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does choice matter? reference-based alignment for molecular epidemiology of tuberculosis.when using genome sequencing for molecular epidemiology, short sequence reads are aligned to an arbitrary reference strain to detect single nucleotide polymorphisms. we investigated whether reference genome selection influences epidemiological inferences of mycobacterium tuberculosis transmission by aligning sequence reads from 162 closely related lineage 4 (euro-american) isolates to 7 different genomes. phylogenetic trees were consistent with use of all but the most divergent genomes, suggesti ...201627076659
a cohesive and integrated platform for immunogenicity prediction.in silico methods for immunogenicity prediction mine the enormous quantity of data arising from deciphered genomes and proteomes to identify immunogenic proteins. while high and productive immunogenicity is essential for vaccines, therapeutic proteins and monoclonal antibodies should be minimally immunogenic. here, we present a cohesive platform for immunogenicity and mhc class i and/or ii binding affinity prediction. the platform integrates three quasi-independent modular servers: vaxijen, epij ...201627076336
delamanid susceptibility testing of mycobacterium tuberculosis using the resazurin microtitre assay and the bactec™ mgit™ 960 system.the objective of this study was to develop standardized protocols for rapid delamanid drug susceptibility testing (dst) using the colorimetric resazurin microtitre assay (rema) and semi-automated bactec™ mgit™ 960 system (mgit) by establishing breakpoints that accurately discriminate between susceptibility and resistance of mycobacterium tuberculosis to delamanid.201627076101
dietary cholesterol increases the risk whereas pufas reduce the risk of active tuberculosis in singapore chinese.experimental studies suggest that cholesterol enhances the intracellular survival of mycobacterium tuberculosis, whereas marine ω-3 (n-3) and ω-6 (n-6) fatty acids (fas) may modulate responses to m. tuberculosis in macrophage and animal models. however, there are no epidemiologic data from prospective studies of the relation between dietary cholesterol and fas and the risk of developing active tuberculosis.201627075903
low-density granulocytes are elevated in mycobacterial infection and associated with the severity of tuberculosis.tuberculosis remains a global health problem caused by infection with mycobacterium tuberculosis. numerous studies have established a close correlation between the development of tuberculosis and the roles of neutrophils. recently, a distinct population of cd15+ granulocytes was found to be present in the peripheral blood mononuclear cell (pbmc) fraction in humans. this population of granulocytes, termed low-density granulocytes (ldgs), was reported to be elevated and associated with disease act ...201627073889
diverse molecular genotypes of mycobacterium tuberculosis complex isolates circulating in the free state, south africa.tuberculosis is a serious public health concern especially in africa and asia. studies describing strain diversity are lacking in the free state region of south africa. the aim of the study was to describe the diversity of mycobacterium tuberculosis (m. tuberculosis) strain families in the free state province of south africa. a total of 86 m. tuberculosis isolates were genotyped using spoligotyping. a 12-locus mycobacterial interspersed repetitive units-variable-number tandem repeats (miru-vntrs ...201627073397
identification of hla-a*11:01-restricted mycobacterium tuberculosis cd8(+) t cell epitopes.new vaccines are needed to combat mycobacterium tuberculosis (mtb) infections. the currently employed bacillus calmette-guérin vaccine is becoming ineffective, due in part to the emergence of multidrug-resistant tuberculosis (mdr-tb) strains and the reduced immune capacity in cases of hiv coinfection. cd8(+) t cells play an important role in the protective immunity against mtb infections, and the identification of immunogenic cd8(+) t cell epitopes specific for mtb is essential for the design of ...201627072810
the potential role of trimethoprim-sulfamethoxazole in the treatment of drug-resistant tuberculosis.tuberculosis (tb) remains a serious public health threat worsened by emerging drug resistance. mycobacterium tuberculosis has become resistant not only to front-line drugs but also to second-line antimicrobials directed at drug-resistant tb. renewed efforts are devoted for the development of new antibiotics active against tb. also, repurposing of other antibiotics is being explored to shorten the time to develop new drugs against m. tuberculosis. as a result, trimethoprim-sulfamethoxazole (sxt) ...201627070731
drug resistant strains of mycobacterium tuberculosis identified through pcr-rflp from patients of central punjab, pakistan.the study was carried out to determine, by pcr-rflp, the magnitude of drug resistance in mycobacterium tuberculosis the study was carried out on 221 random sputum samples collected from patients and 120 suspected cases of drug resistance. genetic variation in drug-resistant strains was evaluated through pcr-rflp for isoniazid, ethambutol, streptomycin, and ofloxacin. out of 341 patients, 91.5% were confirmed as m. tuberculosis complex infected on the basis of pcr. the random samples revealed res ...201627069023
