaluation. PMID:24025375

Uplekar, M; Creswell, J; Ottmani, S-E; Weil, D; Sahu, S; Lönnroth, K

2013-10-01

42

Indoleamides are active against drug-resistant Mycobacterium tuberculosis  

PubMed Central

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.

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

43

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

PubMed Central

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

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

2008-01-01

44

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

Code of Federal Regulations, 2013 CFR

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

2013-07-01

45

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

Code of Federal Regulations, 2010 CFR

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

2010-07-01

46

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

Code of Federal Regulations, 2012 CFR

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

2012-07-01

47

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

Code of Federal Regulations, 2011 CFR

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

2011-07-01

48

Incremental Yield of Serial Sputum Cultures for Diagnosis of Tuberculosis among HIV Infected Smear Negative Pulmonary TB Suspects in Kampala, Uganda  

PubMed Central

Background Sputum culture is the gold standard for diagnosis of pulmonary tuberculosis (PTB). Although mostly used for research, culture is recommended by the World Health Organization for TB diagnosis among HIV infected smear negative PTB suspects. Even then, the number of sputum samples required remains unspecified. Here, we determined the Incremental Yield (IY) and number of samples required to diagnose an additional PTB case upon second and third serial sputum culture. Methods/Findings This was a cross sectional study done between January and March 2011. Serial sputum samples were provided by participants within two days and cultured using Lowenstein Jensen (LJ) and Mycobacteria Growth Indicator Tube (MGIT) methods. A PTB case was defined as a positive culture on either one or both methods. The IY from the second and third serial cultures was determined and the reciprocal of the product of the fractions of IY provided the number of samples required for an additional PTB case. Of the 170 smear negative PTB suspects, 62 (36.5%) met the case definition. The IY of the second sample culture was 12.7%, 23.6% and 12.6% and for the third sample culture was 6.8%, 7.5% and 7.3% with LJ, MGIT and LJ or MGIT, respectively. The number of samples required for an additional PTB case and 95% CI upon the second sample culture were 29.9 (16.6, 156.5), 11.3 (7.6, 21.9) and 20.8 (12.5, 62.7); while for the third sample culture were 55.6 (26.4, 500.4), 35.7 (19.0, 313.8) and 36.1 (19.1, 330.9) by LJ, MGIT and LJ or MGIT respectively. Conclusions/Significance Among HIV infected smear negative PTB suspects in Kampala, 93% of PTB cases are diagnosed upon the second serial sputum culture. The number of cultures needed to diagnose an additional PTB case, ranges from 11–30 and 35–56 by the second and third sputum samples, respectively.

Ssengooba, Willy; Kiwanuka, Noah; Kateete, David P.; Katamba, Achilles; Joloba, Moses L.

2012-01-01

49

Circulating MicroRNAs in Patients with Active Pulmonary Tuberculosis?  

PubMed Central

Emerging evidence shows that microRNAs (miRNAs) play an important role in pathogen-host interactions. Circulating miRNAs have been repeatedly and stably detected in blood and hold promise to serve as molecular markers for diverse physiological and pathological conditions. To date, the relationship between circulating miRNAs and active pulmonary tuberculosis (TB) has not been reported. Using microarray-based expression profiling followed by real-time quantitative PCR validation, the levels of circulating miRNAs were compared between patients with active pulmonary tuberculosis and matched healthy controls. The receiver operating characteristic curve was used to evaluate the diagnostic effect of selected miRNA. Bioinformatic analysis was used to explore the potential roles of these circulating miRNAs in active pulmonary tuberculosis infection. Among 92 miRNAs significantly detected, 59 miRNAs were downregulated and 33 miRNAs were upregulated in the TB serum compared to their levels in the control serum. Interestingly, only two differentially expressed miRNAs were increased not only in the serum but also in the sputum of patients with active pulmonary tuberculosis compared to the levels for the healthy controls. Upregulated miR-29a could discriminate TB patients from healthy controls with reasonable sensitivity and specificity. A number of significantly enriched pathways regulated by these circulating miRNAs were predicted, and most of them were involved in acute-phase response, inflammatory response, and the regulation of the cytoskeleton. In all, for the first time our results revealed that a number of miRNAs were differentially expressed during active pulmonary tuberculosis infection, and circulating miR-29a has great potential to serve as a marker for the detection of active pulmonary tuberculosis infection.

Fu, Yurong; Yi, Zhengjun; Wu, Xiaoyan; Li, Jianhua; Xu, Fuliang

2011-01-01

50

Total hip arthroplasty for active tuberculosis of the hip.  

PubMed

Total hip arthroplasty (THA) has been used as a successful form of treatment in patients with long-standing tuberculosis, but it is unclear whether THA should be performed in patients with current infection. We performed THA in six patients with advanced active tuberculosis of the hip from 2002 to 2006. Tuberculosis was confirmed in all cases by histological examination. All patients were treated with antituberculous medications for at least two weeks followed by thorough debridement and THA. Antituberculous medications were administered postoperatively for at least 12 months. The duration of postoperative follow-up was an average of 49 months. No reactivation of the infection was detected in our series. Using the Harris hip score system, five of the patients were classified as excellent and one as good. THA in advanced active tuberculosis of the hip is a safe procedure providing symptomatic relief and functional improvement. Thorough debridement of infected tissues and postoperative antituberculous therapy are the keys to lowering the potential risk of reactivation of tuberculosis. PMID:19685242

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

2010-12-01

51

Involvement of Antilipoarabinomannan Antibodies in Classical Complement Activation in Tuberculosis  

PubMed Central

We examined alternative and classical complement activation induced by whole bacilli of Mycobacterium bovis BCG and Mycobacterium tuberculosis products. After exposure to BCG, there were higher levels of the terminal complement complex in sera from Indian tuberculosis patients than in sera from healthy controls. The addition of BCG with or without EGTA to these sera indicated that approximately 70 to 85% of the total levels of the terminal complement complex was formed by classical activation. Sera from Indian tuberculosis patients contained more antibody to lipoarabinomannan (LAM) than sera from healthy Indians. Levels of anti-LAM immunoglobulin G2 (IgG2), but not anti-LAM IgM, correlated positively with classical activation induced by BCG in the sera. By flow cytometry, deposition of C3 and terminal complement complex on bacilli incubated with normal human serum was demonstrated. The anticomplement staining was significantly reduced in the presence of EGTA and EDTA. Flow cytometry also revealed the binding of complement to BCG incubated with rabbit anti-LAM and then with factor B-depleted serum. This indicates that classical activation plays a major role in complement activation induced by mycobacteria and that anti-LAM IgG on the bacilli can mediate this response. Classical complement activation may be important for the extent of phagocytosis of M. tuberculosis by mononuclear phagocytes, which may influence the course after infection.

Hetland, Geir; Wiker, Harald G.; H?gasen, Kolbj?rn; Hamasur, Beston; Svenson, Stefan B.; Harboe, Morten

1998-01-01

52

Identification and management of tuberculosis.  

PubMed

Although the resurgence of tuberculosis in the early 1990s has largely been controlled, the risk of contracting this disease remains high in homeless persons, recent immigrants and persons infected with the human immunodeficiency virus (HIV). Purified protein derivative testing should be targeted at these groups and at persons with known or suspected exposure to active tuberculosis. Most patients with latent tuberculosis are treated with isoniazid administered daily for nine months. In patients with active tuberculosis, the initial regimen should include four drugs for at least two months, with subsequent therapy determined by mycobacterial sensitivities and clinical response. To avoid harmful drug interactions, regimens that do not contain rifampin may be employed in HIV-infected patients who are taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. To maximize compliance and minimize the emergence of mycobacterial drug resistance, family physicians should consider using directly observed therapy in all patients with tuberculosis. PMID:10821149

Jerant, A F; Bannon, M; Rittenhouse, S

2000-05-01

53

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

Code of Federal Regulations, 2013 CFR

... 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...

2013-07-01

54

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

PubMed Central

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

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

2011-01-01

55

Tuberculosis  

MedlinePLUS

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

56

Identification of HIV patients with active pulmonary tuberculosis using urine based polymerase chain reaction assay  

Microsoft Academic Search

BACKGROUNDDespite the increased dissemination of tuberculosis among HIV infected patients, the diagnosis is difficult to establish. Traditional microbiological methods lack satisfactory sensitivity. We have developed a highly sensitive and specific nested polymerase chain reaction (PCR) capable of detecting Mycobacterium tuberculosis DNA in urine specimens and have used this test to examine urine specimens from HIV patients with active pulmonary tuberculosis.METHODSUrine

Antonio Aceti; Stefania Zanetti; Maria S Mura; Leonardo A Sechi; Franco Turrini; Franca Saba; Sergio Babudieri; Franca Mannu; Giovanni Fadda

1999-01-01

57

Burden of tuberculosis in Kampala, Uganda.  

PubMed Central

OBJECTIVE: To determine the prevalence and incidence of tuberculosis in one of Uganda's poor peri-urban areas. METHODS: Multi-stage sampling was used to select a sample of households whose members were evaluated for presence of signs and/or symptoms of active tuberculosis; history of tuberculosis treatment; and relevant demographic, socioeconomic, and household environment characteristics. Patients with suspected tuberculosis underwent standardized evaluation for active disease. FINDINGS: A sample of 263 households with 1142 individuals was evaluated. Nineteen people were classified as having had tuberculosis during the one-year reference period (May 2001-April 2002): nine (47%) cases already had been diagnosed through the health care system, while 10 cases (53%) were diagnosed through the survey. The prevalences for all forms of tuberculosis and for sputum smear-positive tuberculosis were 14.0 (95% confidence interval (CI) 7.8-20.3) and 4.4 (CI = 0.83-7.89) per thousand, respectively. The incidences for all forms of tuberculosis and for sputum smear-positive tuberculosis were 9.2 (CI = 3.97-14.4) and 3.7 (CI = 0.39-6.95) per thousand per year, respectively. CONCLUSION: The rate of tuberculosis in this peri-urban community was exceptionally high and may be underestimated by current surveillance systems. The need for interventions aimed at reducing tuberculosis transmission in this, and other similar communities with high case rates, is urgent.

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

2003-01-01

58

Effect of pyrazinamidase activity on pyrazinamide resistance in Mycobacterium tuberculosis.  

PubMed

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

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

2009-03-01

59

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

NASA Technical Reports Server (NTRS)

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

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

1991-01-01

60

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

NASA Astrophysics Data System (ADS)

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

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

1991-03-01

61

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

PubMed Central

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

Brust, Belinda; Lecoufle, Melanie; Tuaillon, Edouard; Dedieu, Luc; Canaan, Stephane; Valverde, Viviane; Kremer, Laurent

2011-01-01

62

In vitro bactericidal activity of oxazolidinone, RBx 8700 against Mycobacterium tuberculosis and Mycobacterium avium complex.  

PubMed

RBx 8700, an investigational oxazolidinone, has excellent activity against respiratory pathogens. We evaluated the in vitro minimum inhibitory concentration (MIC) and bactericidal activity of RBx 8700 against Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) isolates. RBx 8700 had an MIC of 1 gLg/ml against M. tuberculosis isolates resistant to both isoniazid (INH) and rifampicin (RIF), whereas its MIC against M. tuberculosis isolates resistant to either INH or RIF was 0.5 microg/ml. PMID:16736882

Rao, M; Sood, R; Malhotra, S; Fatma, T; Upadhyay, D J; Rattan, A

2006-04-01

63

High Incidence of Tuberculosis Infection in Rheumatic Diseases and Impact for Chemoprophylactic Prevention of Tuberculosis Activation during Biologics Therapy  

PubMed Central

We conducted a long-term follow-up study in patients with rheumatic diseases who were candidates for biologics treatment to evaluate the effects of biologic agents on the risk of tuberculosis infection and the effect of prophylactic treatment on tuberculosis activation. One hundred one patients with rheumatic diseases who were candidates for biologics treatment were recruited, and 57 healthy subjects were recruited as controls. Tuberculin skin test (TST) and the T-SPOT.TB test were performed for all subjects at baseline. Follow-up testing by the T-SPOT.TB assay was performed every 6 months in patients with rheumatic diseases and at 2 years of recruitment in the healthy controls. In patients with rheumatic diseases and healthy controls, the TST-positive (induration, ?10 mm) rates were 37.6% (38/101) and 34.0% (18/53), respectively (P > 0.05), while the T-SPOT.TB-positive rates were 46.5% (47/101) and 21.1 (12/57), respectively (P = 0.0019). Fifty-two patients were followed up at month 6 with a T-SPOT.TB-positive rate of 40.4%, and 49 were followed up for ?12 months with a T-SPOT.TB-positive rate of 36.7%, with no significant difference in the positive rate at different time points including baseline (P > 0.05). Long-term follow-up revealed that conversion to T-SPOT.TB positivity occurred only in the biologics treatment group, with a positive conversion rate of 11.2% (4/38). Most importantly, no latent tuberculosis developed into active tuberculosis during follow-up with T-SPOT.TB screening and preemptive treatment with isoniazid. Biologics treatment appears to increase the risk of tuberculosis infection. However, tuberculosis activation could be prevented by preemptive isoniazid treatment in patients with latent tuberculosis infection while receiving biologics therapy.

Bai, Fengmin; Zhang, Shu; Jiang, Ting; Shen, Jie; Zhu, Qi; Yue, Tao; Shao, Lingyun; Gao, Yan; Feng, Yun; Weng, Xinhua; Zou, Hejian; Zhang, Ying

2013-01-01

64

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

PubMed Central

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

Ryabova, Olga; Kaprelyants, Arseny; Makarov, Vadim

2014-01-01

65

Biological Activity of Peptide SCV-07 Against Murine Tuberculosis.  

PubMed

SCV-07 (gamma-glutamyl-tryptophan) is a new immunomodulatory compound that was developed and patented both for composition and immunomodulatory use. SCV-07 was shown to have a broad spectrum of immunostimulatory activities both in vitro and in vivo. In the present study we investigated the biological activity of SCV-07 in a murine model of experimental tuberculosis (TB) induced with M. bovis-bovinus 8 strain. Therapy with SCV-07 at doses of 0.01, 0.1, and 1 &mgr;g/kg (5 daily injections) decreased the lung damage index compared to untreated controls and to those treated with isoniazid alone. The growth of M. bovis-bovinus 8 in spleen culture was decreased. Cytokine studies showed that on the 24th day after the treatment with SCV-07 the production of IL-2 was restored to the level seen in uninfected animals. Proliferative responses for both thymic and spleen cells were nearly restored to the responses observed in uninfected animals. IFN-gamma production by both thymic and spleen cells, as well as its circulating levels in serum, was increased by the SCV-07 treatment. Concurrently, IL-4 production was decreased in the same cell types and the serum. These changes suggest that SCV-07 is stimulating a shift of T helper cells to a Th1-like immune response. SCV-07 treatment also stimulated the macrophage functions, which had been decreased by tuberculosis infection and isoniazid therapy, with an improved phagocytosis activity of peritoneal macrophage. The obtained results suggest that SCV-07 treatment increases the efficacy of anti-tuberculosis therapy as well as the strength of the immune response. Thus, SCV-07 is a prospective immunomodulator for a complex therapy of TB. PMID:12717550

Simbirtsev, Andrey; Kolobov, Alexander; Zabolotnych, Natalia; Pigareva, Natalia; Konusova, Valentina; Kotov, Alexander; Variouchina, Elena; Bokovanov, Vladimir; Vinogradova, Tatyana; Vasilieva, Svetlana; Tuthill, Cynthia

2003-04-01

66

Management of pulmonary aspergilloma in the presence of active tuberculosis.  

PubMed Central

Eleven cases of pulmonary aspergilloma complicating active cavitating pulmonary tuberculosis are reviewed. Nine of the 10 patients who had combined medical (antituberculosis drugs) and surgical treatment were cured of their disease; one patient, who had bilateral multiple aspergillomas, died from massive haemoptysis after resection of one of the affected lobes. The only medically treated patient who refused surgery had fatal haemoptysis at home. Pulmonary resection is recommended for patients who are fit for operation whenever the diagnosis of aspergilloma is made because most published reports indicate that only a few patients benefit from drug treatment alone. Images

Adeyemo, A O; Odelowo, E O; Makanjuola, D I

1984-01-01

67

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

Microsoft Academic Search

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

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

1995-01-01

68

A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis  

Microsoft Academic Search

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

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

2005-01-01

69

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

PubMed Central

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

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

2012-01-01

70

MEROPENEM INHIBITS D,D-CARBOXYPEPTIDASE ACTIVITY IN MYCOBACTERIUM TUBERCULOSIS  

PubMed Central

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

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

2012-01-01

71

ANALYSIS OF THE SPECTRA OF GENETIC ACTIVITY PRODUCED BY KNOWN OR SUSPECTED HUMAN CARCINOGENS  

EPA Science Inventory

For 24 agents classified by the International Agency for Research on Cancer as known or suspected human carcinogens, we previously catalogued the qualitative genetic bioassay data available in the literature. In the present analysis, dose information, where available, was added t...

72

Different phenotypes of CD8+ T cells associated with bacterial load in active tuberculosis.  

PubMed

Tuberculosis is an infectious disease that affects millions of people worldwide with an annual mortality rate of 1.3 million. The mechanisms contributing to the loss of balance of immune responses and progression to active tuberculosis disease are unknown. Although CD4+ and CD8+ T cells and the cytokines they produce are crucial for protection against tuberculosis they have different roles in tuberculosis immunology. The function of CD4+ T cells has been extensively studied; however, less is known about the phenotype and function of CD8+ T cells. This study evaluated the specific expression of IFN-?, IL-17, IL-10, and TGF-? and ex vivo expression of perforin and granzyme-B by CD8+ T cells from active tuberculosis individuals compared with latent infected individuals and non-latent infected individuals. Tuberculosis responses were correlated with the baciloscopy score. We observed that the presence of IL-10 and TGF-? expression and down-expression of granzyme-B in CD8+ T cells correlated with increased sputum bacillary load in active tuberculosis individuals. These findings provide new insights into the role of CD8+ T cells in Mycobacterium tuberculosis disease. PMID:24694750

Silva, Bruna Daniella de Souza; Trentini, Monalisa Martins; da Costa, Adeliane Castro; Kipnis, Andre; Junqueira-Kipnis, Ana Paula

2014-07-01

73

Tuberculosis screening and active tuberculosis among HIV-infected persons in a Canadian tertiary care centre  

PubMed Central

RATIONALE: HIV infection increases the risk of reactivation of latent tuberculosis (TB). The present study evaluates how latent TB is detected and treated to determine the effectiveness of screening in HIV-infected patients with diverse risk profiles. METHOD: A retrospective medical record database review (1988 to 2007) was conducted at a tertiary care HIV clinic. The proportion of patients receiving tuberculin skin tests (TSTs) and the rate of active TB at each stage of screening and prevention were estimated. Predictors of receiving a TST at baseline, testing positive by TST and developing active TB were evaluated. RESULTS: In the present study, 2123 patients were observed for a total of 9412 person-years. Four hundred seventy-six (22.4%) patients were tested by TST within 90 days of first clinic visit. Having a first clinic visit during the highly active antiretroviral therapy era (OR 3.64; 95% CI 2.66 to 4.99), country of birth (ORs: Africa 3.11, Asia 2.79, Haiti 3.14, and Latin America and the Caribbean 2.38), time between HIV diagnosis and first visit (OR per one-year change 0.97; 95% CI 0.94 to 0.99) and previous antiretroviral exposure (OR 0.61; 95% CI 0.45 to 0.81) were independent predictors of receiving a TST at baseline. Of the 17 patients who developed active TB during follow-up, nine (53%) had no documented TSTs at baseline or during follow-up. Forty-one per cent of all TB patients and 56% of TB patients who were not screened were born in Canada. CONCLUSION: The administration of TSTs to newly diagnosed HIV patients was inconsistent and differential according to country of birth, among other factors, resulting in missed opportunities for TB prevention.

Brassard, Paul; Hottes, Travis Salway; Lalonde, Richard G; Klein, Marina B

2009-01-01

74

Tuberculosis  

MedlinePLUS Videos and Cool Tools

... initial infection can be diagnosed with a skin test called a Mantoux test. This test can identify most people infected with tubercle bacilli ... the disease is not necessarily active. A blood test known as QuantiFERON® -TB can also show if ...

75

[Phosphocalcium metabolism disorders in patients with active pulmonary tuberculosis].  

PubMed

Several parameters of phosphocalcic metabolism were evaluated in 21 patients with active pulmonary tuberculosis. The serum levels of total calcium, ionic calcium, phosphorus, albumin, magnesium and alkaline phosphatase, and calciuria and calcium/creatinine ratio in 24-hour urine were normal and not change during therapy. The patients with tuberculosis showed a significant reduction in the 250HD concentrations (8.8 +/- 5.2 ng/ml vs 19.2 +/- 10.7 ng/ml; p = 0.002), 1.25(OH)2D (25 +/- 8 pg/ml vs 34 +/- 9 pg/ml; p = 0.002) and parathyroid hormone (intact molecule) (1.9 +/- 0.9 pmol/l vs 5.9 +/- 2.0 pmol/l; p = 0.0001). By contrast, the levels of calcitonin (65 +/- 30 pg/ml vs 36 +/- 17 pg/ml; p = 0.001) and tartrate-resistant acid phosphatase (17.3 +/- 2.3 U/l vs 11.8 +/- 1.8 U/l; p = 0.0001) were increased. There also was a mild increase of vitamin D carrier protein (532 +/- 109 mg/l vs 480 +/- 37 mg/l; p = 0.04). These data are consistent with a partial inhibition of parathyroid hormone, associated with vitamin D deficiency. The inhibition of the axis of parathyroid hormone--1.125(OH)2D resulting from calcium release from the bone is advanced as an explanation. This release might be due to the action on the bone of cytokines produced within the inflammatory process itself. The reduction in 250HD could presumably be related with the lower exposure to sun, which is common in sick persons. PMID:2033981

Olmos, J M; Martínez, J; Riancho, J A; Sánchez, I; Amado, J A; González Macías, J

1991-01-26

76

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

PubMed Central

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

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

2013-01-01

77

A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.  

PubMed

The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase. PMID:15591164

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

2005-01-14

78

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

PubMed Central

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

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

2012-01-01

79

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

PubMed

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

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

2012-01-01

80

[A case of pulmonary tuberculosis associated with orbital myositis].  

PubMed

Ocular tuberculosis is rare. We report a case of orbital myositis suspected to be infected with tuberculosis. In January 2008, a 34-year-old man experienced discomfort in the right eye. In May 2008, this patient developed right exophthalmos, diplopia, and pain in the right eye, and he was diagnosed with idiopathic orbital myositis. The patient underwent 2 courses of steroid pulse therapy; after which, the dosage of steroids was reduced. The steroid treatment reduced the eye pain, but his diplopia and exophthalmos persisted. By November of the same year, his general malaise had increased, and chest X-ray radiography and computed tomography were performed on 3rd December. On the basis of the imaging results, we suspected active pulmonary tuberculosis of the right upper lobe. The smear made by using the sample obtained after bronchial brushing was negative for acid-fast bacilli, but a Mycobacterium tuberculosis nucleic acid amplification test of the post-bronchoscopic sputum yielded positive results. Therefore, the patient was diagnosed with pulmonary tuberculosis. After the 2HREZ/7HR regimen of treatment, the extent of the tuberculosis lesions of the lung was reduced and the exophthalmos and eye pain were alleviated. Orbital myositis is inflammation of the extraocular muscles and can be either idiopathic, without a known etiology, or secondary to conditions such as tuberculosis, sarcoidosis, or hyperthyroidism. Our patient was not definitively diagnosed with tuberculosis of the eye. A definitive diagnosis of tuberculosis of the eye would require detection of granulomatous lesions in the eye or isolation of Mycobacterium tuberculosis by puncturing the eye muscles; however, our findings suggested the possibility that it was secondary to tuberculosis. We think that a careful examination of the chest should be performed for patients with ocular abnormalities. PMID:22993891

Nakamura, Kazuyoshi; Horio, Yuko; Yamanaka, Tohru

2012-07-01

81

[Registration of suspected adverse effects by the Bureau Adverse Effects Drugs; research activities in 1993].  