t-cell activation is an immune correlate of risk in bcg vaccinated infants.vaccines to protect against tuberculosis (tb) are urgently needed. we performed a case-control analysis to identify immune correlates of tb disease risk in bacille calmette-guerin (bcg) immunized infants from the mva85a efficacy trial. among 53 tb case infants and 205 matched controls, the frequency of activated hla-dr(+) cd4(+) t cells associates with increased tb disease risk (or=1.828, 95% ci=1.25-2.68, p=0.002, fdr=0.04, conditional logistic regression). in an independent study of mycobacter ...201627068708
antimicrobial resistance in mycobacterium tuberculosis: the odd one out.antimicrobial resistance (amr) threats are typically represented by bacteria capable of extensive horizontal gene transfer (hgt). one clear exception is mycobacterium tuberculosis (mtb). it is an obligate human pathogen with limited genetic diversity and a low mutation rate which lacks any evidence for hgt. such features should, in principle, reduce its ability to rapidly evolve amr. we identify key features in its biology and epidemiology that allow it to overcome its low adaptive potential. we ...201627068531
thioridazine alters the cell-envelope permeability of mycobacterium tuberculosis.the increasing occurrence of multidrug resistant tuberculosis exerts a major burden on treatment of this infectious disease. thioridazine, previously used as a neuroleptic, is active against extensively drug resistant tuberculosis when added to other second- and third-line antibiotics. by quantitatively studying the proteome of thioridazine-treated mycobacterium tuberculosis, we discovered the differential abundance of several proteins that are involved in the maintenance of the cell-envelope pe ...201627068340
pharmacokinetic evaluation of sulfamethoxazole at 800 milligrams once daily in the treatment of tuberculosis.for treatment of multidrug-resistant tuberculosis (mdr-tb), there is a scarcity of antituberculosis drugs. co-trimoxazole is one of the available drug candidates, and it is already frequently coprescribed for tb-hiv-coinfected patients. however, only limited data are available on the pharmacokinetic (pk) and pharmacodynamic (pd) parameters of co-trimoxazole in tb patients. the objective of this study was to evaluate the pk parameters and in vitro pd data on the effective part of co-trimoxazole: ...201627067336
mycobacterium tuberculosis zinc metalloprotease-1 elicits tuberculosis-specific humoral immune response independent of mycobacterial load in pulmonary and extra-pulmonary tuberculosis patients.conventionally, facultative intracellular pathogen, mycobacterium tuberculosis, the tuberculosis (tb) causing bacilli in human is cleared by cell-mediated immunity (cmi) with cd4(+) t cells playing instrumental role in protective immunity, while antibody-mediated immunity (ami) is considered non-protective. this longstanding convention has been challenged with recent evidences of increased susceptibility of hosts with compromised ami and monoclonal antibodies conferring passive protection agains ...201627065979
the small breathing amplitude at the upper lobes favors the attraction of polymorphonuclear neutrophils to mycobacterium tuberculosis lesions and helps to understand the evolution toward active disease in an individual-based model.infection with mycobacterium tuberculosis (mtb) can induce two kinds of lesions, namely proliferative and exudative. the former are based on the presence of macrophages with controlled induction of intragranulomatous necrosis, and are even able to stop its physical progression, thus avoiding the induction of active tuberculosis (tb). in contrast, the most significant characteristic of exudative lesions is their massive infiltration with polymorphonuclear neutrophils (pmns), which favor enlargeme ...201627065951
computational and empirical studies predict mycobacterium tuberculosis-specific t cells as a biomarker for infection outcome.identifying biomarkers for tuberculosis (tb) is an ongoing challenge in developing immunological correlates of infection outcome and protection. biomarker discovery is also necessary for aiding design and testing of new treatments and vaccines. to effectively predict biomarkers for infection progression in any disease, including tb, large amounts of experimental data are required to reach statistical power and make accurate predictions. we took a two-pronged approach using both experimental and ...201627065304
pleural fluid tests to diagnose tuberculous pleuritis.this article summarizes current data regarding the accuracy of pleural fluid tests assisting the diagnosis of tuberculous pleuritis (tbp).201627064428
genomic and functional analyses of mycobacterium tuberculosis strains implicate ald in d-cycloserine resistance.a more complete understanding of the genetic basis of drug resistance in mycobacterium tuberculosis is critical for prompt diagnosis and optimal treatment, particularly for toxic second-line drugs such as d-cycloserine. here we used the whole-genome sequences from 498 strains of m. tuberculosis to identify new resistance-conferring genotypes. by combining association and correlated evolution tests with strategies for amplifying signal from rare variants, we found that loss-of-function mutations ...201627064254
in vitro activity of (-)-deoxypergularinine, on its own and in combination with anti-tubercular drugs, against resistant strains of mycobacterium tuberculosis.the increasing incidence of multidrug-resistant tuberculosis (mdr-tb) infections has created a need for new effective drugs that also target extensively drug-resistant tuberculosis (xdr-tb) and/or augment the activities of existing drugs against tuberculosis.201627064017
benzo[d]thiazol-2-yl(piperazin-1-yl)methanones as new anti-mycobacterial chemotypes: design, synthesis, biological evaluation and 3d-qsar studies.the benzo[d]thiazol-2-yl(piperazin-1-yl)methanones scaffold has been identified as new anti-mycobacterial chemotypes. thirty-six structurally diverse benzo[d]thiazole-2-carboxamides have been prepared and subjected to assessment of their potential anti-tubercular activity through in vitro testing against mycobacterium tuberculosis h37rv strain and evaluation of cytotoxicity against raw 264.7 cell lines. seventeen compounds showed anti-mycobacterial potential having mics in the low (1-10) μm rang ...201627061982
the ag85b protein of the bcg vaccine facilitates macrophage uptake but is dispensable for protection against aerosol mycobacterium tuberculosis infection.defining the function and protective capacity of mycobacterial antigens is crucial for progression of tuberculosis (tb) vaccine candidates to clinical trials. the ag85b protein is expressed by all pathogenic mycobacteria and is a component of multiple tb vaccines under evaluation in humans. in this report we examined the role of the bcg ag85b protein in host cell interaction and vaccine-induced protection against virulent mycobacterium tuberculosis infection. ag85b was required for macrophage in ...201627060378
mathematical modeling and systems pharmacology of tuberculosis: isoniazid as a case study.tuberculosis (tb) treatment needs to be optimized as it is currently long and associated with increasing drug resistance. the antimycobacterial effect of isoniazid (inh) is characterized by a biphasic kill curve, whose causes are still debated. in this work, we developed a complete mathematical model describing the time-course of tb infection and its treatment by inh in human lung. this model was based on a pharmacokinetic model, a pharmacodynamic model and a pathophysiological model. it was use ...201627059890
[multicenter evaluation of the indirect nitrate reductase assay for the rapid detection of multidrug-resistant tuberculosis].multidrug-resistant tuberculosis (mdr-tb) is defined as resistance to at least isoniazid (inh) and rifampicin (rif), and it complicates the implementation of tuberculosis control programmes. the rapid detection of mdr-tb is crucial to reduce the transmission of disease. the nitrate reductase assay (nra) is one of the colorimetric susceptibility test methods for rapid detection of mdr-tb and based on the ability of reduction of nitrate to nitrite by mycobacterium tuberculosis. the aim of this stu ...201627058338
diabetes mellitus and increased tuberculosis susceptibility: the role of short-chain fatty acids.type 2 diabetes mellitus confers a threefold increased risk for tuberculosis, but the underlying immunological mechanisms are still largely unknown. possible mediators of this increased susceptibility are short-chain fatty acids, levels of which have been shown to be altered in individuals with diabetes. we examined the influence of physiological concentrations of butyrate on cytokine responses to mycobacterium tuberculosis (mtb) in human peripheral blood mononuclear cells (pbmcs). butyrate decr ...201627057552
comparison of isothermal helicase-dependent amplification and pcr for the detection of mycobacterium tuberculosis by an electrochemical genomagnetic assay.methods for the early and sensitive detection of pathogenic bacteria suited to low-resource settings could impact diagnosis and management of diseases. helicase-dependent isothermal amplification (hda) is an ideal tool for this purpose, especially when combined with a sequence-specific detection method able to improve the selectivity of the assay. the implementation of this approach requires that its analytical performance is shown to be comparable with the gold standard method, polymerase chain ...201627055885
profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy.new treatment options are needed to maintain and improve therapy for tuberculosis, which caused the death of 1.5 million people in 2013 despite potential for an 86 % treatment success rate. a greater understanding of mycobacterium tuberculosis (m.tb) bacilli that persist through drug therapy will aid drug development programs. predictive biomarkers for treatment efficacy are also a research priority.201627055815
the host response to a clinical mdr mycobacterial strain cultured in a detergent-free environment: a global transcriptomics approach.during mycobacterium tuberculosis (m.tb) infection, the initial interactions between the pathogen and the host cell determines internalization and innate immune response events. it is established that detergents such as tween alter the mycobacterial cell wall and solubilize various lipids and proteins. the implication of this is significant since induced changes on the cell wall affect macrophage uptake and the immune response to m.tb. importantly, during transmission between hosts, aerosolized ...201627055235