PubMed

In 1993, the Netherlands Centre for Monitoring of Adverse Reactions to Drugs received 1585 reports of suspected adverse reactions. The most important reports concerned myocardial infarction due to sumatriptan, cholestatic hepatitis due to itraconazole, agranulocytosis due to trazodone and bleeding due to fluoxetine and fluvoxamine. Other published reports concerned cholestatic hepatitis due to amoxicillin/clavulanic acid, hair loss due to beta-blockers, muscle necrosis due to diclofenac, bronchospasm, apnoea and cardiac arrest due to dipyridamole perfusion scintigraphy, interaction of fluvoxamine/fluoxetine and coumarins, liver enzyme elevations due to heparin, skin reactions due to Imedeen, deafness due to neomycin, addiction to nicotine chewing gum, atrial fibrillation and skin reactions due to nicotine patches, interaction between oral contraceptives and terbinafine, neonatal problems caused by psychopharmacological agents, parapemphigus caused by sulfasalazine, taste loss due to terbinafine en intracranial bleeding after use of tranylcypromine and beer. Pharmacoepidemiological studies were performed concerning methods for record linkage, the communication process with respect to the acitretin alert and the adverse events due to sumatriptan. PMID:7969579

Stricker, B H; Ottervanger, J P; van der Klauw, M M

1994-10-15

82

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

PubMed Central

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

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

1994-01-01

83

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

PubMed

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

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

2012-05-01

84

The Structure Activity Relationship of Urea Derivatives as Anti-Tuberculosis Agents  

PubMed Central

The treatment of tuberculosis is becoming more difficult due to the ever increasing prevalence of drug resistance. Thus, it is imperative that novel anti-tuberculosis agents, with unique mechanisms of action, be discovered and developed. The direct anti-tubercular testing of a small compound library led to discovery of adamantyl urea hit compound 1. In this study, the hit was followed up through the synthesis of an optimization library. This library was generated by systematically replacing each section of the molecule with a similar moiety until a clear structure activity relationship was obtained with respect to anti-tubercular activity. The best compounds in this series contained a 1-adamantyl-3-phenyl urea core and had potent activity against Mycobacterium tuberculosis plus an acceptable therapeutic index. It was noted that the compounds identified and the pharmacophore developed is consistent with inhibitors of epoxide hydrolase family of enzymes. Consequently, the compounds were tested for inhibition of representative epoxide hydrolases: M. tuberculosis EphB and EphE; and human soluble epoxide hydrolase. Many of the optimized inhibitors showed both potent EphB and EphE inhibition suggesting the antitubercular activity is through inhibition of multiple epoxide hydrolyase enzymes. The inhibitors also showed potent inhibition of humans soluble expoxide hydrolyase, but limited cytotoxicity suggesting that future studies must be towards increasing the selectivity of epoxide hydrolyase inhibition towards the M. tuberculosis enzymes.

Brown, Joshua R.; North, Elton J.; Hurdle, Julian G.; Morisseau, Christophe; Scarborough, Jerrod S.; Sun, Dianqing; Kordulakova, Jana; Scherman, Michael S.; Jones, Victoria; Grzegorzewicz, Anna; Crew, Rebecca M.; Jackson, Mary; McNeil, Michael R.; Lee, Richard E.

2011-01-01

85

Impaired activation of Stat1 and c-Jun as a possible defect in macrophages of patients with active tuberculosis  

PubMed Central

Studies of patients with active tuberculosis (TB) and infected healthy individuals have shown that interferon (IFN)-? is present in sites of Mycobacterium tuberculosis infection in comparable levels. This suggests that there is a deficiency in the macrophage response to IFN-? in TB patients. We used recombinant human IFN-? to stimulate adherent monocyte-derived macrophages from three groups of people: patients with active tuberculosis (TBP), their healthy household contacts (HHC) and healthy uninfected controls from the community (CC). We then evaluated the ability of the macrophages to inhibit the growth of M. tuberculosis H37Rv as well as their cytokine profile at early in infection (48 h). After IFN-? treatment, macrophages of healthy individuals (HHC and CC) controlled M. tuberculosis growth and produced mainly nitric oxide (NO) and interleukin (IL)-12p70, whereas TBP macrophages did not kill M. tuberculosis. Additionally, TBP macrophages produced low levels of NO and IL-12p70 and high levels of tumour necrosis factor (TNF)-? and IL-10. Transforming growth factor (TGF)-? levels were similar among all three groups. M. tuberculosis infection had little effect on the cytokine response after IFN-? stimulus, but infection alone induced more IL-10 and TGF-? in TBP macrophages. There were no differences in Stat1 nuclear translocation and DNA binding between the groups. However, the phosphorylated Stat1 and c-Jun (AP-1) in nuclear protein extracts was diminished in TBP macrophages compared to macrophages of healthy individuals. These results indicate an impairment of Stat1-dependent and Stat1-independent IFN-? signalling in macrophages of people with active tuberculosis, suggesting a different molecular regulation that could impact macrophage functionality and disease outcome.

Esquivel-Solis, H; Quinones-Falconi, F; Zarain-Herzberg, A; Amieva-Fernandez, R I; Lopez-Vidal, Y

2009-01-01

86

[Tuberculosis of the breast].  

PubMed

We report a case of granulomatous mastitis caused by Mycobacterium tuberculosis in an immunocompetent woman with chronic inflammatory lesions of the breast. It was diagnosed by detection of mycobacteria DNA using polymerase chain reaction technique targeting IS6110 insertion element of M. tuberculosis complex in a paraffin-embedded histological specimen. The primary breast tuberculosis is rare, even in countries where the incidence and prevalence of pulmonary and extra pulmonary tuberculosis are high. It should be suspected in female patients with chronic granulomatous mastitis with no apparent cause. The cornerstone of treatment is antituberculous chemotherapy, and surgery is rarely required. PMID:23715305

Cuervo, Sonia Isabel; Bonilla, Diego Andrés; Murcia, Martha Isabel; Hernández, Johana; Gómez, Julio César

2013-01-01

87

Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice  

PubMed Central

The hallmark of human Mycobacterium tuberculosis infection is the presence of lung granulomas. Lung granulomas can have different phenotypes, with caseous necrosis and hypoxia present within these structures during active tuberculosis. Production of NO by the inducible host enzyme NOS2 is a key antimycobacterial defense mechanism that requires oxygen as a substrate; it is therefore likely to perform inefficiently in hypoxic regions of granulomas in which M. tuberculosis persists. Here we have used Nos2–/– mice to investigate host-protective mechanisms within hypoxic granulomas and identified a role for host serine proteases in hypoxic granulomas in determining outcome of disease. Nos2–/– mice reproduced human-like granulomas in the lung when infected with M. tuberculosis in the ear dermis. The granulomas were hypoxic and contained large amounts of the serine protease cathepsin G and clade B serine protease inhibitors (serpins). Extrinsic inhibition of serine protease activity in vivo resulted in distorted granuloma structure, extensive hypoxia, and increased bacterial growth in this model. These data suggest that serine protease activity acts as a protective mechanism within hypoxic regions of lung granulomas and present a potential new strategy for the treatment of tuberculosis.

Reece, Stephen T.; Loddenkemper, Christoph; Askew, David J.; Zedler, Ulrike; Schommer-Leitner, Sandra; Stein, Maik; Mir, Fayaz Ahmad; Dorhoi, Anca; Mollenkopf, Hans-Joachim; Silverman, Gary A.; Kaufmann, Stefan H.E.

2010-01-01

88

Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice.  

PubMed

The hallmark of human Mycobacterium tuberculosis infection is the presence of lung granulomas. Lung granulomas can have different phenotypes, with caseous necrosis and hypoxia present within these structures during active tuberculosis. Production of NO by the inducible host enzyme NOS2 is a key antimycobacterial defense mechanism that requires oxygen as a substrate; it is therefore likely to perform inefficiently in hypoxic regions of granulomas in which M. tuberculosis persists. Here we have used Nos2-/- mice to investigate host-protective mechanisms within hypoxic granulomas and identified a role for host serine proteases in hypoxic granulomas in determining outcome of disease. Nos2-/- mice reproduced human-like granulomas in the lung when infected with M. tuberculosis in the ear dermis. The granulomas were hypoxic and contained large amounts of the serine protease cathepsin G and clade B serine protease inhibitors (serpins). Extrinsic inhibition of serine protease activity in vivo resulted in distorted granuloma structure, extensive hypoxia, and increased bacterial growth in this model. These data suggest that serine protease activity acts as a protective mechanism within hypoxic regions of lung granulomas and present a potential new strategy for the treatment of tuberculosis. PMID:20679732

Reece, Stephen T; Loddenkemper, Christoph; Askew, David J; Zedler, Ulrike; Schommer-Leitner, Sandra; Stein, Maik; Mir, Fayaz Ahmad; Dorhoi, Anca; Mollenkopf, Hans-Joachim; Silverman, Gary A; Kaufmann, Stefan H E

2010-09-01

89

Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages  

PubMed Central

Tuberculosis remains one of the major infectious causes of morbidity and mortality in the world, yet the mechanisms by which macrophages defend against Mycobacterium tuberculosis have remained obscure. Results from this study show that murine macrophages, activated by interferon gamma, and lipopolysaccharide or tumor necrosis factor alpha, both growth inhibit and kill M. tuberculosis. This antimycobacterial effect, demonstrable both in murine macrophage cell lines and in peritoneal macrophages of BALB/c mice, is independent of the macrophage capacity to generate reactive oxygen intermediates (ROI). Both the ROI-deficient murine macrophage cell line D9, and its ROI-generating, parental line J774.16, expressed comparable antimycobacterial activity upon activation. In addition, the oxygen radical scavengers superoxide dismutase (SOD), catalase, mannitol, and diazabicyclooctane had no effect on the antimycobacterial activity of macrophages. These findings, together with the results showing the relative resistance of M. tuberculosis to enzymatically generated H2O2, suggest that ROI are unlikely to be significantly involved in killing M. tuberculosis. In contrast, the antimycobacterial activity of these macrophages strongly correlates with the induction of the L-arginine- dependent generation of reactive nitrogen intermediates (RNI). The effector molecule(s) that could participate in mediating this antimycobacterial function are toxic RNI, including NO, NO2, and HNO2, as demonstrated by the mycobacteriocidal effect of acidified NO2. The oxygen radical scavenger SOD adventitiously perturbs RNI production, and cannot be used to discriminate between cytocidal mechanisms involving ROI and RNI. Overall, our results provide support for the view that the L-arginine-dependent production of RNI is the principal effector mechanism in activated murine macrophages responsible for killing and growth inhibiting virulent M. tuberculosis.

1992-01-01

90

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

PubMed

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

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

2014-06-01

91

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

PubMed Central

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

Leygue, Etienne

2007-01-01

92

Guinea Pig Neutrophils Infected with Mycobacterium tuberculosis Produce Cytokines Which Activate Alveolar Macrophages in Noncontact Cultures?  

PubMed Central

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

Sawant, Kirti V.; McMurray, David N.

2007-01-01

93

Pentacyclic nitrofurans with in vivo efficacy and activity against nonreplicating Mycobacterium tuberculosis.  

PubMed

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

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

2014-01-01

94

Long-term outcomes and risk factor analysis after pneumonectomy for active and sequela forms of pulmonary tuberculosis  

Microsoft Academic Search

Objective: The prevalence of pulmonary tuberculosis remains high in several areas of the world, and pneumonectomy is often necessary to treat the disease. We retrospectively analyzed the morbidities, mortalities, and long-term outcomes after pneumonectomy for the treatment of active tuberculosis or its sequelae. Materials and methods: Between 1981 and 2001, 94 patients underwent either pneumonectomy or pleuropneumonectomy for the treatment

Young Tae Kim; Hong Kwan Kim; Sook-Whan Sung; Joo Hyun Kim

2003-01-01

95

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

PubMed Central

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

2014-01-01

96

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

Microsoft Academic Search

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

Sean Ekins; Joel S. Freundlich

97

International Standards for Tuberculosis Care.  

National Technical Information Service (NTIS)

The purpose of the International Standards for Tuberculosis Care (ISTC) is to describe a widely accepted level of care that all practitioners, public and private, should seek to achieve in managing patients who have, or are suspected of having, tuberculos...

2006-01-01

98

Identifying a Theft Suspect  

NSDL National Science Digital Library

This model-eliciting activity (MEA) challenges students to develop a model for predicting the characteristics of a person who has committed a crime. Students work with real data on shoe length, height, and gender to develop the model. Students write a report to the crime victim that identifies a suspect and justifies their decision. The activity sets the stage for students to learn about regression models, and reinforces their understanding of central tendency and variability. It is suggested that this activity be used prior to a formal introduction to linear relationships.

This page was authored by the CATALST Group at the University of Minnesota, based on an activity developed by Roxy Peck at California Polytechnic State University that is based on an original idea by Tom Short, John Carroll University, and Iddo Gal, University of Haifa, Israel.

99

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

PubMed

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

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

2010-05-01

100

Quantitative comparison of active and latent tuberculosis in the cynomolgus macaque model.  

PubMed

We previously described that low-dose Mycobacterium tuberculosis infection in cynomolgus macaques results in a spectrum of disease similar to that of human infection: primary disease, latent infection, and reactivation tuberculosis (S. V. Capuano III, D. A. Croix, S. Pawar, A. Zinovik, A. Myers, P. L. Lin, S. Bissel, C. Fuhrman, E. Klein, and J. L. Flynn, Infect. Immun. 71:5831-5844, 2003). This is the only established model of latent infection, and it provides a unique opportunity to understand host and pathogen differences across of range of disease states. Here, we provide a more extensive and detailed characterization of the gross pathology, microscopic histopathology, and immunologic characteristics of monkeys in each clinical disease category. The data underscore the similarities between human and nonhuman primate M. tuberculosis infection. Furthermore, we describe novel methods of quantifying gross pathology and bacterial burden that distinguish between active disease and latent infection, and we extend the usefulness of this model for comparative studies. Early in infection, an abnormal chest X ray, M. tuberculosis growth by gastric aspirate, and increased mycobacterium-specific gamma interferon (IFN-gamma) in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage (BAL) cells were associated with the development of active disease. At necropsy, disease was quantified with respect to pathology and bacterial numbers. Microscopically, a spectrum of granuloma types are seen and differ with disease type. At necropsy, monkeys with active disease had more lung T cells and more IFN-gamma from PBMC, BAL, and mediastinal lymph nodes than monkeys with latent infection. Finally, we have observed a spectrum of disease not only in monkeys with active disease but also in those with latent infection that provides insight into human latent tuberculosis. PMID:19620341

Lin, Philana Ling; Rodgers, Mark; Smith, Le'kneitah; Bigbee, Matthew; Myers, Amy; Bigbee, Carolyn; Chiosea, Ion; Capuano, Saverio V; Fuhrman, Carl; Klein, Edwin; Flynn, JoAnne L

2009-10-01

101

Potential Role of M. tuberculosis Specific IFN-? and IL-2 ELISPOT Assays in Discriminating Children with Active or Latent Tuberculosis  

PubMed Central

Background Although currently available IGRA have been reported to be promising markers for TB infection, they cannot distinguish active tuberculosis (TB) from latent infection (LTBI). Objective Children with LTBI, active TB disease or uninfected were prospectively evaluated by an in-house ELISPOT assay in order to investigate possible immunological markers for a differential diagnosis between LTBI and active TB. Methods Children at risk for TB infection prospectively enrolled in our infectious disease unit were evaluated by in-house IFN-? and IL-2 based ELISPOT assays using a panel of Mycobacterium tuberculosis antigens. Results Twenty-nine children were classified as uninfected, 21 as LTBI and 25 as active TB cases (including 5 definite and 20 probable cases). Significantly higher IFN-? ELISPOT responses were observed in infected vs. uninfected children for ESAT-6 (p<0.0001), CFP-10 (p<0.0001), TB 10.3 (p?=?0.003), and AlaDH (p?=?0.001), while differences were not significant considering Ag85B (p?=?0.063), PstS1 (p?=?0.512), and HspX (16 kDa) (p?=?0.139). IL-2 ELISPOT assay responses were different for ESAT-6 (p<0.0001), CFP-10 (p<0.0001), TB 10.3 (p<0.0001), HspX (16 kDa) (p<0.0001), PstS1 (p<0.0001) and AlaDH (p?=?0.001); but not for Ag85B (p?=?0.063). Comparing results between children with LTBI and those with TB disease differences were significant for IFN-? ELISPOT only for AlaDH antigen (p?=?0.021) and for IL-2 ELISPOT assay for AlaDH (p<0.0001) and TB 10.3 antigen (p?=?0.043). ROC analyses demonstrated sensitivity of 100% and specificity of 81% of AlaDH-IL-2 ELISPOT assay in discriminating between latent and active TB using a cut off of 12.5 SCF per million PBMCs. Conclusion Our data suggest that IL-2 based ELISPOT with AlaDH antigen may be of help in discriminating children with active from those with latent TB.

Chiappini, Elena; Della Bella, Chiara; Bonsignori, Francesca; Sollai, Sara; Amedei, Amedeo; Galli, Luisa; Niccolai, Elena; Singh, Mahavir; D'Elios, Mario M.; de Martino, Maurizio

2012-01-01

102

Cases of pulmonary tuberculosis among the out-patients attending general health institutions in an Indian city*  

PubMed Central

A study was undertaken in Bangalore City, India, to find out whether people with chest symptoms, including tuberculosis patients, attend general health institutions or report directly to tuberculosis clinics. The attendance for one day at 19 general dispensaries was investigated. Of the total of 2506 eligible persons who were questioned about the presence of chest symptoms, 1170 admitted having symptoms suggestive of pulmonary tuberculosis and 20 cases and 31 suspected cases of pulmonary tuberculosis were diagnosed. The findings indicate that tuberculosis patients do not by-pass the city health institutions. On the other hand, if these institutions take an active part in the tuberculosis programme and undertake diagnostic functions, or refer persons with chest symptoms to a central clinic, they can contribute substantially to case-finding.

Gothi, G. D.; Savic, D.; Baily, G. V. J.; Samuel, Rupert

1970-01-01

103

Transcriptional suppression of IL-27 production by Mycobacterium tuberculosis-activated p38 MAPK via inhibition of AP-1 binding.  

PubMed

Mycobacterium tuberculosis remains a major global challenge to human health care, and the mechanisms of how M. tuberculosis evades host immune surveillance to favor its survival are still largely unknown. In this study, we found that bacillus Calmette-Guérin (BCG) and viable M. tuberculosis as well as M. tuberculosis lysates could activate IL-27 expression in human and mouse macrophages by induction of p28 subunit transcription. However, in parallel with these effects, BCG and M. tuberculosis lysate stimulation of macrophages induced activation of p38 MAPK signaling molecules MLK3/MKK3/MK2 to prevent maximal IL-27 production. M. tuberculosis lysate-induced p28 transcription was dependent on MyD88 signaling pathway. AP-1/c-Fos was shown to bind directly to the p28 promoter and induce p28 expression after M. tuberculosis lysate stimulation. Overexpression of p38? inhibited the binding of c-Fos to the p28 promoter but had no effect on c-Fos protein expression or phosphorylation in response to M. tuberculosis lysate stimulation. Furthermore, blockade of p38 by SB203580 enhanced M. tuberculosis-induced AP-1 binding to the p28 promoter. Importantly, we show that adding exogenous IL-27 to increase the levels produced by PBMCs stimulated with live mycobacteria enhanced the ability of BCG-expanded T cells to inhibit intracellular mycobacterial growth in human macrophages. Taken together, our data demonstrate that mycobacterial stimulation induces both IL-27 production and p38 MAPK activation. Strategies designed to tip the balance toward positive regulation of p28 induction by mycobacteria could lead to enhanced protective tuberculosis immunity. PMID:21482740

Zhang, Jidong; Qian, Xuesong; Ning, Huan; Eickhoff, Christopher S; Hoft, Daniel F; Liu, Jianguo

2011-05-15

104

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

PubMed Central

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

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

2012-01-01

105

DNA fingerprinting as an indicator of active transmission of multidrug-resistant tuberculosis in Poland  

Microsoft Academic Search

Objectives: To use genetic fingerprinting to investigate the epidemiology of tuberculosis (FB) caused by Mycobacterium tuberculosis in Poland, a country with a relatively high incidence of tuberculosis, to improve TB control.Design: One hundred M. tuberculosis isolates from 98 patients in the Institute of Tuberculosis and Lung Diseases in Warsaw from 1993 to 1995 and 85 isolates obtained from 50 patients

Anna Sajduda; Jaroslav Dziadek; Agnieszka Dela; Natalia Zalewska-Schdnthaler; Zofia Zwolska; Johnjoe McFadden

1998-01-01

106

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

PubMed

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

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

2012-08-01

107

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

PubMed

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

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

2014-05-01

108

Development of Cyclobutene- and Cyclobutane-Functionalized Fatty Acids with Inhibitory Activity against Mycobacterium tuberculosis.  

PubMed

Eleven fatty acid analogues incorporating four-membered carbocycles (cyclobutenes, cyclobutanes, cyclobutanones, and cyclobutanols) were investigated for the ability to inhibit the growth of Mycobacterium smegmatis (Msm) and Mycobacterium tuberculosis (Mtb). A number of the analogues 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 observed with the anti-tuberculosis drugs D-cycloserine and isoniazid. In contrast, two of the analogues that display the greatest activity against Mtb failed to inhibit E.?coli growth under either set of conditions. Thus, the active molecules identified herein may provide the basis for the development of anti-mycobacterial agents against Mtb. PMID:24902951

Sittiwong, Wantanee; Zinniel, Denise K; Fenton, Robert J; Marshall, Darrell D; Story, Courtney B; Kim, Bohkyung; Lee, Ji-Young; Powers, Robert; Barletta, Raúl G; Dussault, Patrick H

2014-08-01

109

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

PubMed

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

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

2009-09-01

110

Perforated tuberculosis lymphadenitis.  

PubMed

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

Cataño, Juan; Cardeño, John

2013-06-01

111

In vitro and in vivo activities of levofloxacin against Mycobacterium tuberculosis.  

PubMed Central

In tests with 18 drug-susceptible strains of Mycobacterium tuberculosis, the MIC at which 50% of the strains are inhibited by levofloxacin (LVFX) was one dilution less than that at which 50% of the strains are inhibited by ofloxacin (OFLO), but the MICs at which 90% of the strains are inhibited were similar. The in vivo activity of LVFX against M. tuberculosis was compared with the activities of isoniazid, OFLO, and sparfloxacin (SPFX). Mice were inoculated intravenously with 1.74 x 10(6) CFU of H37Rv, and treatments began the next day and were carried out six times weekly for 4 weeks. The severity of infection and effectiveness of treatment were assessed by survival rate, spleen weights, gross lung lesions, and enumeration of CFU in the spleen. In terms of CFU counts, the ranking of the anti-M. tuberculosis activities of the treatments used ran in the following order: LVFX (300 mg/kg of body weight) = SPFX (100 mg/kg) > isoniazid > SPFX (50 mg/kg) > OFLO (300 mg/kg) = LVFX (150 mg/kg) > OFLO (150 mg/kg) = LVFX (50 mg/kg). It seems, therefore, that the in vivo activity of LVFX is comparable to that produced by a twofold-greater dosage of OFLO. It is assumed that the maximal clinically tolerated dosage of LVFX is similar to that of OFLO, i.e., 800 mg daily, which is equivalent to 300 mg of LVFX per kg in mice. Because LVFX displayed powerful bactericidal activity, promising effects against human tuberculosis may be achieved if patients are treated with the maximal clinically tolerated dosage of LVFX.