granzyme a is expressed in mouse lungs during mycobacterium tuberculosis infection but does not contribute to protection in vivo.granzyme a, a serine protease expressed in the granules of cytotoxic t and natural killer cells, is involved in the generation of pro-inflammatory cytokines by macrophages. granzyme a has been described to induce in macrophages in vitro the activation of pro-inflammatory pathways that impair intracellular mycobacterial replication. in the present study, we explored the physiological relevance of granzyme a in the control of pulmonary mycobacterium tuberculosis infection in vivo. our results show ...201627055232
comparison of xpert mtb/rif assay and genotype mtbdrplus dna probes for detection of mutations associated with rifampicin resistance in mycobacterium tuberculosis.genexpert mtb/rif (xpert) and genotype mtbdrplus (drplus) are two world health organization (who) endorsed probe based molecular drug susceptibility testing (dst) methods for rapid diagnosis of drug resistant tuberculosis. both methods target the same 81 bp rifampicin resistance determining region (rrdr) of bacterial rna polymerase β subunit (rpob) for detection of rifampicin (rif) resistance associated mutations using dna probes. so there is a correspondence of the probes of each other and expe ...201627054344
performance of the new version (v2.0) of the genotype mtbdrsl test for detection of resistance to second-line drugs in multidrug-resistant mycobacterium tuberculosis complex strains.detecting resistance to fluoroquinolones (fq) and second-line injectable drugs (amikacin [amk], kanamycin [kan], and capreomycin [cap]) is crucial given the worldwide increase in the incidence of extensively drug-resistant tuberculosis (xdr-tb). a new version of the genotype mtbdrsl test (v2.0) has been developed to improve the detection of resistance to fq (involving gyra and gyrb mutations) and to second-line injectable drugs (involving rrs and eis promoter mutations) in mycobacterium tubercul ...201627053671
genexpert for diagnosis of tubercular meningitis.diagnosis of tubercular meningitis (tbm) is difficult in children. the genexpert mtb/rif assay has been recommended by who in 2013 to be used in children and in extra pulmonary clinical specimens. the present study was designed to assess the diagnostic utility of genexpert in detecting mycobacterium tuberculosis in cerebrospinal fluid (csf) in tbm cases and to compare the results with liquid culture bactec 460. thirty four subjects <15 y were diagnosed as tbm based on clinical, csf and imaging d ...201627053183
a novel therapeutic strategy of lipidated promiscuous peptide against mycobacterium tuberculosis by eliciting th1 and th17 immunity of host.regardless of the fact that potent drug-regimen is currently available, tuberculosis continues to kill 1.5 million people annually. tuberculosis patients are not only inflicted by the trauma of disease but they also suffer from the harmful side-effects, immune suppression and drug resistance instigated by prolonged therapy. it is an exigency to introduce radical changes in the existing drug-regime and discover safer and better therapeutic measures. hence, we designed a novel therapeutic strategy ...201627052185
tuberculous panophthalmitis with lymphadenitis and central nervous system tuberculoma.tuberculosis (tb) is a serious infectious disease that spreads globally. the ocular manifestations of tb are uncommon and diverse. tb panophthalmitis has been rarely reported. here, we described a 38-year-old thai man presenting with panophthalmitis of the right eye. further investigation showed that he had concurrent tb lymphadenitis and central nervous system (cns) tuberculoma, as well as hiv infection, with a cd4 cell count of 153 cells/mm(3). despite the initial response to antituberculous a ...201627051539
new conjugates of quinoxaline as potent antitubercular and antibacterial agents.considering quinoxaline as a privileged structure for the design of potent intercalating agents, some new sugar conjugates of quinoxaline were synthesized and characterized by ir, (1)hnmr, (13)c nmr, and mass spectral data. in vitro testing for antitubercular and antimicrobial activities was performed against mycobacterium tuberculosis h 37 rv and some pathogenic bacteria. results revealed that conjugate containing ribose moiety demonstrated the most promising activity against mycobacteria and b ...201627051530
treatment of pyoderma gangrenosum with thalidomide in a myelodysplastic syndrome case.thalidomide may be used as a treatment option for pyoderma gangrenosum (pg) and myelodysplastic syndrome (mds). herein, we aimed to report a patient who was treated well with thalidomide and whose diagnosis was pg with mds. a 61-year-old man with painless ecchymotic lesions in his right upper extremity was admitted to the hospital in isparta, turkey, in january 2015. the lesions were diagnosed as pg. in his anamnesis, it was found that he was diagnosed with mds 6 years ago and had been treated w ...201627051318
the functional response of b cells to antigenic stimulation: a preliminary report of latent tuberculosis.mycobacterium tuberculosis (m.tb) remains a successful pathogen, causing tuberculosis disease numbers to constantly increase. although great progress has been made in delineating the disease, the host-pathogen interaction is incompletely described. b cells have shown to function as both effectors and regulators of immunity via non-humoral methods in both innate and adaptive immune settings. here we assessed specific b cell functional interaction following stimulation with a broad range of antige ...201627050308
rifapentine-loaded plga microparticles for tuberculosis inhaled therapy: preparation and in vitro aerosol characterization.inhaled delivery of drugs incorporated into poly (lactic-co-glycolic acid) (plga) microparticles allows a sustained lung concentration and encourages phagocytosis by alveolar macrophages that harboring mycobacterium tuberculosis. however, limited data are available on the effects of physicochemical properties of plga, including the monomer ratio (lactide:glycide) and molecular weight (mw) on the aerosol performance, macrophage uptake, and toxicity profile. the present study aims to address this ...201627049049
the importance of first impressions: early events in mycobacterium tuberculosis infection influence outcome.tuberculosis remains a major health threat in much of the world. new vaccines against mycobacterium tuberculosis are essential for preventing infection, disease, and transmission. however, the host immune responses that need to be induced by an effective vaccine remain unclear. increasingly, it has become clear that early events in infection are of major importance in the eventual outcome of the infection. studying such events in humans is challenging, as they occur within the lung and thoracic ...201627048801
mycobacterial interspersed repetitive unit can predict drug resistance of mycobacterium tuberculosis in china.recently, mycobacterial interspersed repetitive unit (miru) was supposed to be associated with drug resistance in mycobacterium tuberculosis (m. tuberculosis), but whether the association exists actually in local strains in china was still unknown. this research was conducted to explore that association and the predictability of miru to drug resistance of tuberculosis (tb).201627047485
sensititre® mycotb mic plate for drug susceptibility testing of mycobacterium tuberculosis complex isolates.national tuberculosis clinical laboratory, china.201627046713
selective autophagy gets more selective: uncoupling of autophagy flux and xenophagy flux in mycobacterium tuberculosis-infected macrophages.induction of autophagy has been reported as a potential means to eliminate intracellular pathogens. corroborating that, many studies report inhibition of autophagy as a survival strategy of bacterial pathogens. incidentally, autophagy at the basal level is critical for survival of host cells including macrophages. we asked how a bacterial pathogen could inhibit autophagy for its survival if the inhibition resulted in cell death. in a recent study we show distinct regulation of autophagy in mycob ...201627046255
[establishment and preliminary application of detection of mycobacterium tuberculosis in sputum based on variable number tandem repeat].to establish a laboratory method for detection of mycobacterium tuberculosis in sputum based on variable number tandem repeat (vntr).201627045243
oxadiazoles have butyrate-specific conditional activity against mycobacterium tuberculosis.mycobacterium tuberculosis is a global pathogen of huge importance which can adapt to several host niche environments in which carbon source availability is likely to vary. we developed and ran a phenotypic screen using butyrate as the sole carbon source to be more reflective of the host lung environment. we screened a library of ∼87,000 small compounds and identified compounds which demonstrated good antitubercular activity against m. tuberculosis grown with butyrate but not with glucose as the ...201627044545
dilemma of managing asymptomatic children referred with 'culture-confirmed' drug-resistant tuberculosis.the diagnosis of drug-resistant tuberculosis (dr-tb) in children is challenging and treatment is associated with many adverse effects.201627044259
an interesting case of non-resolving hepatogastric fistula - an unseen cause.hepatic tuberculosis presents one of the rare forms of extra-pulmonary tuberculosis. it is usually secondary to infection in the lung or the gut. tuberculous liver abscess is the rarer manifestation even in endemic areas of mycobacterium tuberculosis. hepatogastric fistula secondary to tuberculous liver abscess has never been reported in literature. we herein report a case of a disseminated tuberculous liver abscess complicated by hepatogastric fistula, which posed a considerable diagnostic chal ...201627042532
toward antituberculosis drugs: in silico screening of synthetic compounds against mycobacterium tuberculosisl,d-transpeptidase 2.mycobacterium tuberculosis (mtb) the main causative agent of tuberculosis, is the main reason why this disease continues to be a global public health threat. it is therefore imperative to find a novel antitubercular drug target that is unique to the structural machinery or is essential to the growth and survival of the bacterium. one such target is the enzyme l,d-transpeptidase 2, also known as ldtmt2, a protein primarily responsible for the catalysis of 3→3 cross-linkages that make up the mycol ...201627042006