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

1995-01-01

112

Unique Transcriptome Signature of Mycobacterium tuberculosis in Pulmonary Tuberculosis  

Microsoft Academic Search

Although tuberculosis remains a substantial global threat, the mechanisms that enable mycobacterial persistence and replication within the human host are ill defined. This study represents the first genome-wide expression analysis of Mycobacterium tuberculosis from clinical lung samples, which has enabled the identifi- cation of M. tuberculosis genes actively expressed during pulmonary tuberculosis. To obtain optimal informa- tion from our DNA

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

2006-01-01

113

The role of Ca2+ in the activity of Mycobacterium tuberculosis DNA gyrase  

PubMed Central

DNA gyrase is the only type II topoisomerase in Mycobacterium tuberculosis and needs to catalyse DNA supercoiling, relaxation and decatenation reactions in order to fulfil the functions normally carried out by gyrase and DNA topoisomerase IV in other bacteria. We have obtained evidence for the existence of a Ca2+-binding site in the GyrA subunit of M. tuberculosis gyrase. Ca2+ cannot support topoisomerase reactions in the absence of Mg2+, but partial removal of Ca2+ from GyrA by dialysis against EGTA leads to a modest loss in relaxation activity that can be restored by adding back Ca2+. More extensive removal of Ca2+ by denaturation of GyrA and dialysis against EGTA results in an enzyme with greatly reduced enzyme activities. Mutation of the proposed Ca2+-binding residues also leads to loss of activity. We propose that Ca2+ has a regulatory role in M. tuberculosis gyrase and suggest a model for the modulation of gyrase activity by Ca2+ binding.

Karkare, Shantanu; Yousafzai, Faridoon; Mitchenall, Lesley A.; Maxwell, Anthony

2012-01-01

114

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

National Technical Information Service (NTIS)

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

J. M. Bowling M. Gaines

2000-01-01

115

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

PubMed Central

CD8 T-cells contribute to control of Mycobacterium tuberculosis infection, but little is known about the quality of the CD8 T-cell response in subjects with latent infection and in patients with active tuberculosis disease. CD8 T-cells recognizing epitopes from 6 different proteins of Mycobacterium tuberculosis were detected by tetramer staining. Intracellular cytokines staining for specific production of IFN-? and IL-2 was performed, complemented by phenotyping of memory markers on antigen-specific CD8 T-cells. The ex-vivo frequencies of tetramer-specific CD8 T-cells in tuberculous patients before therapy were lower than in subjects with latent infection, but increased at four months after therapy to comparable percentages detected in subjects with latent infection. The majority of CD8 T-cells from subjects with latent infection expressed a terminally-differentiated phenotype (CD45RA+CCR7?). In contrast, tuberculous patients had only 35% of antigen-specific CD8 T-cells expressing this phenotype, while containing higher proportions of cells with an effector memory- and a central memory-like phenotype, and which did not change significantly after therapy. CD8 T-cells from subjects with latent infection showed a codominance of IL-2+/IFN-?+ and IL-2?/IFN-?+ T-cell populations; interestingly, only the IL-2+/IFN-?+ population was reduced or absent in tuberculous patients, highly suggestive of a restricted functional profile of Mycobacterium tuberculosis-specific CD8 T-cells during active disease. These results suggest distinct Mycobacterium tuberculosis specific CD8 T-cell phenotypic and functional signatures between subjects which control infection (subjects with latent infection) and those who do not (patients with active disease).

Caccamo, Nadia; Guggino, Giuliana; Meraviglia, Serena; Gelsomino, Giuseppe; Di Carlo, Paola; Titone, Lucina; Bocchino, Marialuisa; Galati, Domenico; Matarese, Alessandro; Nouta, Jan; Klein, Michel R.; Salerno, Alfredo; Sanduzzi, Alessandro

2009-01-01

116

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

NASA Astrophysics Data System (ADS)

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

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

2013-10-01

117

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

Microsoft Academic Search

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

Christie Y Jeon; Megan B Murray

2008-01-01

118

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

Microsoft Academic Search

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

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

2003-01-01

119

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

PubMed

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

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

2014-01-01

120

Urease activity represents an alternative pathway for Mycobacterium tuberculosis nitrogen metabolism.  

PubMed

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

Lin, Wenwei; Mathys, Vanessa; Ang, Emily Lei Yin; Koh, Vanessa Hui Qi; Martínez Gómez, Julia María; Ang, Michelle Lay Teng; Zainul Rahim, Siti Zarina; Tan, Mai Ping; Pethe, Kevin; Alonso, Sylvie

2012-08-01

121

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

PubMed Central

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

2014-01-01

122

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

PubMed Central

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

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

2012-01-01

123

Modeling early bactericidal activity in murine tuberculosis provides insights into the activity of isoniazid and pyrazinamide  

PubMed Central

Standard tuberculosis (TB) treatment includes an initial regimen containing drugs that are both rapidly bactericidal (isoniazid) and sterilizing (rifampin and pyrazinamide), and ethambutol to help prevent the emergence of drug resistance. Antagonism between isoniazid and pyrazinamide has been demonstrated in a TB treatment mouse model. Because isoniazid’s bactericidal activity is greatest during the initial two treatment days, we hypothesized that removing isoniazid after the second day would increase the effectiveness of the standard regimen. To test this hypothesis, we developed a mouse model to measure the early bactericidal activity (EBA) of drug regimens designed to analyze the essentiality of both isoniazid and pyrazinamide during the first 14 d of therapy. Our results clearly indicate that discontinuation of isoniazid after the second day of treatment increases the EBA of standard therapy in the mouse model, whereas omitting pyrazinamide during the first 14 d was detrimental. Substitution of moxifloxacin for isoniazid on day 3 did not increase the EBA compared with only removing isoniazid after day 2. Our data show that a mouse model can be used to analyze the EBA of TB drugs, and our findings support pursuing clinical trials to evaluate the possible benefit of removing isoniazid after the first 2 treatment days.

Grosset, Jacques; Almeida, Deepak; Converse, Paul J.; Tyagi, Sandeep; Li, Si-Yang; Ammerman, Nicole C.; Pym, Alexander S.; Wallengren, Kristina; Hafner, Richard; Lalloo, Umesh; Swindells, Susan; Bishai, William R.

2012-01-01

124

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

PubMed Central

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

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

2013-01-01

125

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

PubMed

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

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

2013-03-01

126

Role of Metal Ions on the Activity of Mycobacterium tuberculosis Pyrazinamidase  

PubMed Central

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

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

2012-01-01

127

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

Microsoft Academic Search

The objectives of the study were to assess the performance of the QuantiFERON-TB Gold In-Tube (QFN-G-IT) and the T-SPOT.TB tests in the immunodiagnosis of active tuberculosis (TB) in adult patients, and to study the T-cell interferon ? (IFN-?) responses during treatment and in patients who have recovered after curative treatment and self-healed TB patients. When only analyzing patients included at

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

2009-01-01

128

Immunogenicity of DNA vaccines expressing tuberculosis proteins fused to tissue plasminogen activator signal sequences.  

PubMed

Novel tuberculosis DNA vaccines encoding native ESAT-6, MPT-64, KatG, or HBHA mycobacterial proteins or the same proteins fused to tissue plasminogen activator (TPA) signal sequences were evaluated for their capacity to elicit humoral, cell-mediated, and protective immune responses in vaccinated mice. While all eight plasmids induced specific humoral responses, the constructs expressing the TPA fusions generally evoked higher antibody responses in vaccinated hosts. Although most of the DNA vaccines tested induced a substantial gamma interferon response in the spleen, the antigen-specific lung responses were 2- to 10-fold lower than the splenic responses at the time of challenge. DNA vaccines encoding the ESAT-6, MPT-64, and KatG antigens fused to TPA signal sequences evoked significant protective responses in mice aerogenically challenged with low doses of Mycobacterium tuberculosis Erdman 17 to 21 days after the final immunization. However, the protective response induced by live Mycobacterium bovis BCG vaccine was greater than the response induced by any of the DNA vaccines tested. These results suggest that the tuberculosis DNA vaccines were able to elicit substantial immune responses in suitably vaccinated mice, but further refinements to the constructs or the use of alternative immunization strategies will be needed to improve the efficacy of these vaccine candidates. PMID:10456931

Li, Z; Howard, A; Kelley, C; Delogu, G; Collins, F; Morris, S

1999-09-01

129

Efflux Pumps of Mycobacterium tuberculosis Play a Significant Role in Antituberculosis Activity of Potential Drug Candidates  

PubMed Central

Active efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. To understand these efflux mechanisms in Mycobacterium tuberculosis, we generated knockout (KO) mutants of four efflux pumps of the pathogen belonging to different classes. We measured the MICs and kill values of two different compound classes on the wild type (WT) and the efflux pump (EP) KO mutants in the presence and absence of the efflux inhibitors verapamil and l-phenylalanyl-l-arginyl-?-naphthylamide (PA?N). Among the pumps studied, the efflux pumps belonging to the ABC (ATP-binding cassette) class, encoded by Rv1218c, and the SMR (small multidrug resistance) class, encoded by Rv3065, appear to play important roles in mediating the efflux of different chemical classes and antibiotics. Efflux pumps encoded by Rv0849 and Rv1258c also mediate the efflux of these compounds, but to a lesser extent. Increased killing is observed in WT M. tuberculosis cells by these compounds in the presence of either verapamil or PA?N. The efflux pump KO mutants were more susceptible to these compounds in the presence of efflux inhibitors. We have shown that these four efflux pumps of M. tuberculosis play a vital role in mediating efflux of different chemical scaffolds. Inhibitors of one or several of these efflux pumps could have a significant impact in the treatment of tuberculosis. The identification and characterization of Rv0849, a new efflux pump belonging to the MFS (major facilitator superfamily) class, are reported.

Dinesh, Neela; Sharma, Sreevalli; Kuruppath, Sanjana; Nair, Anju V.; Sharma, Umender

2012-01-01

130

C4-Alkylthiols with activity against Moraxella catarrhalis and Mycobacterium tuberculosis  

PubMed Central

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

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

2013-01-01

131

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

PubMed Central

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

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

2011-01-01

132

Synthetic Calanolides with Bactericidal Activity against Replicating and Nonreplicating Mycobacterium tuberculosis.  

PubMed

It is urgent to introduce new drugs for tuberculosis to shorten the prolonged course of treatment and control drug-resistant Mycobacterium tuberculosis (Mtb). One strategy toward this goal is to develop antibiotics that eradicate both replicating (R) and nonreplicating (NR) Mtb. Naturally occurring (+)-calanolide A was active against R-Mtb. The present report details the design, synthesis, antimycobacterial activities, and structure-activity relationships of synthetic calanolides. We identified potent dual-active nitro-containing calanolides with minimal in vitro toxicity that were cidal to axenic Mtb and Mtb in human macrophages, while sparing Gram-positive and -negative bacteria and yeast. Two of the nitrobenzofuran-containing lead compounds were found to be genotoxic to mammalian cells. Although genotoxicity precluded clinical progression, the profound, selective mycobactericidal activity of these calanolides will be useful in identifying pathways for killing both R- and NR-Mtb, as well as in further structure-based design of more effective and drug-like antimycobacterial agents. PMID:24694175

Zheng, Purong; Somersan-Karakaya, Selin; Lu, Shichao; Roberts, Julia; Pingle, Maneesh; Warrier, Thulasi; Little, David; Guo, Xiaoyong; Brickner, Steven J; Nathan, Carl F; Gold, Ben; Liu, Gang

2014-05-01

133

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

PubMed

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

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

2008-06-01

134

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

PubMed Central

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

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

2014-01-01

135

Synthesis and anti-tuberculosis activity of the marine natural product caulerpin and its analogues.  

PubMed

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

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

2014-01-01

136

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

PubMed Central

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

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

2014-01-01

137

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

PubMed

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

Bretl, Daniel J; Bigley, Tarin M; Terhune, Scott S; Zahrt, Thomas C

2014-01-01

138

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

PubMed Central

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

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

2002-01-01

139

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

PubMed Central

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

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

2012-01-01

140

[Recommendations for the prevention and management of tuberculosis in patients treated with tumor necrosis factor alpha inhibitors: a consensus of lithuanian pulmonologists and rheumatologists].  

PubMed

Patients receiving tumor necrosis factor alpha inhibitors for the treatment of rheumatic diseases (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis) are at high risk of developing tuberculosis during treatment. This article gives the recommendations for the prevention and management of tuberculosis in patients with rheumatic diseases before initiating therapy with tumor necrosis factor alpha inhibitors. They are adapted considering the high prevalence of tuberculosis, high drug resistance of Mycobacterium tuberculosis, and extensive bacille Calmette-Guérin vaccination against tuberculosis in Lithuania. In order to reduce the risk of tuberculosis, the screening should be done before starting antitumor necrosis factor alpha therapy. This includes complete medical history and posterior-anterior, lateral chest radiography. Tuberculin skin test using the Mantoux method with 5 tuberculin units and interferon-gamma release assay should be performed in patients without posttuberculous radiological lesions. If Ghon's complex or untreated posttuberculous lesions are present, or if the results the Mantoux test or interferon-gamma release assay are positive, the patient should be treated for latent tuberculosis. For the treatment of latent tuberculosis, isoniazid and rifampicin are given for 3 months, and the introduction of antitumor necrosis factor alpha therapy is delayed at least for one month. In cases of suspected active Mycobacterium tuberculosis infection, tuberculosis should be confirmed microbiologically or morphologically, and adequate antituberculosis treatment should be initiated. PMID:21822042

Malakauskas, K?stutis; Zablockis, Rolandas; Venalis, Algirdas; Butrimien?, Irena; Baranauskait?, Asta; Narg?la, Remigijus Voldemaras; Sakalauskas, Raimundas

2011-01-01

141

Tuberculosis of the shoulder joint with impingement syndrome as initial presentation  

Microsoft Academic Search

Tuberculosis of the shoulder can be difficult to diagnose in the early stages. If not diagnosed early, bony tuberculosis may reduce quality of life. Therefore, tuberculosis should be suspected in cases of long- standing pain in the shoulder. It is necessary to keep tuberculosis in the differential diagnosis of impingement syndrome of the shoulder. We report a young patient presenting

Chethan Nagaraj; Saurabh Singh; Baldeep Singh; Vivek Trikha; Shishir Rastogi

142

Epidemiological and clinical study of tuberculosis in the district of Kol?n, Czechoslovakia*  

PubMed Central

Many developed countries are faced with the problem of reorganizing their tuberculosis-control programme to bring it into line with modern conditions. The study reported was undertaken to provide guidelines for this reorganization. It was begun in the district of Kolín, Czechoslovakia, with a population of some 100 000, in 1961 and is still in progress. The paper covers the first 4 years of the study. In 1961 a thorough check-up was made on all persons registered as having active or inactive tuberculosis, or fibrotic lung lesions. In 1961 and 1963 a mass X-ray and tuberculin-testing campaign, with 95% coverage, was carried out for all persons over 14 years of age. All persons with active tuberculosis received adequate treatment. Persons registered as having tuberculosis or suspected tuberculosis were subjected to regular photofluorographic and bacteriological investigations. Newborn infants were given BCG vaccination, and persons aged 14 years and 19 years with negative tuberculin reactions were vaccinated. The prevalence of bacillary tuberculosis fell from 150 cases in 1960 to 91 in 1964, mainly owing to a decrease in the number of chronic cases. The incidence of bacillary tuberculosis detectable by direct smear microscopy, however, remained at about 25 cases throughout the period 1961-64. The risk of developing tuberculosis was found to be highest in persons with fibrotic lung lesions or inactive tuberculosis, and in men above 45 years of age and women above 65 with previously normal photofluorograms. It is concluded from the study that in developed countries priority should be given to adequate treatment of all persons with active tuberculosis, and to early diagnosis in persons consulting physicians and in the high-risk population groups.

Styblo, K.; Dankova, D.; Drapela, J.; Galliova, J.; Jezek, Z.; Krivanek, J.; Kubik, A.; Langerova, M.; Radkovsky, J.

1967-01-01

143

Anti-tuberculosis activities of the crude methanolic extract and purified fractions of the bulb of Crinum jagus.  

PubMed

Tuberculosis (TB) is of great public health burden globally especially in developing countries of Africa and Asia . Current TB regimen involves multiple therapies and of long duration leading to poor patient adherence. There is also the challenge of multidrug resistant TB. Hence, there is a need for discovery of new anti- TB drugs. This study was designed to investigate the in -vitro activity of the crude methanolic extract and chromatographic fractions of the bulb of Crinum jagus against Mycobacterium tuberculosis isolates. The extracts were screened for anti- TB activity against three different M. tuberculosis isolates and a drug susceptible reference strain H37Rv using Lowenstein Jensen (L-J) medium and Middlebrook 7H10agar. The crude extract was prepared using soxhlet extraction apparatus while the purified fractions were obtained by column chromatography. The two media were inoculated with M. tuberculosis strains, after which the crude and purified extracts were added. After 4-6 weeks incubation, colony forming units were counted and percentage inhibition calculated. The crude extract and the purified fractions showed inhibitory activity on all the isolates tested including the reference strain. Fraction 3 showed the highest inhibitory percentage (86%) among the extracts. At a concentration of 1.0mg/ml, the percentage inhibition of fraction 3, rifampicin and isoniazid against M. tuberculosis strain 3 were 83%, 95% and 86% in L-J medium respectively while 86%, 96% and 89% were obtained respectively in Middle brook medium. Results showed that the crude methanolic extract and the purified fractions of the bulb of Crinum jagus exhibited anti-mycobacterial activity which is an indication of promising potential of this plant for the development of anti-tuberculosis agent. PMID:24937387

Akintola, A O; Kehinde, A O; Adebiyi, O E; Ademowo, O G

2013-01-01

144

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

SciTech Connect

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

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

2006-01-01

145

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

PubMed

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

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

1999-12-01

146

Loss of kinase activity in Mycobacterium tuberculosis multidomain protein Rv1364c.  

PubMed

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

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

2008-12-01

147

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

PubMed Central

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

2014-01-01

148

Predictive value of interferon-? release assays for incident active tuberculosis: a systematic review and meta-analysis  

PubMed Central

Summary Background We aimed to assess whether interferon-? release assays (IGRAs) can predict the development of active tuberculosis and whether the predictive ability of these tests is better than that of the tuberculin skin test (TST). Methods Longitudinal studies of the predictive value for active tuberculosis of in-house or commercial IGRAs were identified through searches of PubMed, Embase, Biosis, and Web of Science and complementary manual searches up to June 30, 2011. Eligible studies included adults or children, with or without HIV, who were free of active tuberculosis at study baseline. We summarised incidence rates in forest plots and pooled data with random-effects models when appropriate. We calculated incidence rate ratios (IRR) for rates of disease progression in IGRA-positive versus IGRA-negative individuals. Findings 15 studies had a combined sample size of 26 680 participants. Incidence of tuberculosis during a median follow-up of 4 years (IQR 2–6), even in IGRA-positive individuals, was 4–48 cases per 1000 person-years. Seven studies with no possibility of incorporation bias and reporting baseline stratification on the basis of IGRA results showed a moderate association between positive results and subsequent tuberculosis (pooled unadjusted IRR 2·10, 95% CI 1·42–3·08). Compared with test-negative results, IGRA-positive and TST-positive results were much the same with regard to the risk of tuberculosis (pooled IRR in the five studies that used both was 2·11 [95% CI 1·29–3·46] for IGRA vs 1·60 [0·94–2·72] for TST at the 10 mm cutoff). However, the proportion of IGRA-positive individuals in seven of 11 studies that assessed both IGRAs and TST was generally lower than TST-positive individuals. Interpretation Neither IGRAs nor the TST have high accuracy for the prediction of active tuberculosis, although use of IGRAs in some populations might reduce the number of people considered for preventive treatment. Until more predictive biomarkers are identified, existing tests for latent tuberculosis infection should be chosen on the basis of relative specificity in different populations, logistics, cost, and patients’ preferences rather than on predictive ability alone. Funding Special Programme for Research and Training in Tropical Diseases (WHO), Wellcome Trust, Canadian Institutes of Health Research, UK Medical Research Council, and the European and Developing Countries Clinical Trials Partnership.

Rangaka, Molebogeng X; Wilkinson, Katalin A; Glynn, Judith R; Ling, Daphne; Menzies, Dick; Mwansa-Kambafwile, Judith; Fielding, Katherine; Wilkinson, Robert J; Pai, Madhukar

2013-01-01

149

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

PubMed

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

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

2012-04-15

150

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

PubMed Central

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

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

2014-01-01

151

The Impact of IFN-? Receptor on SLPI Expression in Active Tuberculosis: Association with Disease Severity.  

PubMed

Interferon (IFN)-? displays a critical role in tuberculosis (TB), modulating the innate and adaptive immune responses. Previously, we reported that secretory leukocyte protease inhibitor (SLPI) is a pattern recognition receptor with anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb). Herein, we determined whether IFN-? modulated the levels of SLPI in TB patients. Plasma levels of SLPI and IFN-? were studied in healthy donors (HDs) and TB patients. Peripheral blood mononuclear cells from HDs and patients with TB or defective IFN-? receptor 1* were stimulated with Mtb antigen and SLPI, and IFN-?R expression levels were measured. Both SLPI and IFN-? were significantly enhanced in plasma from those with TB compared with HDs. A direct association between SLPI levels and the severity of TB was detected. In addition, Mtb antigen stimulation decreased the SLPI produced by peripheral blood mononuclear cells from HDs, but not from TB or IFN-?R patients. Neutralization of IFN-? reversed the inhibition of SLPI induced by Mtb antigen in HDs, but not in TB patients. Furthermore, recombinant IFN-? was unable to modify the expression of SLPI in TB patients. Finally, IFN-?R expression was lower in TB compared with HD peripheral blood mononuclear cells. These results show that Mtb-induced IFN-? down-modulated SLPI levels by signaling through the IFN-?R in HDs. This inhibitory mechanism was not observed in TB, probably because of the low expression of IFN-?R detected in these individuals. PMID:24606882

Tateosian, Nancy L; Pasquinelli, Virginia; Hernández Del Pino, Rodrigo E; Ambrosi, Nella; Guerrieri, Diego; Pedraza-Sánchez, Sigifredo; Santucci, Natalia; D'Attilio, Luciano; Pellegrini, Joaquín; Araujo-Solis, María A; Musella, Rosa M; Palmero, Domingo J; Hernandez-Pando, Rogelio; Garcia, Verónica E; Chuluyan, H Eduardo

2014-05-01

152

Novel conjugate of moxifloxacin and carboxymethylated glucan with enhanced activity against Mycobacterium tuberculosis.  

PubMed

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

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

2006-06-01

153

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

PubMed Central

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

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

2006-01-01

154

NLCQ-1 and NLCQ-2, two new agents with activity against dormant Mycobacterium tuberculosis.  

PubMed

4-[3-(2-Nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1; NSC 709257) and 4-[4-(2-nitro-1-imidazolyl)-butylamino]-7-chloroquinoline hydrochloride (NLCQ-2), two weak DNA-intercalating nitroimidazole-based bioreductive prodrugs, have been tested against dormant Mycobacterium tuberculosis and demonstrated a significant activity comparable with that of the nitroimidazopyran PA-824. Minimum bactericidal concentrations (MBCs) of 3.1-18.4 and 4.9-9.8 microg/mL were obtained for NLCQ-1 and NLCQ-2, respectively. In the same test setting; the corresponding MBC range for PA-824 was 6.4-12.8 microg/mL. For rifampicin, isoniazid, minocycline, streptomycin, clarithromycin and capreomycin, the corresponding MBC values were 2.5, >100, >156.25, >12.5, >312.5 and 37.5 microg/mL, respectively. Toxicity against Vero cells provided 50% inhibitory concentrations (IC(50)) of 146.7, >640 and >640 microg/mL for NLCQ-1, NLCQ-2 and PA-824, respectively. Therefore, the selectivity index (SI) was 8-47.3, >65.3-130.6 and >50-100 for NLCQ-1, NLCQ-2 and PA-824, respectively. These results suggest the potential usefulness of these compounds in the therapy of the latent form of tuberculosis. PMID:17379483

Papadopoulou, Maria V; Bloomer, William D; McNeil, Michael R

2007-06-01

155

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

PubMed

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

Magombedze, Gesham; Mulder, Nicola

2012-01-01

156

Endobronchial tuberculosis: an overview.  