infection of j774a.1 with different mycobacterium species induces differential immune and mirna-related responses.macrophages act as a reservoir for mycobacterium tuberculosis, producing latent infection in approximately 90% of infected people. in this study, j774a.1 mouse macrophage cell line response and microrna (mirna) expression during infection with the most relevant mycobacterial strains for humans (m. tuberculosis, m. bovis and m. bovis bcg) was explored. no significant differences in bacillary loads were observed between activate and naive macrophages infected with m. tuberculosis and m. bovis. nit ...201627041510
added value of molecular assay xpert mtb/rif compared to sputum smear microscopy to assess the risk of tuberculosis transmission in a low-prevalence country.airborne precautions are required at hospital admission for patients with suspected pulmonary tuberculosis. the isolation is maintained until 3 serially collected sputum smears are acid-fast bacilli negative, a time- and labor-intensive method with limited sensitivity and specificity, which has a great impact on patient flow management. we evaluated the possibility of replacing the result of microscopy by the semiquantitative result of the molecular point-of-care test xpert mtb/rif to assess pat ...201627139592
geographic differences in the contribution of ubia mutations to high-level ethambutol resistance in mycobacterium tuberculosis.ethambutol (emb) resistance can evolve through a multistep process, and mutations in the ubia (rv3806c) gene appear to be responsible for high-level emb resistance in mycobacterium tuberculosis we evaluated the prevalence of ubia and embb (rv3795) mutations in emb-resistant strains originating from africa and south korea. no differences in embb mutation frequencies were observed between strains from both origins. however, ubia mutations were present in 45.5% ± 6.5% of the african emb-resistant i ...201627139478
development and optimization of dual drugs (isoniazid and moxiflox-acin) loaded functional plga nanoparticles for the synergistic treatment of tuberculosis.the management of tb is difficult due to the resistance developed by mycobacterium tuberculosis against anti-tubercular drugs causes the new challenges for treating and managing the disease.201627138300
selectivity of pyridone- and diphenyl ether-based inhibitors for the yersinia pestis fabv enoyl-acp reductase.the enoyl-acp reductase (enr) catalyzes the last reaction in the elongation cycle of the bacterial type ii fatty acid biosynthesis (fas-ii) pathway. while the fabi enr is a well-validated drug target in organisms such as mycobacterium tuberculosis and staphylococcus aureus, alternate enr isoforms have been discovered in other pathogens, including the fabv enzyme that is the sole enr in yersinia pestis (ypfabv). previously, we showed that the prototypical enr inhibitor triclosan was a poor inhibi ...201627136302
design, synthesis, and characterization of some hybridized pyrazolone pharmacophore analogs against mycobacterium tuberculosis.twenty-seven hybridized pyrazolone analogs were designed, docked, synthesized in two series and evaluated for their in vitro antimycobacterial properties. in the first series, four schiff base derivatives, 6b, 7b, 7h, and 7i, show good antitubercular activity with minimum inhibition concentration (mic) values in the range of 32.56-42.55 µm. in the second series, two compounds, 8b and 8c, possessed significant antitubercular activity with mic <0.37 and <0.44 μm, respectively; they were even more ...201627135906
[pleural tuberculosis in a hospital in northeast argentina].pleural tuberculosis ranks first in extrapulmonary sites. the aim of this study was to estimate the proportion pleural tb among tb cases, and characterize the presentation, diagnostic methods and outcomes of patients hospitalized in the ángela i. de llano hospital, corrientes, argentina, between january 1, 2011 and june 30, 2014. we performed a descriptive and observational study. ten patients were diagnosed with tb pleural effusion. the mean age was 48.5 ± 16.9 (16-63) years. the average evolut ...201627135844
heat killed saccharomyces cerevisiae as an adjuvant for the induction of vaccine-mediated immunity against infection with mycobacterium tuberculosis.the use of novel vaccine delivery systems allows for the manipulation of the adaptive immune systems through the use of molecular adjuvants that target specific innate pathways. such strategies have been used extensively for vaccines against cancer and multiple pathogens such as mycobacterium tuberculosis. in the current study we used heat killed non-pathogenic recombinant saccharomyces cerevisiae expressing m. tuberculosis antigen rv1886c (fbpb, mpt59, ag85b) as a delivery system in conjunction ...201627131285
a novel sputum transport solution eliminates cold chain and supports routine tuberculosis testing in nepal.this preliminary study evaluated the transport reagent omnigene sputum (oms) in a real-world, resource-limited setting: a zonal hospital and national tuberculosis (tb) reference laboratory, nepal. the objectives were to: (1) assess the performance of oms for transporting sputum from peripheral sites without cold chain stabilization; and (2) compare with nepal's standard of care (soc) for mycobacterium tuberculosis smear and culture diagnostics. sixty sputa were manually split into a soc sample ( ...201627131103