PubMed

Endobronchial tuberculosis (EBTB), of which the incidence has been increasing in recent years, is a special type of pulmonary tuberculosis. The endobronchial tuberculose focuses often injure the tracheobronchial wall and lead to tracheobronchial stenosis. The tracheobronchial stenosis may cause intractable tuberculosis and make patients become chronic infection sources of tuberculosis, or may even cause pulmonary complications and result in death. The etiological confirmation of Mycobacterium tuberculosis is most substantial for diagnosis. However, because the positive rate of acid-fast bacillus staining for sputum smears is low and the clinical and radiological findings are usually nondistinctive, the diagnosis of EBTB is often mistaken and delayed. For early diagnosis, a high index of awareness of this disease is required and the bronchoscopy should be performed as soon as possible in suspected patients. The eradication of Mycobacterium tuberculosis and the prevention of tracheobronchial stenosis are two most substantial treatment goals. To get treatment goals, the diagnosis must be established early and aggressive treatments must be performed before the disease progresses too far. PMID:21499709

Xue, Q; Wang, N; Xue, X; Wang, J

2011-09-01

157

Elevated Serum Levels of CCL17 Correlate with Increased Peripheral Blood Platelet Count in Patients with Active Tuberculosis in China ?  

PubMed Central

The serum levels of Th2 markers, including CCL17 (thymus and activation-regulated chemokine [TARC]), CCL22 (macrophage-derived chemokine [MDC]), and soluble CD30, were measured in 101 HIV-negative tuberculosis patients, 103 healthy community controls, and 18 tuberculosis patients in recovery. The levels of CCL17/TARC (249.8 ± 19.91 versus 143.9 ± 10.54, P < 0.0001) and sCD30 (7.78 ± 0.44 versus 4.93 ± 0.23, P < 0.0001) were significantly higher in patients with active tuberculosis than in controls; however, the CCL22/MDC serum level had no statistical difference between the groups (579.9 ± 16.42 versus 556.5 ± 15.29, P = 0.298). The counts of platelet and eosinophil in the peripheral blood of patients with active tuberculosis are significantly increased as well (289.4 ± 8.14 versus 248.3 ± 5.34 [P < 0.0001] and 165.1 ± 14.33 versus 102.5 ± 10.72 [P = 0.0005], respectively), and the platelet counts were positively correlated with serum TARC levels (Pearson r = 0.456, P < 0.0001), which indicates a new source of Th2 bias showing in active TB patients.

Feng, Yonghong; Yin, Hongyun; Mai, Guangliang; Mao, Ling; Yue, Jun; Xiao, Heping; Hu, Zhongyi

2011-01-01

158

Elevated serum levels of CCL17 correlate with increased peripheral blood platelet count in patients with active tuberculosis in China.  

PubMed

The serum levels of Th2 markers, including CCL17 (thymus and activation-regulated chemokine [TARC]), CCL22 (macrophage-derived chemokine [MDC]), and soluble CD30, were measured in 101 HIV-negative tuberculosis patients, 103 healthy community controls, and 18 tuberculosis patients in recovery. The levels of CCL17/TARC (249.8 ± 19.91 versus 143.9 ± 10.54, P < 0.0001) and sCD30 (7.78 ± 0.44 versus 4.93 ± 0.23, P < 0.0001) were significantly higher in patients with active tuberculosis than in controls; however, the CCL22/MDC serum level had no statistical difference between the groups (579.9 ± 16.42 versus 556.5 ± 15.29, P = 0.298). The counts of platelet and eosinophil in the peripheral blood of patients with active tuberculosis are significantly increased as well (289.4 ± 8.14 versus 248.3 ± 5.34 [P < 0.0001] and 165.1 ± 14.33 versus 102.5 ± 10.72 [P = 0.0005], respectively), and the platelet counts were positively correlated with serum TARC levels (Pearson r = 0.456, P < 0.0001), which indicates a new source of Th2 bias showing in active TB patients. PMID:21270281

Feng, Yonghong; Yin, Hongyun; Mai, Guangliang; Mao, Ling; Yue, Jun; Xiao, Heping; Hu, Zhongyi

2011-04-01

159

Phytoconstituents from Alpinia purpurata and their in vitro inhibitory activity against Mycobacterium tuberculosis.  

PubMed

Alpinia purpurata or red ginger was studied for its phytochemical constituents as part of our growing interest on Philippine Zingiberaceae plants that may exhibit antimycobacterial activity. The hexane and dichloromethane subextracts of the leaves were fractionated and purified using silica gel chromatography to afford a mixture of C(28)-C(32) fatty alcohols, a 3-methoxyflavone and two steroidal glycosides. The two latter metabolites were spectroscopically identified as kumatakenin (1), sitosteryl-3-O-6-palmitoyl-?-D-glucoside (2) and b-sitosteryl galactoside (3) using ultraviolet (UV), infrared (IR), electron impact mass spectrometer (EIMS) and nuclear magnetic resonance (NMR) experiments, and by comparison with literature data. This study demonstrates for the first time the isolation of these constituents from A. purpurata. In addition to the purported anti-inflammatory activity, its phytomedicinal potential to treat tuberculosis is also described. PMID:21120040

Villaflores, Oliver B; Macabeo, Allan Patrick G; Gehle, Dietmar; Krohn, Karsten; Franzblau, Scott G; Aguinaldo, Alicia M

2010-10-01

160

Phytoconstituents from Alpinia purpurata and their in vitro inhibitory activity against Mycobacterium tuberculosis  

PubMed Central

Alpinia purpurata or red ginger was studied for its phytochemical constituents as part of our growing interest on Philippine Zingiberaceae plants that may exhibit antimycobacterial activity. The hexane and dichloromethane subextracts of the leaves were fractionated and purified using silica gel chromatography to afford a mixture of C28–C32 fatty alcohols, a 3-methoxyflavone and two steroidal glycosides. The two latter metabolites were spectroscopically identified as kumatakenin (1), sitosteryl-3-O-6-palmitoyl-?-D-glucoside (2) and b-sitosteryl galactoside (3) using ultraviolet (UV), infrared (IR), electron impact mass spectrometer (EIMS) and nuclear magnetic resonance (NMR) experiments, and by comparison with literature data. This study demonstrates for the first time the isolation of these constituents from A. purpurata. In addition to the purported anti-inflammatory activity, its phytomedicinal potential to treat tuberculosis is also described.

Villaflores, Oliver B.; Macabeo, Allan Patrick G.; Gehle, Dietmar; Krohn, Karsten; Franzblau, Scott G.; Aguinaldo, Alicia M.

2010-01-01

161

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

PubMed Central

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

Geffner, Laura; Kviatcovsky, Denise; Sabio y Garcia, Carmen; Ritacco, Viviana; Lopez, Beatriz; Sasiain, Maria del Carmen; de la Barrera, Silvia

2014-01-01

162

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

PubMed Central

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

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

2012-01-01

163

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

PubMed

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

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

2004-01-30

164

Tuberculosis among Children in Alaska.  

ERIC Educational Resources Information Center

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

Gessner, Bradford D.

1997-01-01

165

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

PubMed Central

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

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

2014-01-01

166

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

PubMed

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

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

2014-02-01

167

In vitro activity of isoimperatorin, alone and in combination, against Mycobacterium tuberculosis.  

PubMed

Previous studies have shown that isoimperatorin (IO), a furanocoumarin isolated from several medicinal plants, has antimycobacterial activity against Mycobacterium tuberculosis strain H37Rv (ATCC 27294). This study demonstrated that IO has antimycobacterial activity against 2 drug-sensitive and 6 drug-resistant isolates, with minimum inhibitory concentrations (MICs) of 50-100 ?g ml(-1) and 100-200 ?g ml(-1), respectively. IO exhibited synergistic antimycobacterial effects with rifampin (RMP), isoniazid (INH) and ethambutol (EMB) against 6 drug-resistant strains, with fractional inhibitory concentration index (FICI) values of 0·133-0·472, 0·123-0·475 and 0·124-0·25, respectively. The IO/RMP, IO/INH and IO/EMB combination treatments had synergistic effects or no interaction in the 2 drug-sensitive strains and the standard strain ATCC 27294. The synergism of combined drugs against drug-resistant strains was better than drug-sensitive strains. No antagonism was observed in with the aforementioned combinations against all strains tested. IO exhibited relatively low cytotoxicity to Vero cells. Our results indicate that IO may serve as promising a template for future antimycobacterial drug development. Significance and impact of the study: This is the first report on the in vitro synergistic antimycobacterial effects of isoimperatorin (IO) in combination with three first-line drugs: rifampin (RMP), isoniazid (INH) and ethambutol (EMB). The results indicated that the antimycobacterial activity of IO was modest; however, IO was a useful and effective agent against Myco. tuberculosis when it was combined with first-line antimycobacterial drugs and is worthy of further development as a lead compound for the development of novel antimycobacterial therapeutic agents. PMID:24330002

Guo, N; Wu, J; Fan, J; Yuan, P; Shi, Q; Jin, K; Cheng, W; Zhao, X; Zhang, Y; Li, W; Tang, X; Yu, L

2014-04-01

168

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

PubMed

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

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

2012-11-01

169

Depressed Interleukin12 (IL12), but not IL18, Production in Response to a 30- or 32-Kilodalton Mycobacterial Antigen in Patients with Active Pulmonary Tuberculosis  

Microsoft Academic Search

The secreted 30-kDa antigen (Ag) of Mycobacterium tuberculosis directly stimulates Th1-type protective cytokine responses in healthy tuberculin reactors but not in patients with active tuberculosis (TB). To examine the cytokine profiles attributable to Th1 suppression associated with active TB, interleukin-12 (IL-12), IL-18, and IL-10 production in response to a 30- or 32-kDa Ag in 16 patients with active pulmonary TB

CHANG-HWA SONG; HWA-JUNG KIM; JEONG-KYU PARK; JAE-HYUN LIM; UN-OK KIM; JUN-SANG KIM; TAE-HYUN PAIK; KYUNG-JIN KIM; JI-WON SUHR; EUN-KYEONG JO

2000-01-01

170

Cordilleran suspect terranes  

USGS Publications Warehouse

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

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

1980-01-01

171

Molecular characterization of T cell receptor beta variable in the peripheral blood T cell repertoire in subjects with active tuberculosis or latent tuberculosis infection  

PubMed Central

Background T cells are closely linked to the clinical manifestations of subjects with Mycobacterium tuberculosis (MTB) infection. T cell receptor beta variable (TCRBV) is a signal and indicative molecule on the membrane of T lymphocytes, reflecting the composition and specificity of T cells. The molecular profiles of TCRBV in peripheral blood mononuclear cells (PBMCs) and their subpopulations (CD4+ and CD8+ T cells) from subjects with active tuberculosis (TB) or latent TB infection (LTBI) have not been well described. Methods In 42 subjects with active TB or LTBI, PMBCs and their subsets were separated and sorted. The molecular profiles of the TCRBV complementarity determining region 3 (CDR3) in the three cell populations were investigated using our recently developed gene melting spectral pattern (GMSP) assay. The TCRBV members were then cloned and sequenced when their GMSP image profiles showed a single-peak. Results The average number of skewed TCRBV molecules in the CD4+ cell subset was significantly higher than that in PBMCs and CD8+ T cells. TCRBV12, BV13.1, BV13.2, and BV24 were expressed more prevalently than other TCRBV gene families in the three cell populations. In addition, relatively conserved amino acid motifs were identified in TCRBV5.1 and BV20 CDR3 in PBMCs and its subsets. The monoclonal TCRBV14 and BV23 expressed were different between active TB and LTBI subjects. Conclusions These results indicate that the T cell immune response is complex and multi-specific in active TB and LTBI subjects. Analysis of TCRBV expression in CD4+ T cells suggest that it could be useful in assessing the composition and status of circulating T cells. Furthermore, the expression of TCRBV14, BV23 and the sequencing of CDR3 amino acid motifs of TCRBV5.1, BV20 could be used in the differential diagnosis and treatment of subjects with active TB or LTBI.

2013-01-01

172

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

PubMed

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

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

2011-01-01

173

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

Microsoft Academic Search

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

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

174

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

Microsoft Academic Search

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

NATAN MOR; ADELEH ESFANDIARI

1997-01-01

175

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

ERIC Educational Resources Information Center

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

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

2011-01-01

176

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

PubMed

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

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

2014-05-01

177

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

PubMed

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

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

2012-11-01

178

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

PubMed Central

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

2014-01-01

179

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

PubMed Central

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

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

2013-01-01

180

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

PubMed Central

Quinolinic acid phosphoribosyltransferase (QAPRTase, EC 2.4.2.19) is a key enzyme in the de novo pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis and a target for the development of new anti-tuberculosis drugs. QAPRTase catalyzes the synthesis of nicotinic acid mononucleotide from quinolinic acid (QA) and 5-phosphoribosyl-1-pyrophosphate (PRPP) through a phosphoribosyl transfer reaction followed by decarboxylation. The crystal structure of QAPRTase from Mycobacterium tuberculosis H37Rv (MtQAPRTase) has been determined; however, a detailed functional analysis of MtQAPRTase has not been published. Here, we analyzed the enzymatic activities of MtQAPRTase and determined the effect on catalysis of the anti-tuberculosis drug pyrazinamide (PZA). The optimum temperature and pH for MtQAPRTase activity were 60°C and pH 9.2. MtQAPRTase required bivalent metal ions and its activity was highest in the presence of Mg2+. Kinetic analyses revealed that the Km values for QA and PRPP were 0.08 and 0.39 mM, respectively, and the kcat values for QA and PRPP were 0.12 and 0.14 [s-1], respectively. When the amino acid residues of MtQAPRTase, which may interact with QA, were substituted with alanine residues, catalytic activity was undetectable. Further, PZA, which is an anti-tuberculosis drug and a structural analog of QA, markedly inhibited the catalytic activity of MtQAPRTase. The structure of PZA may provide the basis for the design of new inhibitors of MtQAPRTase. These findings provide new insights into the catalytic properties of MtQAPRTase.

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

2014-01-01

181

Synergistic activity of R207910 combined with pyrazinamide against murine tuberculosis.  

PubMed

In previous studies, the diarylquinoline R207910 (also known as TMC207) was demonstrated to have high bactericidal activity when combined with first- or second-line antituberculous drugs. Here we extend the evaluation of R207910 in the curative model of murine tuberculosis by assessing the activities of one-, two-, and three-drug combinations containing R207910 and isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), or moxifloxacin (MXF) in the setting of a high initial bacillary load (7.2 log(10) CFU). Two months of treatment with the combinations R207910-PZA, R207910-PZA-INH, R207910-PZA-RIF, or R207910-PZA-MXF resulted in culture-negative lung homogenates in 70 to 100% of the mice, while mice treated with INH-RIF-PZA (the reference regimen) or RIF-MXF-PZA remained culture positive. Combinations including R207910 but not PZA (e.g., R207910-INH-RIF and R207910-MXF-RIF) were less active than R207910-PZA-containing regimens administered either alone or with the addition of INH, RIF, or MXF. These results reveal a synergistic interaction between R207910 and PZA. Three-drug combinations containing these two drugs and INH, RIF, or MXF have the potential to significantly shorten the treatment duration in patients, provided that these results can be confirmed in long-term experiments including periods of relapse. PMID:17178794

Ibrahim, M; Andries, K; Lounis, N; Chauffour, A; Truffot-Pernot, C; Jarlier, V; Veziris, N

2007-03-01

182

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

PubMed

A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-?-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1. These in vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents. PMID:23776209

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

2013-07-01

183

Seasonality of Tuberculosis  

PubMed Central

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

Fares, Auda

2011-01-01

184

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

Microsoft Academic Search

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

Sugopa Sengupta; Soumitra Ghosh; Valakunja Nagaraja

2008-01-01

185

Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis.  

PubMed

Tibotec Medicinal Compound 207 (TMC207) is a novel diarylquinoline with a unique mode of action that targets mycobacterial ATP synthase. TMC207 exhibits high in vitro activity against mycobacterial strains either susceptible or resistant to all first-line and many second-line drugs, including fluoroquinolones, and has shown exceptional in vivo activity against several mycobacterial species in different animal models. In this early bactericidal activity study, 75 treatment-naïve patients with smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Sixteen-hour overnight sputum collected at baseline and on each treatment day was plated in serial dilutions on selective agar plates. The bactericidal activity was expressed as the log(10) decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of TMC207 administration up to 24 h postdose. The decreases in log(10) CFU counts (+/- standard deviation) from baseline to day 7 were 0.04 +/- 0.46 for 25 mg TMC207 (n = 14), 0.26 +/- 0.64 for 100 mg TMC207 (n = 14), 0.77 +/- 0.58 for 400 mg TMC207 (n = 14), 1.88 +/- 0.74 for INH (n = 11), and 1.70 +/- 0.71 for RIF (n = 14). Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in magnitude to those of INH and RIF over the same period. The pharmacokinetics of TMC207 were linear across the dose range. In summary, TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred. PMID:18505852

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

2008-08-01

186

Sterilizing Activities of Novel Combinations Lacking First- and Second-Line Drugs in a Murine Model of Tuberculosis  

PubMed Central

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

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

2012-01-01

187

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

PubMed

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

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

2012-06-01

188

Serum Chitotriosidase Activity in Pulmonary Tuberculosis: Response to Treatment and Correlations with Clinical Parameters  

PubMed Central

Background Chitotriosidase is an accepted marker of macrophage activation. In this study, we investigated serum chitotriosidase levels in pulmonary tuberculosis (PTB). Methods Forth-two patients with PTB and 30 healthy subjects were enrolled in the study. The radiological extent of PTB, radiological sequela after treatment, and the degree of smear positivity were assessed. Chitotriosidase levels were measured by a fluorometric method. Results The serum chitotriosidase levels of the PTB patients were significantly higher than those of the control subjects (39.73±24.97 vs. 9.63±4.55 nmol/mL/h, P<0.001). After completion of the standard 6-month antituberculous treatment, chitotriosidase levels in PTB patients significantly decreased (10.47±4.54 nmol/mL/h, P<0.001). Chitotriosidase levels correlated significantly with the radiological extent of PTB, degree of smear positivity, and post-treatment radiological sequela score (r=0.439, r=0.449, and r=0.337, respectively). Conclusions This study demonstrated that serum chitotriosidase levels increase in PTB; therefore, chitotriosidase can be used as a marker of disease activity, severity, and response to treatment.

Cak?r, Gulhan; Ucar, Ergun; Kaya, Hatice; Tozkoparan, Ergun; Akgul, Emin Ozgur; Karaman, Bulent; Deniz, Omer; Kurt, Ismail; Ozkan, Metin; Bilgic, Hayati

2012-01-01

189

Tuberculosis trends in the U.S. Armed Forces, active component, 1998-2012.  

PubMed

Members of the Armed Forces represent a segment of the U.S. population that may be at increased risk for tuberculosis (TB) infection, disease, and transmission due to overseas service in endemic areas and residence in congregate settings. The purpose of this study was to examine recent surveillance trends and risk factors associated with TB disease in the active component U.S. military. The rate of TB in the U.S. military -0.6 per 100,000 population (n=128) over the interval from 1998 to 2012 - was lower than the age-adjusted rate among the U.S. population (adjusted rate ratio=0.20) over the same time interval. During the last five years of the surveillance period, the most common factor associated with the diagnosis of TB disease during military service was latent infection at time of accession; also, as many as nine (24%) cases of TB were associated with deployment to Iraq or other military exposures. TB control activities should continue to mitigate unique military exposures such as crowding during recruit training and deployments to TB endemic areas. PMID:23731007

Mancuso, James D; Aaron, Christopher L

2013-05-01

190

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

PubMed Central

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.

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

1998-01-01

191

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

PubMed Central

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

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

2010-01-01

192

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

PubMed

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

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

2013-07-01

193

Cutaneous Tuberculosis  

PubMed Central

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

Frankel, Amylynne; Penrose, Carolin

2009-01-01

194

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

PubMed Central

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

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

2013-01-01

195

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

PubMed

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

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

1996-01-01

196

Pediatric glaucoma suspects  

PubMed Central

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

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

2014-01-01

197

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

Microsoft Academic Search

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

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

2008-01-01

198

Programmed death ligand 1 is over-expressed by neutrophils in the blood of patients with active tuberculosis  

PubMed Central

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the world's largest infectious disease problems. Despite decades of intensive study, the immune response to Mtb is incompletely characterised, reflecting the extremely complex interaction between pathogen and host. Pathways that may alter the balance between host protection and pathogenesis are therefore of great interest. One pathway shown to play a role in the pathogenesis of chronic infections, including TB, is the programmed death-1 (PD-1) pathway. We show here that the expression of the programmed death ligand 1 (PD-L1), which interacts with PD-1, is increased in whole blood from active TB patients compared with whole blood from healthy controls or Mtb-exposed individuals, and that expression by neutrophils is largely responsible for this increase.

McNab, Finlay W; Berry, Matthew P R; Graham, Christine M; Bloch, Susannah A A; Oni, Tolu; Wilkinson, Katalin A; Wilkinson, Robert J; Kon, Onn M; Banchereau, Jacques; Chaussabel, Damien; O'Garra, Anne

2011-01-01

199

Unique transcriptome signature of Mycobacterium tuberculosis in pulmonary tuberculosis.  

PubMed

Although tuberculosis remains a substantial global threat, the mechanisms that enable mycobacterial persistence and replication within the human host are ill defined. This study represents the first genome-wide expression analysis of Mycobacterium tuberculosis from clinical lung samples, which has enabled the identification of M. tuberculosis genes actively expressed during pulmonary tuberculosis. To obtain optimal information from our DNA array analyses, we analyzed the differentially expressed genes within the context of computationally inferred protein networks. Protein networks were constructed using functional linkages established by the Rosetta stone, phylogenetic profile, conserved gene neighbor, and operon computational methods. This combined approach revealed that during pulmonary tuberculosis, M. tuberculosis actively transcribes a number of genes involved in active fortification and evasion from host defense systems. These genes may provide targets for novel intervention strategies. PMID:16428773

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

2006-02-01

200

[The diagnosis of pulmonary tuberculosis].  

PubMed

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

Koyama, Sekiya; Sakaguchi, Nobuki; Hotta, Jyunnichi

2012-08-01

201

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

PubMed Central

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

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

2012-01-01

202

Modulation of DNA-binding activity of Mycobacterium tuberculosis HspR by chaperones.  

PubMed

In Mycobacterium tuberculosis, hspR is the last gene of the dnaKJE operon. It encodes the repressor HspR, which regulates the expression from this operon by binding to a consensus upstream sequence known as HAIR (HspR-associated inverted repeats). Previous investigations in the related Gram-positive bacterium Streptomyces coelicolor have revealed that DnaK acts as a co-repressor for HspR. In this investigation, a similar situation was encountered using the corresponding mycobacterial pair. However, the novel feature unearthed in this study is that the mycobacterial GroELs, GroEL1 and GroEL2, considerably stimulate the HAIR-binding activity of the HspR-DnaK combination. That these GroELs play a role in the folding process was evident from the observation that when heat- or chemically denatured HspR was renatured, the protein gained optimal activity only if one of these GroEL class chaperones was present along with DnaK. The renaturation process was found to be dependent on ATP hydrolysis. The DnaK-dependent DNA-binding activity of HspR could also be stimulated by DnaJ, but GrpE, which is known to release DnaK-bound substrates, was found to be inhibitory. The results of this study suggest that protein folding plays a substantial role in the activation of HspR following heat shock and that DnaK may be involved in two ways -- first, as a chaperone acting in concert with GroEL and/or DnaJ and second, as a co-repressor bound to HspR. PMID:18227252

Das Gupta, Twishasri; Bandyopadhyay, Boudhayan; Das Gupta, Sujoy K

2008-02-01

203

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

PubMed Central

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

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

2009-01-01

204

Tuberculosis Fluoroscopy  

Cancer.gov

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

205

Tuberculosis (TB)  

MedlinePLUS

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

206

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

PubMed Central

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

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

2012-01-01

207

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

PubMed Central

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

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

2012-01-01

208

The immune response in tuberculosis.  

PubMed

There are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and remains asymptomatic. Of these latent individuals, only 5-10% will develop active tuberculosis disease in their lifetime. CD4(+) T cells, as well as the cytokines IL-12, IFN-?, and TNF, are critical in the control of Mycobacterium tuberculosis infection, but the host factors that determine why some individuals are protected from infection while others go on to develop disease are unclear. Genetic factors of the host and of the pathogen itself may be associated with an increased risk of patients developing active tuberculosis. This review aims to summarize what we know about the immune response in tuberculosis, in human disease, and in a range of experimental models, all of which are essential to advancing our mechanistic knowledge base of the host-pathogen interactions that influence disease outcome. PMID:23516984

O'Garra, Anne; Redford, Paul S; McNab, Finlay W; Bloom, Chloe I; Wilkinson, Robert J; Berry, Matthew P R

2013-01-01

209

Psoriatic Disease and Tuberculosis Nowadays  

PubMed Central

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

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

2012-01-01

210

Mean platelet volume as an inflammation marker in active pulmonary tuberculosis  

PubMed Central

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

2014-01-01

211

Oral vaccination with heat inactivated Mycobacterium bovis activates the complement system to protect against tuberculosis.  

PubMed

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

Beltrán-Beck, Beatriz; de la Fuente, José; 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

212

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

PubMed Central

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

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

2014-01-01

213

The condensing activities of the Mycobacterium tuberculosis type II fatty acid synthase are differentially regulated by phosphorylation.  

PubMed

Phosphorylation of proteins by Ser/Thr protein kinases (STPKs) has recently become of major physiological importance because of its possible involvement in virulence of bacterial pathogens. Although Mycobacterium tuberculosis has eleven STPKs, the nature and function of the substrates of these enzymes remain largely unknown. In this work, we have identified for the first time STPK substrates in M. tuberculosis forming part of the type II fatty acid synthase (FAS-II) system involved in mycolic acid biosynthesis: the malonyl-CoA::AcpM transacylase mtFabD, and the beta-ketoacyl AcpM synthases KasA and KasB. All three enzymes were phosphorylated in vitro by different kinases, suggesting a complex network of interactions between STPKs and these substrates. In addition, both KasA and KasB were efficiently phosphorylated in M. bovis BCG each at different sites and could be dephosphorylated by the M. tuberculosis Ser/Thr phosphatase PstP. Enzymatic studies revealed that, whereas phosphorylation decreases the activity of KasA in the elongation process of long chain fatty acids synthesis, this modification enhances that of KasB. Such a differential effect of phosphorylation may represent an unusual mechanism of FAS-II system regulation, allowing pathogenic mycobacteria to produce full-length mycolates, which are required for adaptation and intracellular survival in macrophages. PMID:16873379

Molle, Virginie; Brown, Alistair K; Besra, Gurdyal S; Cozzone, Alain J; Kremer, Laurent

2006-10-01

214

Chemical composition of hexane extract of Citrus aurantifolia and anti-Mycobacterium tuberculosis activity of some of its constituents.  

PubMed

The main aim of this study was to isolate and characterize the active compounds from the hexane extract of the fruit peels of Citrus aurantiifolia, which showed activity against one sensitive and three monoresistant (isoniazid, streptomycin or ethambutol) strains of Mycobacterium tuberculosis H37Rv. The active extract was fractionated by column chromatography, yielding the following major compounds: 5-geranyloxypsoralen (1); 5-geranyloxy-7-methoxycoumarin (2); 5,7-dimethoxycoumarin (3); 5-methoxypsoralen (4); and 5,8-dimethoxypsoralen (5). The structures of these compounds were elucidated by 1D and 2D NMR spectroscopy. In addition, GC-MS analysis of the hexane extract allowed the identification of 44 volatile compounds, being 5,7-dimethoxycoumarin (15.79%), 3-methyl-1,2-cyclopentanedione (8.27%), 1-methoxy-ciclohexene (8.0%), corylone (6.93%), palmitic acid (6.89%), 5,8-dimethoxypsoralen (6.08%), a-terpineol (5.97%), and umbelliferone (4.36%), the major constituents. Four isolated coumarins and 16 commercial compounds identified by GC-MS were tested against M. tuberculosis H37Rv and three multidrug-resistant M. tuberculosis strains using the Microplate Alamar Blue Assay. The constituents that showed activity against all strains were 5 (MICs = 25-50 mg/mL), 1 (MICs = 50-100 mg/mL), palmitic acid (MICs = 25-50 mg/mL), linoleic acid (MICs = 50-100 mg/mL), oleic acid (MICs = 100 mg/mL), 4-hexen-3-one (MICs = 50-100 mg/mL), and citral (MICs = 50-100 mg/mL). Compound 5 and palmitic acid were the most active ones. The antimycobacterial activity of the hexane extract of C. aurantifolia could be attributed to these compounds. PMID:22992784

Sandoval-Montemayor, Nallely E; García, Abraham; Elizondo-Treviño, Elizabeth; Garza-González, Elvira; Alvarez, Laura; del Rayo Camacho-Corona, María

2012-01-01

215

Standardized Treatment of Active Tuberculosis in Patients with Previous Treatment and/or with Mono-resistance to Isoniazid: A Systematic Review and Meta-analysis  

PubMed Central

Background A standardized regimen recommended by the World Health Organization for retreatment of active tuberculosis (TB) is widely used, but treatment outcomes are suspected to be poor. We conducted a systematic review of published evidence of treatment of patients with a history of previous treatment or documented isoniazid mono-resistance. Methods and Findings PubMed, EMBASE, and the Cochrane Central database for clinical trials were searched for randomized trials in previously treated patients and/or those with with mono-resistance to isoniazid, published in English, French, or Spanish between 1965 and June 2008. The first two sources were also searched for cohort studies evaluating specifically the current retreatment regimen. In studies selected for inclusion, rifampin-containing regimens were used to treat patients with bacteriologically confirmed pulmonary TB, in whom bacteriologically confirmed failure and/or relapse had been reported. Pooled cumulative incidences and 95% CIs of treatment outcomes were computed with random effects meta-analyses and negative binomial regression. No randomized trials of the currently recommended retreatment regimen were identified. Only six cohort studies were identified, in which failure rates were 18%–44% in those with isoniazid resistance. In nine trials, using very different regimens in previously treated patients with mono-resistance to isoniazid, the combined failure and relapse rates ranged from 0% to over 75%. From pooled analysis of 33 trials in 1,907 patients with mono-resistance to isoniazid, lower failure, relapse, and acquired drug resistance rates were associated with longer duration of rifampin, use of streptomycin, daily therapy initially, and treatment with a greater number of effective drugs. Conclusions There are few published studies to support use of the current standardized retreatment regimen. Randomized trials of treatment of persons with isoniazid mono-resistance and/or a history of previous TB treatment are urgently needed. Please see later in the article for the Editors' Summary

Menzies, Dick; Benedetti, Andrea; Paydar, Anita; Royce, Sarah; Pai, Madhukar; Burman, William; Vernon, Andrew; Lienhardt, Christian

2009-01-01

216

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

PubMed Central

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

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

2014-01-01

217

Active pulmonary tuberculosis and latent tuberculosis infection among homeless people in Seoul, South Korea: a cross-sectional study  

PubMed Central

Background The aim of this study was to determine the prevalence rate of latent TB infection (LTBI) and active TB among homeless in Seoul metropolitan city, South Korea, and to compare the TB burden among homeless people with that of a control group. Methods The homeless participants were recruited from five sites between October 30, 2009 and April 12, 2010. LTBI was diagnosed through the QuantiFERON(R) TB Gold In-Tube(QFT-GIT) assay and a tuberculin skin test(TST) and, and active PTB was diagnosed based on chest radiography. Results Among 313 participants, the prevalence of LTBI was 75.9% (95% CI, 71.1-80.8%) and 79.8% (95% CI, 74.9-84.7%) based on a QFT-GIT assay and the TST, respectively, and that of active PTB was 5.8% (95% CI, 3.2-8.3%). The prevalence of LTBI among homeless participants was about five times higher than controls. Also, the age-specific prevalence rate ratio of active PTB was as high as 24.86. Conclusions The prevalence rate of LTBI as well as active PTB among homeless people was much higher than that of the general population in South Korea. Thus, adequate strategies to reduce the TB burden among homeless people are needed.

2013-01-01

218

Gingival tuberculosis  

PubMed Central

Tuberculosis is a chronic specific granulomatous disease and a major cause of death in developing countries. The clinical presentation of tuberculosis lesions of oral cavity varies widely, including ulceration, diffuse inflammatory lesions, granulomas and fissures. Oral lesions usually appear as secondary to primary tuberculosis infection elsewhere, although primary infection of the oral mucosa by Mycobacterium tuberculosis has been described. We report a case of tuberculosis of gingiva, manifesting as gingival enlargement. Diagnosis was based on histopathological examination, complete blood count, X-ray chest and immunological investigations with detection of antibodies against Mycobacterium tuberculosis. Anti-tuberculous therapy was carried out for over six months. This case report emphasizes the need for dentists to include tuberculosis in the differential diagnosis of various types of gingival enlargements.

Jain, Sanjeev; Vipin, Bharti; Khurana, Pankaj

2009-01-01

219

A missed tuberculosis diagnosis resulting in hospital transmission.  

PubMed

Objective.?To find the source of tuberculin skin test conversions among 38 hospital employees on 1 floor during routine testing January-February 2010. Methods.?Record review of patients at a private hospital during September-December 2009 and interviews with hospital employees. Names of patients from the state tuberculosis (TB) registry were cross-referenced with hospital records for admissions. Mycobacterium tuberculosis genotype results in the county and adjacent counties were examined, and contacts were evaluated for TB infection and disease. Results.?One of the 38 employees, a nurse, was diagnosed with pulmonary TB with a matching M. tuberculosis genotype and drug resistance pattern (isoniazid monoresistant) to those of a county jail inmate also recently diagnosed with pulmonary TB. The nurse had no known contact with that inmate; however, another inmate in his 20's from the same jail had been hospitalized under that nurse's care in October 2009. That young man died, and a postmortem examination result subsequently confirmed TB, which had not been suspected. Exposure to this man with undiagnosed TB could explain the transmission: 87 (27%) of the 318 hospital-based contacts without previous positive tuberculin skin test results were infected, and 9 contacts had active TB. Conclusions.?This investigation demonstrated M. tuberculosis transmission in a hospital due to a missed diagnosis and nonadherence to national TB infection control guidelines. Routine TB screening of employees allowed early detection of this missed TB diagnosis, facilitating prompt evaluation of contacts. Healthcare providers should suspect TB in symptomatic persons and adhere to TB control policies. PMID:24709722

Medrano, Belinda A; Salinas, Gloria; Sanchez, Connie; Miramontes, Roque; Restrepo, Blanca I; Haddad, Maryam B; Lambert, Lauren A

2014-05-01

220

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

PubMed Central

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

Molina-Salinas, Gloria Maria; Pena-Rodriguez, Luis Manuel; Mata-Cardenas, Benito David; Escalante-Erosa, Fabiola; Gonzalez-Hernandez, Silvia; Torres de la Cruz, Victor Manuel; Martinez-Rodriguez, Herminia Guadalupe; Said-Fernandez, Salvador

2011-01-01

221

Comparative antimicrobial activities of the newly synthesized quinolone WQ-3034, levofloxacin, sparfloxacin, and ciprofloxacin against Mycobacterium tuberculosis and Mycobacterium avium complex.  

PubMed

WQ-3034 is a newly synthesized acidic fluoroquinolone. We assessed its in vitro activity against Mycobacterium tuberculosis and M. avium complex using levofloxacin (LVFX), ciprofloxacin (CPFX), sparfloxacin (SPFX), and KRM-1648 (KRM) as reference drugs. The MICs of these agents were determined by the agar dilution method with 7H11 medium. The MICs at which 50 and 90% of the test strains were inhibited (MIC(50)s, and MIC(90)s, respectively) for the test quinolones for rifampin (RMP)-susceptible M. tuberculosis strains were in the order SPFX < LVFX tuberculosis strains were in the order SPFX tuberculosis were much lower than those of the test quinolones, while the MIC(90) of KRM for RMP-resistant M. tuberculosis strains was higher than those of the quinolones. The MIC(50)s and MIC(90)s of the test drugs for M. avium were in the order KRM < SPFX < CPFX activities of the test drugs against M. tuberculosis organisms residing in cells of the Mono Mac 6 macrophage (Mphi)-like cell line (MM6-Mphis) and of the A-549 type II alveolar cell line (A-549 cells). When drugs were added at the concentration that achieves the maximum concentration in blood, progressive killing or inhibition of the M. tuberculosis organisms residing in MM6-Mphis and A-549 cells was observed in the order KRM > SPFX >/= LVFX > WQ-3034 > CPFX. The efficacies of all quinolones against intracellular M. tuberculosis organisms were significantly lower in A-549 cells than in MM6-Mphis. WQ-3034 at the MIC caused more marked growth inhibition of intramacrophage M. tuberculosis than did LVFX. These findings indicate that the in vitro anti-M. tuberculosis activity of WQ-3034 is greater than that of CPFX and is comparable to that of LVFX. PMID:10639351

Tomioka, H; Sato, K; Kajitani, H; Akaki, T; Shishido, S

2000-02-01

222

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

PubMed Central

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

2010-01-01

223

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

PubMed

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

Khan, Arshad; Sarkar, Sampa; Sarkar, Dhiman

2008-07-01

224

Comparative cytotoxic and anti-tuberculosis activity of Aplysina caissara marine sponge crude extracts  

Microsoft Academic Search

Three crude extracts of Aplysina caissara, a marine sponge endemic to Brazil, were tested against a hepatoma cell line and Mycobacterium tuberculosis. The results demonstrate that all extracts are toxic and capable of inhibiting cellular growth. Additionally, the extracts produced morphological aberrations and inhibited cell attachment to culture substrates. These effects were dose\\/time dependent. Our results also suggest that reactive

Luciana G. Azevedo; Ana L. Muccillo-Baisch; Daza de M. V. B. Filgueira; Robert T. Boyle; Daniela F. Ramos; Andrea D. Soares; Clea Lerner; Pedro A. Silva; Gilma S. Trindade

2008-01-01

225

Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing.  

PubMed

Over 30% of the world's population is infected with Mycobacterium tuberculosis (Mtb), yet only ?5-10% will develop clinical disease. Despite considerable effort, researchers understand little about what distinguishes individuals whose infection progresses to active tuberculosis (TB) from those whose infection remains latent for decades. The variable course of disease is recapitulated in cynomolgus macaques infected with Mtb. Active disease occurs in ?45% of infected macaques and is defined by clinical, microbiologic and immunologic signs, whereas the remaining infected animals are clinically asymptomatic. Here, we use individually marked Mtb isolates and quantitative measures of culturable and cumulative bacterial burden to show that most lung lesions are probably founded by a single bacterium and reach similar maximum burdens. Despite this observation, the fate of individual lesions varies substantially within the same host. Notably, in active disease, the host sterilizes some lesions even while others progress. Our data suggest that lesional heterogeneity arises, in part, through differential killing of bacteria after the onset of adaptive immunity. Thus, individual lesions follow diverse and overlapping trajectories, suggesting that critical responses occur at a lesional level to ultimately determine the clinical outcome of infection. Defining the local factors that dictate outcome will be useful in developing effective interventions to prevent active TB. PMID:24336248

Lin, Philana Ling; Ford, Christopher B; Coleman, M Teresa; Myers, Amy J; Gawande, Richa; Ioerger, Thomas; Sacchettini, James; Fortune, Sarah M; Flynn, JoAnne L

2014-01-01

226

Sterilization of granulomas is common in both active and latent tuberculosis despite extensive within-host variability in bacterial killing  

PubMed Central

Over 30% of the world’s population is infected with Mycobacterium tuberculosis (Mtb), yet only ~5–10% will develop clinical disease1. Despite considerable effort, we understand little about what distinguishes individuals who progress to active tuberculosis (TB) from those who remain latent for decades. The variable course of disease is recapitulated in cynomolgus macaques infected with Mtb2. Active disease in macaques is defined by clinical, microbiologic and immunologic signs and occurs in ~45% of animals, while the remaining are clinically asymptomatic2,3. Here, we use barcoded Mtb isolates and quantitative measures of culturable and cumulative bacterial burden to show that most lesions are likely founded by a single bacterium and reach similar maximum burdens. Despite common origins, the fate of individual lesions varies substantially within the same host. Strikingly, in active disease, the host sterilizes some lesions even while others progress. Our data suggest that lesional heterogeneity arises, in part, through differential killing of bacteria after the onset of adaptive immunity. Thus, individual lesions follow diverse and overlapping trajectories, suggesting critical responses occur at a lesional level to ultimately determine the clinical outcome of infection. Defining the local factors that dictate outcome will be important in developing effective interventions to prevent active TB.

Lin, Philana Ling; Ford, Christopher B.; Coleman, M. Teresa; Myers, Amy J.; Gawande, Richa; Ioerger, Thomas; Sacchettini, James; Fortune, Sarah M.; Flynn, JoAnne L.

2013-01-01

227

miRNA Signatures in Sera of Patients with Active Pulmonary Tuberculosis  

PubMed Central

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

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

2013-01-01

228

Public health aspects of tuberculosis.  

PubMed

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

Blatchford, O; Cameron, J C

2012-01-01

229

38 CFR 3.959 - Tuberculosis.  

Code of Federal Regulations, 2013 CFR

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

2013-07-01

230

38 CFR 3.959 - Tuberculosis.  

Code of Federal Regulations, 2012 CFR

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

2012-07-01

231

38 CFR 3.959 - Tuberculosis.  

Code of Federal Regulations, 2011 CFR

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

2011-07-01

232

38 CFR 3.959 - Tuberculosis.  

Code of Federal Regulations, 2010 CFR

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

2010-07-01

233

Hepatobiliary tuberculosis  

PubMed Central

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

Chaudhary, Poras

2014-01-01

234

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

PubMed

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

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

2010-11-19

235

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

PubMed

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

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

2011-10-01

236

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

PubMed Central

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

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

2013-01-01

237

Bactericidal activity of PA-824 against Mycobacterium tuberculosis under anaerobic conditions and computational analysis of its novel analogues against mutant Ddn receptor  

PubMed Central

Background The resurgence of multi-drug resistant tuberculosis (MDR-TB) and HIV associated tuberculosis (TB) are of serious global concern. To contain this situation, new anti-tuberculosis drugs and reduced treatment regimens are imperative. Recently, a nitroimidazole, PA-824, has been shown to be active against both replicating and non-replicating bacteria. It is activated by the enzyme Deazaflavin-dependent nitroreductase (Ddn) present in Mycobacterium tuberculosis which catalyzes the reduction of PA-824, resulting in the release of lethal reactive nitrogen species (RNS) within the bacteria. In this context, PA-824 was analyzed for its activity against latent tuberculosis under anaerobic conditions and compared with rifampicin (RIF) and pyrazinamide (PZA). Recent mutagenesis studies have identified A76E mutation which affects the above mentioned catalysis and leads to PA-824 resistance. Hence, novel analogues which could cope up with their binding to mutant Ddn receptor were also identified through this study. Results PA-824 at an optimum concentration of 12.5 ?g/ml showed enhanced bactericidal activity, resulting in 0 CFU/ml growth when compared to RIF and PZA at normal pH and anaerobic condition. Further docking studies revealed that a combinatorial structure of PA-824 conjugated with moxifloxacin (ligand 8) has the highest binding affinity with the wild type and mutant Ddn receptor. Conclusions PA-824 has been demonstrated to have better activity under anaerobic condition at 12.5 ?g/ml, indicating an optimized dose that is required for overcoming the detoxifying mechanisms of M. tuberculosis and inducing its death. Further, the development of resistance through A76E mutation could be overcome through the in silico evolved ligand 8.

2013-01-01

238

Enhancement of Mycobacterium tuberculosis-Induced Tumor Necrosis Factor Alpha Production from Primary Human Monocytes by an Activated T-Cell Membrane-Mediated Mechanism  

PubMed Central

Mycobacterium tuberculosis alone induces small, donor-variable amounts of tumor necrosis factor alpha (TNF-?) from primary human monocytes in vitro. However, TNF-? release is increased 5- to 500-fold when fixed activated T cells (FAT) or their isolated, unfixed membranes are added to this system. This FAT-induced synergy was at least as potent as that induced by gamma interferon (IFN-?) at 100 U/ml. FAT-enhanced TNF-? production is at least in part transcriptionally mediated, as reflected by quantitative changes in TNF-? mRNA between 2 and 6 h poststimulation. Unlike IFN-?-cocultured cells, FAT-treated monocytes appeared not to have enhanced TNF-? message stability, suggesting that de novo transcription may be involved in this effect. Furthermore, M. tuberculosis alone induced only minimal DNA binding of monocyte NF-?B, but cells treated with M. tuberculosis and FAT potentiated NF-?B activity more effectively. It is therefore possible that one mechanism by which FAT synergize with M. tuberculosis to stimulate TNF-? production is via NF-?B-enhanced transcription. These data strongly suggest that in the interaction of cells involved in the immune response to M. tuberculosis, T-cell stimulation of monocyte TNF-? production involves a surface membrane interaction(s) as well as soluble mediators.

Warwick-Davies, Jan; Watson, Amanda J.; Griffin, George E.; Krishna, Sanjeev; Shattock, Robin J.

2001-01-01

239

[Tuberculosis in compromised hosts].  

PubMed

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

2003-11-01

240

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

PubMed Central

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

2013-01-01

241

Optimization of pyrrolamides as mycobacterial GyrB ATPase inhibitors: structure-activity relationship and in vivo efficacy in a mouse model of tuberculosis.  

PubMed

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

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

2014-01-01

242

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

PubMed Central

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

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

2014-01-01

243

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

PubMed Central

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

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

2014-01-01

244

Oxidative activation of thiacetazone by the Mycobacterium tuberculosis flavin monooxygenase EtaA and human FMO1 and FMO3.  

PubMed

Thiacetazone (TAZ) and ethionamide (ETA) are, respectively, thiourea- and thioamide-containing second line antitubercular prodrugs for which there is an extensive clinical history of cross-resistance in Mycobacterium tuberculosis. EtaA, a recently identified flavin-containing monooxygenase (FMO), is responsible for the oxidative activation of ETA in M. tuberculosis. We report here that EtaA also oxidizes TAZ and identify a sulfinic acid and a carbodiimide as the isolable metabolites. Both of these metabolites are derived from an initial sulfenic acid intermediate. Oxidation of TAZ by EtaA at basic pH favors formation of the carbodiimide, whereas neutral or acidic conditions favor formation of the sulfinic acid. The same metabolites are formed from TAZ by human FMO1 and FMO3. The sulfenic acid and carbodiimide metabolites, but not the sulfinic acid product, readily react with glutathione, the first to regenerate the parent drug and the second to give a glutathione adduct. These reactions may contribute to the antitubercular activity and/or toxicity of TAZ. PMID:16544950

Qian, Lian; Ortiz de Montellano, Paul R

2006-03-01

245

Oxidative Activation of Thiacetazone by the Mycobacterium tuberculosis Flavin Monooxygenase EtaA and Human FMO1 and FMO3  

PubMed Central

Thiacetazone (TAZ) and ethionamide (ETA) are, respectively, thiourea and thioamide-containing second line antitubercular prodrugs for which there is an extensive clinical history of cross-resistance in Mycobacterium tuberculosis. EtaA, a recently identified flavin-containing monooxygenase (FMO), is responsible for the oxidative activation of ETA in M. tuberculosis. We report here that EtaA also oxidizes TAZ and identify a sulfinic acid and a carbodiimide as the isolable metabolites. Both of these metabolites are derived from an initial sulfenic acid intermediate. Oxidation of TAZ by EtaA at basic pH favors formation of the carbodiimide, whereas neutral or acidic conditions favor formation of the sulfinic acid. The same metabolites are formed from TAZ by human FMO1 and FMO3. The sulfenic acid and carbodiimide metabolites, but not the sulfinic acid product, readily react with glutathione, the first to regenerate the parent drug and the second to give a glutathione adduct. These reactions that may contribute to the antitubercular activity and/or toxicity of TAZ.