comparison of genexpert mtb/rif and conventional methods for the diagnosis of tuberculosis in kosovo.tuberculosis (tb) is a major public health problem worldwide, with the highest mortality occurring in developing countries. the burden of tb in kosovo is among the highest in europe. the aim of this study was to compare cepheid genexpert mtb/rif assay for direct detection of mycobacterium tuberculosis complex (mtbc) and rifampin (rif) resistance with conventional methods.201627131007
frequency of mutational changes in the embb among the ethambutol-resistant strains of mycobacterium tuberculosis in iran.early detection of drug resistant tuberculosis is one of the main priorities of tb control program. ethambutol (emb) is a first-line anti-tb drug that is effective for preventing treatment failures caused by mycobacterium tuberculosis strains that are resistant to other drugs. the aim of this study was to sequence the embb gene to characterize the mutations causing resistance to emb and to analyze the relationship between bacterial genotype and emb resistance among m. tuberculosis isolates in ir ...201627130997
[role of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of mediastinal tuberculosis].mediastinal tuberculosis (tb) is rare and a diagnostic challenge. transbronchial needle aspiration guided by endoscopic ultrasonography (ebus-tbna) is an essential tool for staging and diagnosing patients with lung cancer but to date there are no studies in our environment evaluating its efficacy in mediastinal tb.201627130566
donor-derived tuberculosis in an anesthetist after short-term exposure : an old demon transplanted from the past to the present.we report a case of a 27-year-old anesthetist who acquired tuberculosis (tb) while performing general anesthesia in a renal transplant (rtx) patient who had donor-derived contagious tb. the anesthetist developed pleural tb 6 months after exposure. contact investigations (cis) did not include health care workers (hcws) of the department of anesthesiology, thereby missing the opportunity for the early diagnosis and treatment of tb. genomic fingerprinting revealed identical mycobacterium tuberculos ...201627129535
xct increases tuberculosis susceptibility by regulating antimicrobial function and inflammation.the physiological functions of macrophage, which plays a central role in the pathogenesis of tuberculosis, depend on its redox state. system xc-, a cystine-glutamate transporter, which consists of xct and cd98, influences many ros-dependent pathways by regulating the production of the antioxidant glutathione. xct's ability to alter this critical host redox balance by increasing the glutathione synthesis aspect of phagocyte physiology suggested that it might influence tuberculosis pathogenesis. i ...201627129162
corrigendum: integration of metabolic modeling with gene co-expression reveals transcriptionally programmed reactions explaining robustness in mycobacterium tuberculosis. 201627129109
probing the sophisticated synergistic allosteric regulation of aromatic amino acid biosynthesis in mycobacterium tuberculosis using ᴅ-amino acids.chirality plays a major role in recognition and interaction of biologically important molecules. the enzyme 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (dah7ps) is the first enzyme of the shikimate pathway, which is responsible for the synthesis of aromatic amino acids in bacteria and plants, and a potential target for the development of antibiotics and herbicides. dah7ps from mycobacterium tuberculosis (mtudah7ps) displays an unprecedented complexity of allosteric regulation, with thre ...201627128682
investigation of elimination rate, persistent subpopulation removal, and relapse rates of mycobacterium tuberculosis by using combinations of first-line drugs in a modified cornell mouse model.currently, the most effective tuberculosis control method involves case finding and 6 months of chemotherapy. there is a need to improve our understanding about drug interactions, combination activities, and the ability to remove persistent bacteria using the current regimens, particularly in relation to relapse. we aimed to investigate the therapeutic effects of three main components, rifampin (rmp), isoniazid (inh), and pyrazinamide (pza), in current drug regimens using a modified version of t ...201627216065
synthesis, characterization and antitubercular activities of novel pyrrolyl hydrazones and their cu-complexes.novel pyrrolyl hydrazones and their copper complexes have been synthesized and characterized using analytical and spectral techniques to show the tetrahedral geometry for cu(ii) complexes. biological activities of hydrazones have been assessed to understand the role of metal ion on their biological activity and the effect of pyrrolyl hydrazones. in vitro antitubercular activity against mycobacterium tuberculosis of the metal complexes (13b and 13r) exhibited the highest antitubercular activity t ...201627214509
nontoxic metal-cyclam complexes, a new class of compounds with potency against drug-resistant mycobacterium tuberculosis.tuberculosis (tb) accounted for 1.5 million deaths in 2014, and new classes of anti-tb drugs are required. we report a class of functionalized 1,8-disubstituted cyclam derivatives that display low micromolar activity against pathogenic mycobacteria. these compounds inhibit intracellular growth of mycobacterium tuberculosis, are nontoxic to human cell lines, and are active against multidrug-resistant m. tuberculosis strains, indicating a distinct mode of action. these compounds warrant further ap ...201627214150