Qian, Lian; Ortiz de Montellano, Paul R.

2008-01-01

246

Treatment of Active Pulmonary Tuberculosis in Adults: Current Standards and Recent Advances  

PubMed Central

Tuberculosis is a global pandemic, with 9 million new cases of the disease and approximately 2 million deaths each year. More than 98% of patients treated for tuberculosis in the United States between 1993 and 2007 had drug-susceptible strains. The standard treatment regimen for drug-susceptible tuberculosis has not changed in decades and was developed on the basis of empiric observations of different treatment regimens. Only recently has the veracity of the scientific basis for standard therapy been examined. The backbone of therapy is still isoniazid, rifampin, and pyrazinamide, although fluoroquinolones are being investigated as a replacement for isoniazid. Recent population pharmacokinetic studies have demonstrated the importance of individualized dosing of isoniazid, pyrazinamide, and rifampin. Isoniazid serum clearance differs depending on the patient’s number of N-acetyltransferase 2 gene *4 (NAT2*4) alleles. Pyrazinamide serum clearance has been shown to increase with increases in body weight. Rifampin’s volume of distribution, clearance, and absorption have wide between-patient and within-patient variability. Microbial pharmacokinetic-pharmacodynamic (PK-PD) indexes and targets to optimize microbial killing and minimize resistance have been identified for rifampin, isoniazid, pyrazinamide, and the fluoroquinolones. These PK-PD indexes suggest that different doses and dosing schedules than those currently recommended could optimize therapy and perhaps shorten duration of therapy. Efflux pump inhibition is also being investigated to enhance first-line antituberculosis drug therapy. Comorbid conditions such as diabetes mellitus and genetically determined iron overload syndromes have been associated with significantly worse patient outcomes. Therapy for these and other patient groups needs further improvement. These patient factors, the covariates for pharmacokinetic variability, and PK-PD factors suggest the need to individualize therapy for patients with tuberculosis in order to optimize outcomes and reduce the duration of therapy.

Hall, Ronald G.; Leff, Richard D.; Gumbo, Tawanda

2010-01-01

247

Total Hip Arthroplasty in Patients with Active Tuberculosis of the Hip with Advanced Arthritis  

Microsoft Academic Search

Osteoarticular tuberculosis (TB) in the hip and other joints is increasing and patients in developing countries commonly present\\u000a with advanced joint destruction. We asked whether TB is reactivated after THA in these patients. We retrospectively reviewed\\u000a 12 patients with an average age of 45 years who had advanced stages of hip destruction secondary to mycobacterium TB and who\\u000a were treated with

Devdatta Suhas Neogi; Chandra Shekhar Yadav; Ashok Kumar; Shah Alam Khan; Shishir Rastogi

2010-01-01

248

Active Pulmonary Tuberculosis Case Detection and Treatment Among Floating Population in China: An Effective Pilot  

Microsoft Academic Search

China has more and more floating population because of reform and opening-up. As one of the high burden countries in tuberculosis\\u000a (TB) control in the world, China has to face more challenges about the TB case detection and treatment among floating population\\u000a in China. Aim to evaluate the effect of case detection and treatment of the Floating Population TB Control

Xinxu LiHui; Hui Zhang; Shiwen Jiang; Jia Wang; Xiaoqiu Liu; Weibin Li; Hongyan Yao; Lixia Wang

2010-01-01

249

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

Microsoft Academic Search

Analysis by two-dimensional gel electrophoresis revealed that Mycobacterium avium expresses several pro- teins unique to an intracellular infection. One abundant protein with an apparent molecular mass of 50 kDa was isolated, and the N-terminal sequence was determined. It matches a sequence in the M. tuberculosis database (Sanger) with similarity to the enzyme isocitrate lyase of both Corynebacterium glutamicum and Rhodococcus

KERSTIN HONER; ANDRAS MICZAK; DANA L. SWENSON

1999-01-01

250

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

PubMed

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

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

2011-10-01

251

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

PubMed Central

Background Mycobacterium tuberculosis DNA topoisomerase I is an attractive target for discovery of novel TB drugs that act by enhancing the accumulation of the topoisomerase-DNA cleavage product. It shares a common transesterification domain with other type IA DNA topoisomerases. There is, however, no homology between the C-terminal DNA binding domains of Escherichia coli and M. tuberculosis DNA topoisomerase I proteins. Results A new protocol for expression and purification of recombinant M. tuberculosis DNA topoisomerase I (MtTOP) has been developed to produce enzyme of much higher specific activity than previously characterized recombinant enzyme. MtTOP was found to be less efficient than E. coli DNA topoisomerase I (EcTOP) in removal of remaining negative supercoils from partially relaxed DNA. DNA cleavage by MtTOP was characterized for the first time. Comparison of DNA cleavage site selectivity with EcTOP showed differences in cleavage site preferences, but the preferred sites of both enzymes have a C nucleotide in the -4 position. Conclusion Recombinant M. tuberculosis DNA topoisomerase I can be expressed as a soluble protein and purified in high yield from E. coli host with a new protocol. Analysis of DNA cleavage with M. tuberculosis DNA substrate showed that the preferred DNA cleavage sites have a C nucleotide in the -4 position.

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

2009-01-01

252

Diagnosis and therapy for prostate tuberculosis  

PubMed Central

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

Brizhatyuk, Elena; Khomyakov, Victor

2014-01-01

253

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

PubMed Central

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

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

2013-01-01

254

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

PubMed

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

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

2011-01-01

255

[Tuberculosis among health care workers in Okinawa Prefecture].  

PubMed

In health care setting, transmission of M. tuberculosis (TB) is considerable risk not only to patients but to health care workers (HCWs). The total number of registered TB cases in Okinawa prefecture was 1,202 in 1993-1995 (incidence rate 28.3 per 100,000 in 1995) and that of HCWs was 23. Using data from TB registration system, relative risk of tuberculous disease of nurses was estimated to be 2.3 higher than general population. Nosocomial transmission of TB to HCWs in a general hospital was occurred in 1993. After 2 nurses in the same ward were diagnosed as active pulmonary TB by routine screening chest X-ray, a contact investigation was performed in their family, friends and the ward staffs. On the result of initial evaluation of PPD test, 22 of 26 HCWs were suspected to be infected and preventive therapy with isoniazid were given to 16 HCWs. Follow-up chest radiographs for 3 years revealed 5 HCWs were active TB. According to RFLP analysis of M. tuberculosis isolates, 3 HCWs and 1 patient had identical RFLP pattern to 65-year-old female SLE patient, who was admitted for fever in Nov. 1993 and was diagnosed as miliary tuberculosis after 2 weeks admission. As she had no cough and sputum, the infectiousness of the case was suspected to be increased by cough-inducing procedure. The following TB infection control measures were conducted in the hospital; (1) Education and training to all HCWs for early identification of TB patient and adequate treatment (2) Surveillance and reporting system of TB patient from laboratory and ward to infection-control committee (3) Introduction of PPD test program for HCWs (4) Use of HEPA masks as personal respiratory protection. We need further evaluation of engineering controls e.g. ventilation and isolation room. PMID:10355225

Nakasone, T

1999-04-01

256

Characterization of suspected illegal skin whitening cosmetics.  

PubMed

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

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

2014-03-01

257

Combining Cheminformatics Methods and Pathway Analysis To Identify Molecules With Whole-Cell Activity Against Mycobacterium tuberculosis  

PubMed Central

Purpose New strategies for developing inhibitors of Mycobacterium tuberculosis (Mtb) are required in order to identify the next generation of tuberculosis (TB) drugs. Our approach leverages the integration of intensive data mining and curation and computational approaches, including cheminformatics combined with bioinformatics, to suggest biological targets and their small molecule modulators. Knowledge of which biological targets are essential for Mtb viability, under a given set of in vitro or in vivo assay conditions, and absent in the human host is a crucial input. We draw on the mimicry of the associated “essential metabolites” to suggest small molecule inhibitors of the essential protein target. Empirical studies are then utilized to delineate the effect of the small molecule putative mimic on cultured Mtb growth. Methods We now describe a combined cheminformatics and bioinformatics approach that uses the TBCyc pathway and genome database, the Collaborative Drug Discovery database of molecules with activity against Mtb and their associated targets, a 3D pharmacophore approach and Bayesian models of TB activity in order to select pathways and metabolites and ultimately prioritize molecules that may be acting as metabolite mimics and exhibit activity against TB. Results In this study we combined the TB cheminformatics and pathways databases that enabled us to computationally search >80,000 vendor available molecules and ultimately test 23 compounds in vitro that resulted in two compounds (N-(2-furylmethyl)-N?-[(5-nitro-3-thienyl)carbonyl]thioureaand N-[(5-nitro-3-thienyl)carbonyl]-N?-(2-thienylmethyl)thiourea) proposed as mimics of D-fructose 1,6 bisphosphate, (MIC of 20 and 40?g/ml, respectively). Conclusion This is a simple yet novel approach that has the potential to identify inhibitors of bacterial growth as illustrated by compounds identified in this study that have activity against Mtb.

Sarker, Malabika; Talcott, Carolyn; Madrid, Peter; Chopra, Sidharth; Bunin, Barry A.; Lamichhane, Gyanu; Freundlich, Joel S.; Ekins, Sean

2013-01-01

258

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

Code of Federal Regulations, 2013 CFR

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

2013-07-01

259

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

Code of Federal Regulations, 2010 CFR

...for work-related tuberculosis cases. (a) Basic...known case of active tuberculosis (TB), and that employee...subsequently develops a tuberculosis infection, as evidenced...positive skin test or diagnosis by a physician or...

2010-07-01

260

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

Code of Federal Regulations, 2010 CFR

...for work-related tuberculosis cases. (a) Basic...known case of active tuberculosis (TB), and that employee...subsequently develops a tuberculosis infection, as evidenced...positive skin test or diagnosis by a physician or...

2009-07-01

261

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

Code of Federal Regulations, 2011 CFR

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

2011-07-01

262

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

Code of Federal Regulations, 2012 CFR

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

2012-07-01

263

The identification of tuberculosis biomarkers in human urine samples.  

PubMed

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

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

264

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

PubMed Central

Background Humans infected with Mycobacterium tuberculosis (MTB) can delete the pathogen or otherwise become latent infection or active disease. However, the factors influencing the pathogen clearance and disease progression from latent infection are poorly understood. This study attempted to use a genome-wide transcriptome approach to identify immune factors associated with MTB infection and novel biomarkers that can distinguish active disease from latent infection. Methodology/Principal Findings Using microarray analysis, we comprehensively determined the transcriptional difference in purified protein derivative (PPD) stimulated peripheral blood mononuclear cells (PBMCs) in 12 individuals divided into three groups: TB patients (TB), latent TB infection individuals (LTBI) and healthy controls (HC) (n?=?4 per group). A transcriptional profiling of 506 differentially expressed genes could correctly group study individuals into three clusters. Moreover, 55- and 229-transcript signatures for tuberculosis infection (TB<BI) and active disease (TB) were identified, respectively. The validation study by quantitative real-time PCR (qPCR) performed in 83 individuals confirmed the expression patterns of 81% of the microarray identified genes. Decision tree analysis indicated that three genes of CXCL10, ATP10A and TLR6 could differentiate TB from LTBI subjects. Additional validation was performed to assess the diagnostic ability of the three biomarkers within 36 subjects, which yielded a sensitivity of 71% and specificity of 89%. Conclusions/Significance The transcription profiles of PBMCs induced by PPD identified distinctive gene expression patterns associated with different infectious status and provided new insights into human immune responses to MTB. Furthermore, this study indicated that a combination of CXCL10, ATP10A and TLR6 could be used as novel biomarkers for the discrimination of TB from LTBI.

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

2011-01-01

265

Comparison of histologic techniques for the diagnosis of bovine tuberculosis in the framework of eradication programs.  

PubMed

Rapid diagnosis of tuberculosis in cattle reacting positive in antemortem assays is crucial in countries where eradication programs are operated to confirm the presence of the infection in tuberculosis-free herds. This study evaluated the accuracy of histopathologic examination by hematoxylin and eosin and Ziehl-Neelsen (ZN) staining applied in this framework, when suspected lesions are caused by low infectious doses and are detected in early stages of the disease. For this purpose, histologic methods were compared with mycobacterial culture as reference test on suspected lymph node samples from 173 cattle reacting positive in antemortem tests. Histopathology demonstrated high sensitivity (93.4%) and specificity (92.3%), while ZN sensitivity and specificity were respectively 33.9% and 100%. There was good agreement between histopathology and bacterial culture, suggesting that histopathologic examination is a reliable tool for rapid diagnosis in countries where active tuberculosis eradication programs allow the prompt identification and elimination of reactor cattle. Histopathology permits identification of typical mycobacterial lesions and its differentiation from other causes. PMID:18319428

Varello, Katia; Pezzolato, Marzia; Mascarino, Daniela; Ingravalle, Francesco; Caramelli, Maria; Bozzetta, Elena

2008-03-01

266

Antimicrobial activity of MHC class I-restricted CD8+ T cells in human tuberculosis  

PubMed Central

Studies of mouse models of tuberculosis (TB) infection have indicated a central role for MHC class I-restricted CD8+ T cells in protective immunity. To define antigens and epitopes of Mycobacterium tuberculosis (MTB) proteins that are presented by infected cells to CD8+ T cells, we screened 40 MTB proteins for HLA class I A*0201-binding motifs. Peptides that bound with high affinity to purified HLA molecules were subsequently analyzed for recognition by CD8+ cytotoxic T lymphocytes. We identified three epitopes recognized by CD8+ T cells from patients recovering from TB infection. Those three epitopes were derived from three different antigens: thymidylate synthase (ThyA30–38), RNA polymerase ?-subunit (RpoB127–135), and a putative phosphate transport system permease protein A-1 (PstA175–83). In addition, CD8+ T cell lines specific for three peptides (ThyA30–38, PstA175–83, and 85B15–23) were generated from peripheral blood mononuclear cells of normal HLA-A*0201 donors. These CD8+ T cell lines specifically recognized MTB-infected macrophages, as demonstrated by production of IFN-? and lysis of the infected target cells. Finally, CD8+ cytotoxic T lymphocytes reduced the viability of the intracellular MTB, providing evidence that CD8+ T cell recognition of MHC class I-restricted epitopes of these MTB antigens can contribute to effective immunity against the pathogen.

Cho, Sungae; Mehra, Vijay; Thoma-Uszynski, Sybille; Stenger, Steffen; Serbina, Natalya; Mazzaccaro, Richard J.; Flynn, JoAnne L.; Barnes, Peter F.; Southwood, Scott; Celis, Esteban; Bloom, Barry R.; Modlin, Robert L.; Sette, Alessandro

2000-01-01

267

Target prioritization and strategy selection for active case-finding of pulmonary tuberculosis: a tool to support country-level project planning  

PubMed Central

Background Despite the progress made in the past decade, tuberculosis (TB) control still faces significant challenges. In many countries with declining TB incidence, the disease tends to concentrate in vulnerable populations that often have limited access to health care. In light of the limitations of the current case-finding approach and the global urgency to improve case detection, active case-finding (ACF) has been suggested as an important complementary strategy to accelerate tuberculosis control especially among high-risk populations. The present exercise aims to develop a model that can be used for county-level project planning. Methods A simple deterministic model was developed to calculate the number of estimated TB cases diagnosed and the associated costs of diagnosis. The model was designed to compare cost-effectiveness parameters, such as the cost per case detected, for different diagnostic algorithms when they are applied to different risk populations. The model was transformed into a web-based tool that can support national TB programmes and civil society partners in designing ACF activities. Results According to the model output, tuberculosis active case-finding can be a costly endeavor, depending on the target population and the diagnostic strategy. The analysis suggests the following: (1) Active case-finding activities are cost-effective only if the tuberculosis prevalence among the target population is high. (2) Extensive diagnostic methods (e.g. X-ray screening for the entire group, use of sputum culture or molecular diagnostics) can be applied only to very high-risk groups such as TB contacts, prisoners or people living with human immunodeficiency virus (HIV) infection. (3) Basic diagnostic approaches such as TB symptom screening are always applicable although the diagnostic yield is very limited. The cost-effectiveness parameter was sensitive to local diagnostic costs and the tuberculosis prevalence of target populations. Conclusions The prioritization of appropriate target populations and careful selection of cost-effective diagnostic strategies are critical prerequisites for rational active case-finding activities. A decision to conduct such activities should be based on the setting-specific cost-effectiveness analysis and programmatic assessment. A web-based tool was developed and is available to support national tuberculosis programmes and partners in the formulation of cost-effective active case-finding activities at the national and subnational levels.

2013-01-01

268

Discovery of novel acetohydroxyacid synthase inhibitors as active agents against Mycobacterium tuberculosis by virtual screening and bioassay.  

PubMed

Acetohydroxyacid synthase (AHAS) has been regarded as a promising drug target against Mycobacterium tuberculosis (MTB) as it catalyzes the biosynthesis of branched-chain amino acids. In this study, 23 novel AHAS inhibitors were identified through molecular docking followed by similarity search. The determined IC(50) values range from 0.385 ± 0.026 ?M to >200 ?M against bacterium AHAS. Five of the identified compounds show significant in vitro activity against H37Rv strains (MICs in the range of 2.5-80 mg/L) and clinical MTB strains, including MDR and XDR isolates. More impressively, compounds 5 and 7 can enhance the killing ability against macrophages infected pathogen remarkably. This study suggests our discovered inhibitors can be further developed as novel anti-MTB therapeutics targeting AHAS. PMID:23316686

Wang, Di; Zhu, Xuelian; Cui, Changjun; Dong, Mei; Jiang, Hualiang; Li, Zhengming; Liu, Zhen; Zhu, Weiliang; Wang, Jian-Guo

2013-02-25

269

Sternal tuberculosis.  

PubMed

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

Sachdeva, R; Sachdeva, S; Arora, S

2013-11-01

270

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

PubMed Central

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

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

2012-01-01

271

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

SciTech Connect

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

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

2009-05-26

272

Bilateral Suspected Tuberculous Empyema Thoracis  

PubMed Central

Empyema thoracis is a well known complication following para-pneumonic effusions in paediatric age group. Usually it is unilateral but rarely could be bilateral. Herein we report a case of bilateral tuberculous empyema thoracis in a 12 years old, unvaccinated girl with a positive history of contact with tuberculosis. She was managed conservatively with tube thoracostomies and anti-tuberculous drugs. Emphasis is on the conservative approach and patience in management of patients with bilateral empyema thoracis.

2012-01-01

273

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

PubMed

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

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

274

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

PubMed

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

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

2014-07-01

275

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

PubMed Central

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

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

2013-01-01

276

Functional analysis in mouse embryonic stem cells reveals wild-type activity for three MSH6 variants found in suspected Lynch syndrome patients.  

PubMed

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

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

2013-01-01

277

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

PubMed Central

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

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

2013-01-01

278

Diagnosis of childhood tuberculosis and host RNA expression in Africa.  

PubMed

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

Anderson, Suzanne T; Kaforou, Myrsini; Brent, Andrew J; Wright, Victoria J; Banwell, Claire M; Chagaluka, George; Crampin, Amelia C; Dockrell, Hazel M; French, Neil; Hamilton, Melissa S; Hibberd, Martin L; Kern, Florian; Langford, Paul R; Ling, Ling; Mlotha, Rachel; Ottenhoff, Tom H M; Pienaar, Sandy; Pillay, Vashini; Scott, J Anthony G; Twahir, Hemed; Wilkinson, Robert J; Coin, Lachlan J; Heyderman, Robert S; Levin, Michael; Eley, Brian

2014-05-01

279

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

PubMed Central

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

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

2014-01-01

280

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

PubMed

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

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

2013-01-01

281

Characterization of Phosphofructokinase Activity in Mycobacterium tuberculosis Reveals That a Functional Glycolytic Carbon Flow Is Necessary to Limit the Accumulation of Toxic Metabolic Intermediates under Hypoxia  

PubMed Central

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

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

2013-01-01

282

In vitro activities of levofloxacin used alone and in combination with first- and second-line antituberculous drugs against Mycobacterium tuberculosis.  

PubMed Central

By using the radiometric BACTEC 460-TB methodology, the inhibitory and bactericidal activity of the optically active L-isomer of ofloxacin (levofloxacin) was compared with those of the D-isomer and the commercially available mixture containing equal amounts of DL-isomers (ofloxacin) against the Mycobacterium tuberculosis complex (type strain H37Rv, a panel of drug-susceptible and -resistant clinical isolates including multidrug-resistant isolates of M. tuberculosis, as well as M. africanum, M. bovis, and M. bovis BCG). Levofloxacin MICs (range 0.50 to 0.75 microgram/ml) were about 1 dilution lower than those of ofloxacin (MIC range, 0.75 to 1.00 microgram/ml) and 5 to 6 dilutions lower than those of the D-isomer (MIC range, 32 to 60 micrograms/ml). The MICs of levofloxacin, ofloxacin, and D-ofloxacin at which 90% of the strains are inhibited were 0.50, 1.00, and 64 micrograms/ml, respectively. The multidrug-resistant M. tuberculosis strains resistant to first-line drugs were as susceptible to quinolones as the wild-type drug-susceptible isolates. Levofloxacin at 0.5 microgram/ml showed bactericidal activity comparable to the activities of 1.0 microgram of ofloxacin per ml and 64 micrograms of D-ofloxacin per ml, with MBCs within the range of 0.5 to 2.0 micrograms/ml, compared with MBCs of 0.75 to 4.0 micrograms of ofloxacin per ml for M. tuberculosis, M. africanum, M. bovis BCG. Combination testing of sub-MICs of levolofoxacin with other first-line (isoniazid, rifampin, and ethambutol) and second-line (amikacin and clofazimine) antituberculous drugs was evaluated with various two-, three-, and four-drug combinations; enhanced drug activity was observed in 8 of 25, 12 of 20, and 8 of 15 tests, respectively, indicating that levofloxacin acts in synergy with other antituberculous drugs.

Rastogi, N; Goh, K S; Bryskier, A; Devallois, A

1996-01-01

283

Cost-effectiveness of a tuberculosis active case finding program targeting household and neighborhood contacts in Cambodia.  

PubMed

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

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

2014-05-01

284

Restarting biologics and management of patients with flares of inflammatory rheumatic disorders or psoriasis during active tuberculosis treatment.  

PubMed

Our aim was to review the evidence concerning optimal timing for restarting biologics in patients with active tuberculosis (TB), and the management of relapsing rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and psoriasis during treatment for TB. Few or no indications are available for 2 important challenges for clinicians: the timing for restarting biologics in patients with TB reactivation and the management of the underlying disorder. In the absence of clear evidence, guidelines and experts suggest restarting anti-tumor necrosis factor-? (TNF-?) agents after completion of an active TB therapy course, but no indications are available on the appropriate management of patients with flares of underlying rheumatic disease or psoriasis. Among anti-TNF-? agents, etanercept is associated with the lowest risk of TB reactivation, and non-anti-TNF-? biologics and several nonbiologic drugs are associated with low/no risk of TB reactivation. Therefore, for patients with relapsing RA, PsA, AS, or psoriasis during TB treatment we propose a therapeutic schedule modulated by disease activity and individual single drug-related TB risk. PMID:24789004

Cantini, Fabrizio; Prignano, Francesca; Goletti, Delia

2014-05-01

285

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

PubMed Central

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.

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

2014-01-01

286

Mutational analysis of the (p)ppGpp synthetase activity of the Rel enzyme of Mycobacterium tuberculosis.  

PubMed

RelMtb, a GTP pyrophosphokinase encoded by the Mycobacterium tuberculosis (Mtb) genome, catalyzes synthesis of (p)ppGpp from ATP and GDP(GTP) and its hydrolysis to GDP(GTP) and pyrophosphate to mediate stringent response, which helps bacteria to survive during nutrient limitation. Like other members of Rel_Spo homologs, RelMtb has four distinct domains: HD, Rel_Spo (RSD), TGS and ACT. The N-terminal HD and RSD are responsible for (p)ppGpp hydrolysis and synthesis, respectively. In this study, we have dissected the rel Mtb gene function and determined the minimal region essential for (p)ppGpp synthetic activity. The RelMtb and its truncated derivatives were expressed from an arabinose inducible promoter (P BAD ), and in vivo functional analyses were done in a (p)ppGpp null Escherichia coli strain. Our results indicate that only 243 amino acids (188-430 residues) containing fragment are sufficient for RelMtb (p)ppGpp synthetic activity. The results were further confirmed by in vitro assays using purified proteins. We further characterized the RSD of RelMtb by substituting several conserved amino acids with structurally related residues and identified six such residues, which appeared to be critical for maintaining its catalytic activity. Furthermore, we have also extended our analysis to an RSD encoding gene rv1366 of Mtb, and experimental results indicated that the encoded protein Rv1366 is unable to synthesize (p)ppGpp. PMID:24859914

Bag, Satyabrata; Das, Bhabatosh; Dasgupta, Shreya; Bhadra, Rupak K

2014-08-01

287

CURRENT VIEWS ON GENITOURINARY TUBERCULOSIS  

PubMed Central

Tubercle bacilli are spread by the blood stream to the kidney in miliary fashion from the primary pulmonary lesion. Activation, followed by arrest, may delay development of the disease in the kidney for many years or “healing” may occur. Renal ulcerative lesions are the most frequent source of infection of other genitourinary organs. In pyelograms there is no particular characteristic of lesions of tuberculosis. Cellular elements in the urine of a patient with tuberculosis of other organs should lead to urine culture and guinea pig inoculation for mycobacterium tuberculosis. Treatment with streptomycin, isonicotinic acid and/or para-aminosalicylic acid should be started as soon as genitourinary tuberculosis is proved. Patients with advanced lesions usually receive great benefit from these medications; even though organisms may not be eliminated they are definitely diminished in activity. Excision of diseased organs or tissue may be necessary in a few cases.

Malcolm, Donald C.

1954-01-01

288

Anti-Tuberculosis Activity of ?-Helical Antimicrobial Peptides: De Novo Designed L- and D-Enantiomers Versus L- and D-LL37  

PubMed Central

With the emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis (Mtb), new classes of anti-mycobacterial agents with very different modes of action compared to classical antibiotics, are urgently needed. In this study, a series of 26-residue, amphipathic ?-helical antimicrobial peptides consisting of all D-amino acid residues and synthetic human L-LL37 (L-enantiomer) and D-LL37 (D-enantiomer) were investigated against M. tuberculosis susceptible strain (H37Rv) and a clinical multi-drug resistant strain (Vertulo). Minimal inhibitory concentrations (MICs) were determined through a peptide killing assay. D5, the most active analog against M. tuberculosis had a MIC value of 11.2 ?M (35.2 ?g/ml) against H37Rv strain and 15.6 ?M (49 ?g/ml) against the MDR strain. Peptide D1 had similar activity as D5 against the MDR strain (57 ?g/mL), a 9-fold improvement in hemolytic activity and a 7.4-fold better therapeutic index compared to D5. Surprisingly, LL37 enantiomers showed little to no activity compared to the de-novo designed ?-helical antimicrobial peptides.

Jiang, Ziqing; Higgins, Michael P.; Whitehurst, James; Kisich, Kevin O.; Voskuil, Martin I.; Hodges, Robert S.

2011-01-01

289

Anti-tuberculosis activity of ?-helical antimicrobial peptides: de novo designed L- and D-enantiomers versus L- and D-LL-37.  

PubMed

With the emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis (Mtb), a new class of antimycobacterial agents with very different modes of action compared to classical antibiotics, are urgently needed. In this study, a series of 26-residue, amphipathic, ?-helical antimicrobial peptides consisting of all D-amino acid residues and synthetic human L-LL37 (L-enantiomer) and D-LL37 (D-enantiomer) were investigated against M. tuberculosis susceptible strain (H37Rv) and a clinical multi-drug resistant strain (Vertulo). Minimal inhibitory concentrations (MICs) were determined through a peptide killing assay. D5, the most active analog against M. tuberculosis had a MIC value of 11.2 ?M (35.2 ?g/ml) against H37Rv strain and 15.6 ?M (49 ?g/ml) against the MDR strain. Peptide D1 had similar activity as D5 against the MDR strain (57 ?g/mL), a 9-fold improvement in hemolytic activity and a 7.4-fold better therapeutic index compared to D5. Surprisingly, LL37 enantiomers showed little to no activity compared to the de-novo designed ?-helical antimicrobial peptides. PMID:20858205

Jiang, Ziqing; Higgins, Michael P; Whitehurst, James; Kisich, Kevin O; Voskuil, Martin I; Hodges, Robert S

2011-03-01

290

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

SciTech Connect

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

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

2009-03-02

291

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

Microsoft Academic Search

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

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

2003-01-01

292

Time to detection of the growth of Mycobacterium tuberculosis in MGIT 960 for determining the early bactericidal activity of antituberculosis agents  

Microsoft Academic Search

Evaluation of early bactericidal activity (EBA) by the determination of a fall in viable colony-forming units (CFU) of Mycobacterium tuberculosis in sputum is a first step in the clinical study of new antituberculosis agents. The time to detection (TTD) of growth in\\u000a liquid media is more sensitive and could substitute for CFU counting on solid media. Overnight sputum samples collected

A. H. Diacon; J. S. Maritz; A. Venter; P. D. van Helden; K. Andries; D. F. McNeeley; P. R. Donald

2010-01-01

293

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

Code of Federal Regulations, 2013 CFR

... 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...

2013-07-01

294

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

Code of Federal Regulations, 2012 CFR

... 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...

2012-07-01

295

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

Code of Federal Regulations, 2011 CFR

... 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...

2011-07-01

296

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

Code of Federal Regulations, 2010 CFR

... 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...

2010-07-01

297

[Genital tuberculosis--etiologically proved case report].  

PubMed

We report a clinical case of 36 year old woman with genital tuberculosis, who had no correct diagnosis and treatment for nine months. The etiological diagnosis was set after good collaboration between gynaecologists and microbiologists who had been looking for tuberculosis very active. The laboratory identification was based on conventional and new generation methods: fully automated system and modern molecular tests. The patient responded to anti-tuberculosis therapy and her condition improved. PMID:23234037

Bachiiska, E; Manev, S; Atanasova, Y; Jordanova, S; Kantardzhiev, T

2012-01-01

298

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

PubMed Central

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

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

2013-01-01

299

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

PubMed

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

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

2010-04-01

300

The active ClpP protease from M. tuberculosis is a complex composed of a heptameric ClpP1 and a ClpP2 ring  

PubMed Central

Mycobacterium tuberculosis (Mtb) contains two clpP genes, both of which are essential for viability. We expressed and purified Mtb ClpP1 and ClpP2 separately. Although each formed a tetradecameric structure and was processed, they lacked proteolytic activity. We could, however, reconstitute an active, mixed ClpP1P2 complex after identifying N-blocked dipeptides that stimulate dramatically (>1000-fold) ClpP1P2 activity against certain peptides and proteins. These activators function cooperatively to induce the dissociation of ClpP1 and ClpP2 tetradecamers into heptameric rings, which then re-associate to form the active ClpP1P2 2-ring mixed complex. No analogous small molecule-induced enzyme activation mechanism involving dissociation and re-association of multimeric rings has been described. ClpP1P2 possesses chymotrypsin and caspase-like activities, and ClpP1 and ClpP2 differ in cleavage preferences. The regulatory ATPase ClpC1 was purified and shown to increase hydrolysis of proteins by ClpP1P2, but not peptides. ClpC1 did not activate ClpP1 or ClpP2 homotetradecamers and stimulated ClpP1P2 only when both ATP and a dipeptide activator were present. ClpP1P2 activity, its unusual activation mechanism and ClpC1 ATPase represent attractive drug targets to combat tuberculosis.

Akopian, Tatos; Kandror, Olga; Raju, Ravikiran M; UnniKrishnan, Meera; Rubin, Eric J; Goldberg, Alfred L

2012-01-01

301

Chronic conjunctivitis due to Mycobacterium tuberculosis.  

PubMed

To report the clinical characteristics and treatment outcome in six patients with chronic conjunctivitis due to Mycobacterium tuberculosis. In this retrospective observational case series, all patients with a diagnosis of conjunctival tuberculosis seen in our clinics between January 2000 and January 2010 were reviewed. The clinical presentation, diagnostic investigations and response to medical therapy and outcomes were analyzed. Six patients (age range 15-47 years) were diagnosed with conjunctival tuberculosis. The mean duration from onset of symptoms to diagnosis was 6.5 months (range 1-12 months). Of the six patients, two had ulceration, one had a nodulo-ulcerative lesion, one had bilateral nodular epibulbar masses, and one had a hypertrophied papillary lesion. Systemic signs of tuberculosis were noted in two patients-pleural effusion in one and preauricular and submandibular lymph node involvement in the other. All patients had resolution of symptoms after treatment with four-drug anti-tuberculosis therapy (ATT). None had ocular or systemic recurrences after completion of ATT. Tuberculosis of the conjunctiva can have varied clinical presentation. Although a rare entity, it should be suspected in non-responding chronic conjunctivitis. A high index of suspicion and clinical examination aided by appropriate microbiological and histopathological testing can help in early diagnosis and management. PMID:23928944

Chaurasia, Sunita; Ramappa, Muralidhar; Murthy, Somasheila I; Vemuganti, Geeta K; Fernandes, Merle; Sharma, Savitri; Sangwan, Virender

2014-06-01

302

Tuberculosis and Diabetes  

MedlinePLUS

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

303

Tuberculosis (For Parents)  

MedlinePLUS

Tuberculosis (popularly known as "TB") is a disease caused by the bacteria Mycobacterium tuberculosis . It mainly infects the lungs, although it also ... and Symptoms In older infants and children, latent tuberculosis infection (LTBI), which is the first infection with ...

304

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

PubMed Central

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

2013-01-01

305

Latent tuberculosis: what the host "sees"?  

PubMed Central

Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), is the most successful pathogen of mankind and remains a major threat to global health as the leading cause of death due to a bacterial pathogen. Yet 90–95% of those who are infected with MTB remain otherwise healthy. These people are classified as “latently infected,” but remain a reservoir from which active TB cases will continue to develop (“reactivation tuberculosis”). Latent infection is defined by the absence of clinical symptoms of TB in addition to a delayed hypersensitivity reaction to the purified protein derivative of MTB used in tuberculin skin test or a T-cell response to MTB-specific antigens. In the absence of reliable control measures for tuberculosis, understanding latent MTB infection and subsequent reactivation is a research priority. This review aims to summarize the recent findings in human and non-human primate models of tuberculosis that have led to new concepts of latent tuberculosis.

Gideon, Hannah P.

2013-01-01

306

Smear positive extra pulmonary tuberculosis disease at University of Gondar Hospital, Northwest Ethiopia  

PubMed Central

Background While pulmonary tuberculosis is the most common presentation, extra pulmonary tuberculosis is also an important clinical problem. However, no adequate information had been made available on the prevalence of smear positive extra pulmonary tuberculosis in Gondar. The aim of this study was to assess the prevalence and possible risk factors of smear positive extra pulmonary tuberculosis among suspected patients at University of Gondar Hospital. Methods A cross-sectional study on extra pulmonary tuberculosis suspected patients was conducted at University of Gondar Hospital from January 2012 to April, 2012. Specimens of patients suspected of extra pulmonary tuberculosis were obtained from fine needle aspiration and body fluid samples collected by pathologist. Demographic characteristics and other variables were collected using a pretested semi-structured questionnaire. Smears were prepared from each sample and stained by Ziehel Neelson and Wright stain. The result of the study was analyzed with bivariate and multivariate logistic regression. Result A total of 344 extra pulmonary tuberculosis suspected clients were included in the study and specimens were taken from lymph node aspirates and body fluids. The overall prevalence of smear positive extra pulmonary tuberculosis was 34 (9.9%). Of these cases of extra pulmonary tuberculosis, lymph node tuberculosis constituted the largest proportion (82.4%). Among the 34 extra pulmonary tuberculosis patients, over half of them (52.9%) were positive for human immunodeficiency virus. The largest proportion of tuberculosis and human immunodeficiency virus cases occurred among persons with in the age group of 31–40 years. Previous history of tuberculosis (OR?=?4.77, 95% CI 1.86-12.24), contact to a known tuberculosis cases (OR?=?6.67 95% CI 2.78-16.90), history of underlying diseases (OR?=?2.79 95% CI 1.15-6.78) and income (OR?=?12.9 95% CI 2.25-68.02) were significantly associated with extra pulmonary tuberculosis infection. Conclusion The prevalence of smear positive extra pulmonary tuberculosis infection in Gondar is high. Screening of lymph node and other body fluid specimens for extra pulmonary tuberculosis could help for treatment, control and prevention of the disease.

2013-01-01

307

Amino-terminal extension present in the methionine aminopeptidase type 1c of Mycobacterium tuberculosis is indispensible for its activity  

PubMed Central

Background Methionine aminopeptidase (MetAP) is a ubiquitous enzyme in both prokaryotes and eukaryotes, which catalyzes co-translational removal of N-terminal methionine from elongating polypeptide chains during protein synthesis. It specifically removes the terminal methionine in all organisms, if the penultimate residue is non-bulky and uncharged. The MetAP action for exclusion of N-terminal methionine is mandatory in 50-70% of nascent proteins. Such an activity is required for proper sub cellular localization, additional processing and eventually for the degradation of proteins. Results We cloned genes encoding two such metalloproteases (MtMetAP1a and MtMetAP1c) present in Mycobacterium tuberculosis and expressed them as histidine-tagged proteins in Escherichia coli. Although they have different substrate preferences, for Met-Ala-Ser, we found, MtMetAP1c had significantly high enzyme turnover rate as opposed to MtMetAP1a. Circular dichroism spectroscopic studies as well as monitoring of enzyme activity indicated high temperature stability (up to 50°C) of MtMetAP1a compared to that of the MtMetAP1c. Modelling of MtMetAP1a based on MtMetAP1c crystal structure revealed the distinct spatial arrangements of identical active site amino acid residues and their mutations affected the enzymatic activities of both the proteins. Strikingly, we observed that 40 amino acid long N-terminal extension of MtMetAP1c, compared to its other family members, contributes towards the activity and stability of this enzyme, which has never been reported for any methionine aminopeptidase. Furthermore, mutational analysis revealed that Val-18 and Pro-19 of MtMetAP1c are crucial for its enzymatic activity. Consistent with this observation, molecular dynamic simulation studies of wild-type and these variants strongly suggest their involvement in maintaining active site conformation of MtMetAP1c. Conclusion Our findings unequivocally emphasized that N-terminal extension of MtMetAP1c contributes towards the functionality of the enzyme presumably by regulating active site residues through "action-at-a-distance" mechanism and we for the first time are reporting this unique function of the enzyme.

2011-01-01

308

Engaging communities in tuberculosis research.  

PubMed

According to a growing consensus among biomedical researchers, community engagement can improve the ethics and outcomes of clinical trials. Although successful efforts to develop community engagement practices in HIV/AIDS research have been reported, little attention has been given to engagement with the community in tuberculosis research. This article aims to draw attention to some existing community engagement initiatives in tuberculosis research and to resources that might help tuberculosis researchers to establish and implement community engagement programmes for their trials. One of these resources-the good participatory practice guidelines for tuberculosis drug trials-offers a conceptual framework and practical guidance for community engagement in tuberculosis research. To build momentum and to improve community engagement, lessons need to be shared, and formal assessment strategies for community engagement initiatives need to be developed. To build successfully on the promising activities described in this personal view, research funders and sponsors should show leadership in allocation of resources for the implementation and assessment of community engagement programmes in tuberculosis trials. PMID:23531390

Boulanger, Renaud F; Seidel, Stephanie; Lessem, Erica; Pyne-Mercier, Lee; Williams, Sharon D; Mingote, Laia Ruiz; Scott, Cherise; Chou, Alicia Y; Lavery, James V

2013-06-01

309

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

PubMed Central

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

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

2013-01-01

310

Using Peer Helpers for Tuberculosis Prevention.  

ERIC Educational Resources Information Center

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

McCue, Maureen; Afifi, Larry Anna

1996-01-01

311

System and method for disrupting suspect objects  

SciTech Connect

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

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

2013-07-09

312

Gold(I) analogues of a platinum-acridine antitumor agent are only moderately cytotoxic but show potent activity against Mycobacterium tuberculosis.  

PubMed

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

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

2009-11-12

313

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

PubMed Central

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

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

2011-01-01

314

Abdominal tuberculosis.  

PubMed Central

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

Kapoor, V. K.

1998-01-01

315

Oesophageal tuberculosis  

PubMed Central

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

Bonthala, Latha; Wood, Eleanor

2011-01-01

316

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

PubMed

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

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

2014-03-01

317

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

PubMed

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

Bhaskar; Khonglah, Tashi; Bareh, Jerryson

2013-01-01

318

Pulmonary embolism and tuberculosis.  

PubMed

Tuberculosis has a high prevalence in Tunisia, but pulmonary embolism is rarely reported in Mycobacterium tuberculosis infection. We describe 3 cases of pulmonary embolism associated with severe pulmonary tuberculosis. Pulmonary embolism occurred within 2 to 13 days of pulmonary tuberculosis diagnosis. Clinical, bacteriological, and radiological evolutions were noted within 6 months for pulmonary tuberculosis, but controlling the international normalized ratio was difficult in 2 cases, and low-molecular-weight heparin was prescribed for 6 months in one case. The association between tuberculosis and pulmonary embolism is rare, but it should be systematically investigated, particularly in those with severe pulmonary or disseminated tuberculosis. PMID:24771743

Kwas, Hamida; Habibech, Sonia; Zendah, Ines; Elmjendel, Imen; Ghedira, Habib

2014-05-01

319

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

PubMed Central

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

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

2014-01-01

320

Thiolates Chemically Induce Redox Activation of BTZ043 and Related Potent Nitro Aromatic Anti-Tuberculosis Agents  

PubMed Central

The development of multidrug resistant (MDR) and extensively drug resistant (XDR) forms of tuberculosis (TB) has stimulated research efforts globally to expand the new drug pipeline. Nitro aromatic compounds, including 1, 3-Benzothiazin-4-ones (BTZs) and related agents, are a promising new class for the treatment of TB. Research has shown that the nitroso intermediates of BTZs that are generated in vivo cause suicide inhibition of decaprenylphosphoryl-?-D-ribose 2? oxidase (DprE1), which is responsible for cell wall arabinogalactan biosynthesis. We have designed and synthesized novel anti-TB agents inspired from BTZs and other nitroaromatic compounds. Computational studies indicated that the unsubstituted aromatic carbons of BTZ043 and related nitroaromatic compounds are the most electron deficient and might be prone to nucleophilic attack. Our chemical studies on BTZ043 and the additional nitro aromatic compounds synthesized by us and the others confirmed the postulated reactivity. The results indicate that nucleophiles such as thiolates, cyanide and hydride induce non-enzymatic reduction of the nitro groups present in these compounds to the corresponding nitroso intermediates by addition at the unsubstituted electron deficient aromatic carbon present in these compounds. Furthermore we demonstrate here that these compounds are good candidates for the classical von Richter reaction. These chemical studies offer an alternate hypotheses for the mechanism of action of nitro aromatic anti-TB agents in that the cysteine thiol(ate) or a hydride source at the active site of DprE1 may trigger the reduction of the nitro groups in a manner similar to the von Richter reaction to the nitroso intermediates, to initiate the inhibition of DprE1.

Tiwari, Rohit; Moraski, Garrett C.; Krchnak, Viktor; Miller, Patricia A.; Colon-Martinez, Mariangelli; Herrero, Eliza; Oliver, Allen G.; Miller, Marvin J.

2013-01-01

321

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

PubMed

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

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

1991-01-01

322

Lung cancer, brucellosis and tuberculosis: remarkable togetherness  

PubMed Central

A 68 years old male farmer referred with cough, expectorating sputum, intermittant fever, night sweats, fatigue and anorexia persisting for two weeks. There was a history of 80 packs each year of smoking and he was still an active smoker. Pneumonectomy was performed because of pulmonary epidermoid cancer and he received chemotherapy. He was diagnosed lung tuberculosis and using anti-tuberculous treatment for 4 months. He had a weight loss of 8 kg in last month. His body tempereature was 38.5 °C. Heart rate was 100/min. ESR was 51mm/h and CRP was 5.6 mg/dL. There was no proliferation in blood and sputum cultures. Three sputum specimens were examined and AFB wasn't detected. Fibronodular infiltration was seen in right lower zone of chest X-ray. In thorax CT, fibronodular densities were seen in lower lobe anterior and posterior segments. Brucella melitensis was isolated in blood culture. Second bronchoscopy was performed with suspect of brucellosis pneumonia. Brucella tube agglutination test was positive at titer 1/320 in the bronchial lavage fluid and 1/640 in concurrent serum sample. In cases with chronic cough or pneumonia which is irresponsive to nonspecific antibiotherapy, respiratory brucellosis must be rememberred in endemic areas.

Akkoyunlu, Muhammed Emin; Akkoyunlu, Yasemin; Hakyemez, Ismail Necati; Erboy, Fatma; Arvas, Gulhan; Aslan, Turan

2013-01-01

323

Bactericidal activity of the diarylquinoline TMC207 against Mycobacterium tuberculosis outside and within cells.  

PubMed

The bactericidal activities of the diarylquinoline TMC207 in a liquid culture medium started with a bacteriostatic phase lasting about 7 days and then continued with a dose-related bactericidal phase. In comparison, its intra-cellular activity in primary mouse peritoneal macrophages (PM) and in the J774 macrophage-like cell line had little or no static phase so that the bactericidal kill was evident by 5-7 days presumably due to low bacterial ATP levels. Bactericidal activities in the three systems were compared by estimating the rate of bacterial killing (K) during exposure to 0.12-1.0 ?g/ml TMC207 which were similar at, -0.35 in the J774 cells and -0.27 in mouse PM (p = 0.6) with each lower than -0.11 in extra-cellular cultures (p < 0.001) and [2] the TMC207 concentration at the intersection between the curve relating cfu count to TMC207 concentration and the cfu count at day-0, defined as the static concentration. Static concentrations were 0.22 ?g/ml for extra-cellular cultures, 0.17 ?g/ml for mouse PM and 0.06 ?g/ml for J774 cells, significantly lower than the extra-cellular value (p < 0.001). Thus, the intra-cellular activity of TMC207 is clearly greater than its extra-cellular activity mainly because the preliminary static phase was a shorter or absent. PMID:20732832

Dhillon, Jasvir; Andries, Koen; Phillips, Patrick P J; Mitchison, Denis A

2010-09-01

324

[The effect of long-wave laser radiation on the NADP-dependent dehydrogenase activity of the blood lymphocytes in healthy persons and pulmonary tuberculosis patients].  

PubMed

A study was made to elucidate the in vitro effects of long-wave laser irradiation on NAD(P)-dependent lymphocytic dehydrogenases in peripheral blood of healthy subjects and patients with fibrous-cavernous tuberculosis of the lungs. In addition to suppression of T-cell immunity and reinforcement of humoral factors, such patients demonstrated predominance of catabolic processes over anabolic, reduction of the substrate flow by Krebs cycle. The above phenomena explain different responses to long-wave laser irradiation (632 nm) in healthy subjects and tuberculous patients who are noticed to develop more active transfer of the lipid catabolism products to glycolysis. PMID:8290529

Savchenko, A A; Borisov, A G; Glozman, N E

1993-01-01

325

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

PubMed Central

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

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

2013-01-01

326

Risk of Tuberculosis Reactivation With Tofacitinib (CP-690550)  

PubMed Central

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

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

2012-01-01

327

Brainstem tuberculosis.  

PubMed

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

Demetriou, George A

2013-01-01

328

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

SciTech Connect

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

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

2004-09-15

329

Early Bactericidal Activity of Paromomycin (Aminosidine) in Patients with Smear-Positive Pulmonary Tuberculosis  

Microsoft Academic Search

The early bactericidal activity of the aminoglycoside paromomycin (aminosidine) in doses of 7.5 and 15 mg\\/ kg of body weight was measured in 22 patients with previously untreated smear-positive pulmonary tubercu- losis. The fall in log10 CFU per milliliter of sputum per day during the first 2 days of treatment for 7 patients receiving a paromomycin dosage of 7.5 mg\\/kg\\/day

P. R. Donald; F. A. Sirgel; T. P. Kanyok; L. H. Danziger; A. Venter; F. J. Botha; D. P. Parkin; H. I. Seifart; B. W. Van de Wal; J. S. Maritz; D. A. Mitchison

2000-01-01

330

Central nervous system tuberculosis.  

PubMed

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

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

2014-06-01

331

Tuberculosis biomarkers discovery: developments, needs, and challenges.  

PubMed

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

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

2013-04-01

332

TBNET - Collaborative research on tuberculosis in Europe  

PubMed Central

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

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

2012-01-01

333

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

PubMed

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

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

2013-11-01

334

Peritoneal tuberculosis in laparoscopic era.  

PubMed

Peritoneal tuberculosis is uncommon in developed countries, but as the general incidence of tuberculosis is on the rise in Romania so is the case with peritoneal localization of the disease. The present study retrospectively analyzed 18 patients (8 males and 10 females, mean age 50 years, range 17-74 years) diagnosed in our department with peritoneal tuberculosis between 1995 and 2007. Results: Ascites was present in all but one case. Other common findings were weight loss (12 cases), weakness (5 cases), abdominal pain (16 cases), anorexia (6 cases) and night sweat (3 cases). Abdominal ultrasound has been used to demonstrate ascites in 16 cases. Only two patients had chest radiography suggestive for active tuberculosis. Laparotomy was performed in four cases, laparoscopy in 14 cases (two conversions). Intraoperative findings included multiple diffuse involvements of the visceral and parietal peritoneum, white "miliary nodules" or plaques, enlarged lymph nodes, ascites, "violin string" fibrinous strands, and omental thickening. Biopsy specimens showed granulomas, while ascitic fluid showed numerous lymphocytes. We conclude that the symptoms of abdominal tuberculosis vary greatly, and laparoscopy can be essential for diagnosis and management. The operation is safe, reliable with few complications and permits a prompt diagnosis, necessary to cure the patient. PMID:19341199

Târcoveanu, E; Dimofte, G; Bradea, C; Lupa?cu, C; Moldovanu, R; Vasilescu, A

2009-01-01

335

Tuberculosis in Chronic Care Homes  

PubMed Central

Caucasian Canadians are in the tertiary phase of a 300-year tuberculosis epidemic. In this phase, the pattern of disease over the age spectrum is low in the young and middle-aged groups and rises to four times this rate in the elderly. The concentration of the elderly in chronic care homes (CCHs) magnifies the tuberculosis problem by increasing case rates another four times above the rate of elderly persons living separately, and 20 times above the overall Canadian rate. In spite of effective drugs with cure rates of over 95%, tuberculosis in the institutionalized elderly continues at an alarming rate. The difficulty lies in case finding. The prevailing attitude is that tuberculosis is no longer a problem. Surveillance programs are rudimentary. Between 35% and 40% of active cases in CCHs are the result of primary infection, mimicking bacterial pneumonia clinically and radiographically. In this target group of high-incidence tuberculosis, surveillance of residents is necessary, and the diagnosis needs to be considered in antibiotic-unresponsive pneumonia and in fever of unknown origin.

Hoeppner, Vernon H.; Ring, Edward D.

1987-01-01

336

Computerized feature systems for identifying suspects  

NASA Astrophysics Data System (ADS)

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

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

1995-09-01

337

New drugs to treat tuberculosis  

PubMed Central

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

2012-01-01

338

Surgical management of renal tuberculosis  

PubMed Central

Tuberculosis (TB) is one of the major health problems that our country is facing today. Despite active interventions by our government, control of TB still remains to be achieved. The emergence and exponential growth of the human immunodeficiency virus and drug-resistant strains threaten to further complicate the TB situation in our country. Even in this era of advanced chemotherapy, many lives are lost every day in our country. Tuberculosis of the urinary tract, despite being one of the commonest forms of extra-pulmonary TB, is generally overlooked. Most patients present with vague lower urinary symptoms typical of urinary tract infection. In this article, we shall highlight the various issues related to the surgical management of renal and ureteral tuberculosis.

Krishnamoorthy, Sriram; Gopalakrishnan, Ganesh

2008-01-01

339

Optimal intervention strategies for tuberculosis  

NASA Astrophysics Data System (ADS)

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

Bowong, Samuel; Aziz Alaoui, A. M.

2013-06-01

340

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

PubMed Central

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

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

2013-01-01

341

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

PubMed

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

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

2008-01-01

342

Periodontal disease as the initial oral manifestation of abdominal tuberculosis.  

PubMed

Tuberculosis is a chronic, specific granulomatous disease and a major cause of death in developing countries. We report a case of tuberculosis presenting first as periodontal loss of tooth support leading to loose teeth and gingival enlargement affecting a 17-year-old female patient without any pulmonary lesion. Diagnosis was based on histopathological examination and positive adenosine deaminase activity Mycobacterium tuberculosis test. The clinical presentation of tuberculosis may take many forms. However, with the decline in numbers, tuberculosis lesions of the oral cavity have become so rare that they are frequently overlooked in the differential diagnosis of oral lesions. Also, this case report emphasizes the need for dental clinicians to be aware of the possibility of tuberculosis presenting first in the oral cavity, and contribute in control of tuberculosis through early detection and referring the patients to physicians for proper treatment. PMID:23559932

Javali, Mukhatar Ahmed; Patil, Vishwanath; Ayesha, Humera

2012-09-01

343

Periodontal disease as the initial oral manifestation of abdominal tuberculosis  

PubMed Central

Tuberculosis is a chronic, specific granulomatous disease and a major cause of death in developing countries. We report a case of tuberculosis presenting first as periodontal loss of tooth support leading to loose teeth and gingival enlargement affecting a 17-year-old female patient without any pulmonary lesion. Diagnosis was based on histopathological examination and positive adenosine deaminase activity Mycobacterium tuberculosis test. The clinical presentation of tuberculosis may take many forms. However, with the decline in numbers, tuberculosis lesions of the oral cavity have become so rare that they are frequently overlooked in the differential diagnosis of oral lesions. Also, this case report emphasizes the need for dental clinicians to be aware of the possibility of tuberculosis presenting first in the oral cavity, and contribute in control of tuberculosis through early detection and referring the patients to physicians for proper treatment.

Javali, Mukhatar Ahmed; Patil, Vishwanath; Ayesha, Humera

2012-01-01

344

Tuberculosis IRIS: a mediastinal problem  

PubMed Central

We present a case of a 39 year old male patient with Acquired Immune Deficiency Syndrome (AIDS) who developed Mycobacterium tuberculosis related Immune Reconstitution Inflammatory Syndrome (IRIS) after initiation of Highly Active Antiretroviral Therapy (HAART) treatment. The inflammatory response resulted in mediastinal necrotic lymphadenopathy and subsequent perforation of the esophageal wall.

Valentin, Leonardo

2013-01-01

345

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

PubMed Central

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

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

2011-01-01

346

Guidelines for identifying suspect/counterfeit material  

SciTech Connect

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

NONE

1995-09-01

347

The Phenomenology of Specialization of Criminal Suspects  

PubMed Central

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

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

2013-01-01

348

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

PubMed

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

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

2012-05-15

349

Tuberculosis (TB): Treatment  

MedlinePLUS

... Iseman, MD Dept. of Medicine View full profile 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 ...

350

Play the Tuberculosis Game  

MedlinePLUS

... Malaria MRI Nerve Signaling Pavlov's Dog Split Brain Experiments The Cell and its Organelles The Genetic Code ... Life and Work Teachers' Questionnaire Tuberculosis Play Tuberculosis Experiments & Discoveries About the game Discover and experience some ...

351

Trends in Tuberculosis, 2012  

MedlinePLUS

... Laws Publications & Products Fact Sheets General Fact sheets - Spanish TB - General Information The Difference Between Latent TB ... HIV Coinfection Patient Education Series English Only English/Spanish English/Tagalog Tuberculosis - Get the Facts Tuberculosis - La ...

352

Tuberculosis in Blacks  

MedlinePLUS

... Laws Publications & Products Fact Sheets General Fact sheets - Spanish TB - General Information The Difference Between Latent TB ... HIV Coinfection Patient Education Series English Only English/Spanish English/Tagalog Tuberculosis - Get the Facts Tuberculosis - La ...

353

[Detection of mycobacteria tuberculosis in patients with urogenital tuberculosis by PCR method].  

PubMed

The study was carried out in hospital patients as well as in outpatients at the National Centre of Tuberculosis and Lung Diseases of Georgia (2002-2004). The group consisting of 32 patients with tuberculosis of urogenital system has been studied (newly detected forms). Except clinical laboratory, culture and X-ray contrast methods, two additional methods were used in testing of this group of patients. The examination of their urine, at the same time, was carried out by the Polymerase Chain Reaction method in order to detect Kochi bacillus and by three-time bacterioscopy of urine for acid resistant bacteria. Mycobacterium tuberculosis in urine has been detected in 26 (81,25%) patients by PCR method, and by urine bacterioscopy--acid fast bacilli (AFB+) in 18 (56,25%) patients. The histo-morphological investigation of specimens obtained by surgery confirmed the TB diagnosis in all patients. This study on patients suspected of Tuberculosis of genital-urinary system gives us an opportunity to update the diagnostic algorithm by including the modern molecular methods. This algorithm will help in timely detection of Tuberculosis, in selection of adequate therapy and in prevention of the further progression of the disease. PMID:15834172

Dochviri, T Z; Katsitadze, V A; Khosiashvili, G Z; Chigogidze, T G

2005-02-01

354

[Tuberculosis as occupational disease].  

PubMed

There is enough evidence to declare tuberculosis as an occupational disease among healthcare workers. In Peru, there are regulations granting employment rights regarding tuberculosis as an occupational disease, such as healthcare coverage for temporary or permanent disability. However, these rights have not been sufficiently socialized. This study presents information on the risk of acquiring tuberculosis in the workplace, and a review of the evidence to declare tuberculosis as an occupational disease among health care workers, presenting the current Peruvian law related. PMID:22858771

Mendoza-Ticona, Alberto

2012-06-01

355

Bilateral Parotid Tuberculosis  

PubMed Central

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.

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

2011-01-01

356

Characterization of the memory/activated T cells that mediate the long-lived host response against tuberculosis after bacillus Calmette-Gu?rin or DNA vaccination  

PubMed Central

The memory/activated T cells, which mediate the long-lived host response against tuberculosis, in mice immunized with either bacillus Calmette–Guérin (BCG) or mycobacterium heat-shock protein 65 (hsp 65) antigen expressed from plasmid DNA (DNA-hsp 65), were characterized. Protection against Mycobacterium tuberculosis challenge by DNA-hsp 65 vaccination was associated with the presence of lymph node T-cell populations in which CD8+/CD44hi interferon-? (IFN-?)-producing/cytotoxic cells were prominent even after 8 or 15 months of plasmid DNA-mediated immunizations, whereas after BCG vaccination the majority were CD4+/CD44lo IFN-?-producing T cells. When the cells were separated into CD4+CD8? and CD8+CD4? and then into CD44hi and CD44lo types, CD44lo cells were essentially unable to transfer protection in adoptive transfer experiments, the most protective CD44hi cells were CD8+CD4? and those from DNA-vaccinated mice were much more protective than those from BCG-immunized mice. The frequency of protective T cells and the level of protection were increased up to 8 months and decreased after 15 months following DNA or BCG immunizations.

Silva, C L; Bonato, V L D; Lima, V M F; Faccioli, L H; Leao, S C

1999-01-01

357

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

PubMed

Sputum induction, bronchoalveolar lavage, or gastric aspiration are often needed to produce adequate diagnostic respiratory samples from people with HIV in whom tuberculosis is suspected. Since these procedures are rarely appropriate in less-developed countries, we compared the performances of a simple string test and the gold-standard sputum induction. 160 HIV-positive adults under investigation for tuberculosis, and 52 asymptomatic HIV-positive control patients underwent the string test followed by sputum induction. The string test detected tuberculosis in 14 patients in whom this disease was suspected; sputum induction detected only eight of them (McNemar's test, p=0.03). These preliminary data suggest that the string test is safe and effective for retrieval of useful clinical specimens for diagnosis of pulmonary tuberculosis, and is at least as sensitive as sputum induction. PMID:15639297

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

358

Isolated colonic tuberculosis  

Microsoft Academic Search

Two cases of isolated colonic tuberculosis are reported, and recent literature on this field is reviewed. Isolated colonic tuberculosis is defined as a tuberculosis which exists in the colon except for ileocaecum, without focus in any other organ. The morphological changes are tuberculous granulation primarily located to the submucosa layer of the colon with smooth surfaces of both mucous and

Y. A. Wang; W. Y. Yu

1987-01-01

359

Growth hormone activation of human monocytes for superoxide production but not tumor necrosis factor production, cell adherence, or action against Mycobacterium tuberculosis.  

PubMed Central

We have previously demonstrated that growth hormone (GH) is a human macrophage-activating factor which primes monocytes for enhanced production of H2O2 in vitro. This report extends our observations to other monocyte functions relevant to infection. We find that GH also primes monocytes for O2- production, to a degree similar to the effect of gamma interferon. Neither macrophage-activating factor alone stimulates monocytes to release bioactive tumor necrosis factor. However, GH, unlike gamma interferon, does not synergize with endotoxin for enhanced tumor necrosis factor production. In further contrast, GH does not alter monocyte adherence or morphology, while phagocytosis and killing of Mycobacterium tuberculosis by GH-treated monocytes are also unaffected. Therefore, despite the multiplicity of the effects of GH on the immune system in vivo, its effects on human monocytes in vitro appear to be limited to priming for the release of reactive oxygen intermediates.

Warwick-Davies, J; Lowrie, D B; Cole, P J

1995-01-01

360

Suspected myotoxicity of edible wild mushrooms.  

PubMed

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

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

2006-02-01

361

Tuberculosis among health care workers.  

PubMed

To assess the annual risk for latent tuberculosis infection (LTBI) among health care workers (HCWs), the incidence rate ratio for tuberculosis (TB) among HCWs worldwide, and the population-attributable fraction of TB to exposure of HCWs in their work settings, we reviewed the literature. Stratified pooled estimates for the LTBI rate for countries with low (<50 cases/100,000 population), intermediate (50-100/100,000 population), and high (>100/100,000 population) TB incidence were 3.8% (95% confidence interval [CI] 3.0%-4.6%), 6.9% (95% CI 3.4%-10.3%), and 8.4% (95% CI 2.7%-14.0%), respectively. For TB, estimated incident rate ratios were 2.4 (95% CI 1.2-3.6), 2.4 (95% CI 1.0-3.8), and 3.7 (95% CI 2.9-4.5), respectively. Median estimated population-attributable fraction for TB was as high as 0.4%. HCWs are at higher than average risk for TB. Sound TB infection control measures should be implemented in all health care facilities with patients suspected of having infectious TB. PMID:21392441

Baussano, Iacopo; Nunn, Paul; Williams, Brian; Pivetta, Emanuele; Bugiani, Massimiliano; Scano, Fabio

2011-03-01

362

Acute Myeloid Leukemia Presenting with Pulmonary Tuberculosis  

PubMed Central

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

Thomas, Merlin; AlGherbawe, Mushtak

2014-01-01

363

Spectroscope: Fingerprinting the Luminous Suspects  

NSDL National Science Digital Library

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

364

Beyond the IFN-? horizon: biomarkers for immunodiagnosis of infection with Mycobacterium tuberculosis.  

PubMed

Latent infection with Mycobacterium tuberculosis (LTBI) is defined by the presence of M. tuberculosis-specific immunity in the absence of active tuberculosis. LTBI is detected using interferon-? release assays (IGRAs) or the tuberculin-skin-test (TST). In clinical practice, IGRAs and the TSTs have failed to distinguish between active tuberculosis and LTBI and their predictive value to identify individuals at risk for the future development of tuberculosis is limited. There is an urgent need to identify biomarkers that improve the clinical performance of current immunodiagnostic methods for tuberculosis prevention, diagnosis and treatment monitoring. Here, we review the landscape of potential alternative biomarkers useful for detection of infection with M. tuberculosis. We describe what individual markers add in terms of specificity for active/latent infection, prediction of progression to active tuberculosis and immunodiagnostic potential in high-risk groups' such as HIV-infected individuals and children. PMID:24311770

Chegou, Novel N; Heyckendorf, Jan; Walzl, Gerhard; Lange, Christoph; Ruhwald, Morten

2014-05-01

365

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

Microsoft Academic Search

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

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

2006-01-01

366

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

PubMed Central

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

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

2012-01-01

367

A case study of female genital tuberculosis in a Western European setting.  

PubMed

We have studied five women with genital tuberculosis (TB), which is an uncommon disease in Western European countries. However, young women that have emigrated from a country with high TB-prevalence and have complaints of unexplained infertility and nonspecific abdominal or pelvic symptoms should be checked for this disease. Because genital tuberculosis frequently causes infertility, early diagnosis and treatment are crucial, necessitating rapid microscopic, histological, and microbiological (culture) testing in suspected cases. PMID:21153428

Kocher, C; Weber, R; Friedl, A

2011-02-01

368

Isolation Rates of Mycobacterium tuberculosis from Smear-negative and Smear-positive Sputum Specimen Using the Ogawa Culture Technique and the Standard Lowenstein Jensen Culture Technique  

Microsoft Academic Search

A study to determine the efficacy of 3% Ogawa Vs Lowenstein-Jensen (LJ) culture media for culture isolation of Mycobacterium tuberculosis (M. tb) from smear positive and smear negative sputum specimen from patients suspected of pulmonary tuberculosis was conducted at the Medical Microbiology Research Laboratory, Philippine General Hospital, University of the Philippines Manila Sputum specimen received from the medical wards and

Concepcion F. Ang; Myrna T. Mendoza; Heidi R. Santos; Regina Celada-Ong; Carmela P. Enrile; Wilma C. Bulatao; Aileen M. Aguila

369

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

Microsoft Academic Search

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

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

370

Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis.  

PubMed

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

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

2011-12-01

371

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

PubMed

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

Choi, Eun Kyung

2013-12-01

372

Effect of cyclopiazonic acid on delayed hypersensitivity to Mycobacterium tuberculosis , complement activity, serum enzymes, and bilirubin in guinea pigs  

Microsoft Academic Search

Cyclopiazonic acid (CPA) was given daily to groups of guinea pigs at doses of 0.00625, 0.0125, 0.025, 0.05, 0.1, 0.2, 0.4, 0.8, 1.6, and 1.95 mg\\/day for 30 days. All guinea pigs were sensitized and survivors were skin tested twenty-five days later with Mycobacterium tuberculosis. Mortalities occurred only in the two greatest dose groups. Signs of disease included anorexia, roughened

John L. Richard; W. Michael Peden; Rod E. Fichtner; Richard J. Cole

1986-01-01

373

Mycobacterium tuberculosis produces pili during human infection  

PubMed Central

Mycobacterium tuberculosis is responsible for nearly 3 million human deaths worldwide every year. Understanding the mechanisms and bacterial factors responsible for the ability of M. tuberculosis to cause disease in humans is critical for the development of improved treatment strategies. Many bacterial pathogens use pili as adherence factors to colonize the host. We discovered that M. tuberculosis produces fine (2- to 3-nm-wide), aggregative, flexible pili that are recognized by IgG antibodies contained in sera obtained from patients with active tuberculosis, indicating that the bacilli produce pili or pili-associated antigen during human infection. Purified M. tuberculosis pili (MTP) are composed of low-molecular-weight protein subunits encoded by the predicted M. tuberculosis H37Rv ORF, designated Rv3312A. MTP bind to the extracellular matrix protein laminin in vitro, suggesting that MTP possess adhesive properties. Isogenic mtp mutants lost the ability to produce Mtp in vitro and demonstrated decreased laminin-binding capabilities. MTP shares morphological, biochemical, and functional properties attributed to bacterial pili, especially with curli amyloid fibers. Thus, we propose that MTP are previously unidentified host-colonization factors of M. tuberculosis.

Alteri, Christopher J.; Xicohtencatl-Cortes, Juan; Hess, Sonja; Caballero-Olin, Guillermo; Giron, Jorge A.; Friedman, Richard L.

2007-01-01

374

An Epidemic of Tuberculosis with a High Rate of Tuberculin Anergy among a Population Previously Unexposed to Tuberculosis, the Yanomami Indians of the Brazilian Amazon  

Microsoft Academic Search

A survey of an emerging tuberculosis epidemic among the Yanomami Indians of the Amazonian rain forest provided a unique opportunity to study the impact of tuberculosis on a population isolated from contact with the tubercle bacillus for millennia until the mid-1960s. Within the Yanomami population, an extraordinary high prevalence of active tuberculosis (6.4% of 625 individuals clinically examined) was observed,

Alexandra O. Sousa; Julia I. Salem; Francis K. Lee; Maria C. Vercosa; Philippe Cruaud; Barry R. Bloom; Philippe H. Lagrange; Hugo L. David

1997-01-01

375

Cutaneous tuberculosis in children.  

PubMed

Cutaneous tuberculosis is a rare form of extrapulmonary tuberculosis that accounts for 1% to 2% of cases. Childhood skin tuberculosis represents 18% to 82% of all cutaneous tuberculosis cases. Scrofuloderma and lupus vulgaris are the two most common clinical forms in children. An increase in the number of tuberculids, especially lichen scrofulosorum, has been observed in the last several years. Cutaneous tuberculosis in children can be severe and have a protracted course. Multiplicity of lesions and multifocal disseminated involvement in scrofuloderma and lupus vulgaris is common. Scrofuloderma progressing to gummatous lesions (scrofulous gumma) is mostly described in children. Morbidities and deformities are more severe in children. PMID:23173930

Sethuraman, Gomathy; Ramesh, Venkatesh

2013-01-01

376

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

PubMed Central

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

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

2013-01-01

377

Congenital transmission of multidrug-resistant tuberculosis.  

PubMed

This article presents a case of multidrug-resistant tuberculosis (TB) in a Peruvian infant. His mother was diagnosed with disseminated TB, and treatment commenced 11 days postpartum. The infant was diagnosed with TB after 40 days and died at 2 months and 2 days of age. Congenital transmission of TB to the infant was suspected, because direct postpartum transmission was considered unlikely; also, thorough screening of contacts for TB was negative. Spoligotyping confirmed that both mother and baby were infected with identical strains of the Beijing family (SIT1). PMID:24821847

Espiritu, Nora; Aguirre, Lino; Jave, Oswaldo; Sanchez, Luis; Kirwan, Daniela E; Gilman, Robert H

2014-07-01

378

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

Microsoft Academic Search

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

Dermot Maher

2010-01-01

379