tlr1 variant h305l associated with protection from pulmonary tuberculosis.toll like receptors (tlr) are key elements of the innate immune response and involved in the recognition of pathogens. to test common and rare tlr variants involved in susceptibility or resistance to infection with mycobacterium tuberculosis we screened the exons of the genes encoding tlr 1, 2, 4, and the adaptor molecule tirap in more than 4500 tuberculosis (tb) cases and controls from ghana. the analysis yielded 109 variants with possible functional impact, including 101 non-synonymous variant ...201627214039
rapid and simple identification of beijing genotype strain of mycobacterium tuberculosis using a loop-mediated isothermal amplification assay.beijing genotype strains of mycobacterium tuberculosis are geographically widespread and pose a notorious public health problem, these strains causing outbreaks of multidrug-resistant tuberculosis (tb); some studies have reported an association with drug resistance. because the prevalence of beijing strain has a substantial impact on tb control programs, the availability of a rapid and reliable method for detecting these strains is important for epidemiological monitoring of their circulation. t ...201627213686
dry powder inhalable formulations for anti-tubercular therapy.tuberculosis (tb) is an intracellular infectious disease caused by the airborne bacterium, mycobacterium tuberculosis. despite considerable research efforts, the treatment of tb continues to be a great challenge in part due to the requirement of prolonged therapy with multiple high-dose drugs and associated side effects. the delivery of pharmacological agents directly to the respiratory system, following the natural route of infection, represents a logical therapeutic approach for treatment or v ...201627212477
development of efflux pump inhibitors in antituberculosis therapy.resistance and tolerance to antituberculosis (anti-tb) drugs, especially the first-line drugs, has become a serious problem in anti-tb therapy. efflux of antimicrobial agents via bacterial efflux pumps is one of the main reasons for drug resistance. efflux pump inhibitors (epis) bind to efflux pumps to inhibit drug efflux and thus enhance the drug effect and reduce drug resistance. studies on epis targeting the efflux pumps of mycobacterium tuberculosis (mtb) help to understand mtb resistance an ...201627211826
a long-term co-perfused disseminated tuberculosis-3d liver hollow fiber model for both drug efficacy and hepatotoxicity in babies.treatment of disseminated tuberculosis in children≤6years has not been optimized. the pyrazinamide-containing combination regimen used to treat disseminated tuberculosis in babies and toddlers was extrapolated from adult pulmonary tuberculosis. due to hepatotoxicity worries, there are no dose-response studies in children. we designed a hollow fiber system model of disseminated intracellular tuberculosis with co-perfused three-dimensional organotypic liver modules to simultaneously test for effic ...201627211555
in vitro culture conditions affecting minimal inhibitory concentration of bedaquiline against m. tuberculosis.in developing a standardized drug susceptibility test for bedaquiline, it is very important to know which parameters might impact its activity in vitro and result in false resistance of the bacterium to bedaquiline. we aimed to assess the impact of different in vitro conditions on the minimal inhibitory concentration (mic) of bedaquiline against mycobacterium tuberculosis h37rv reference strain.201627210281
endobronchial tuberculosis in anthracotic bronchitis.endobronchial tuberculosis (ebtb) is a serious form of pulmonary tuberculosis. in ebtb, mycobacterium tuberculosis involves trachea, large airways and bronchial trees combustion of biomass fuels causes anthracotic bronchitis that is characterized by black pigmentation in bronchial tissue. the majority of anthracotic bronchitis are in aged patients, particularly rural women, that use biomass fuel for cooking or traditional bakery .the aim of this study was to evaluate the endobronchial tuberculos ...201627209834
drug-resistant tuberculosis: challenges and progress.antimicrobial resistance is a natural evolutionary process, which in the case of mycobacterium tuberculosis is based on spontaneous chromosomal mutations, meaning that well-designed combination drug regimens provided under supervised therapy will prevent the emergence of drug-resistant strains. unfortunately, limited resources, poverty, and neglect have led to the emergence of drug-resistant tuberculosis throughout the world. the international community has responded with financial and scientifi ...201627208770
transcriptional regulation of topology modulators and transcription regulators of mycobacterium tuberculosis.mycobacterium tuberculosis (mtb) is a formidable pathogen which has the ability to survive the hostile environment of the host by evading the host defense system. the re-configuration of its transcriptional and metabolic process allows the pathogen to confront the adverse environment within the host macrophages. the factors that assist the transcription and modulate the dna topology would have to play a key role in the regulation of global gene expression of the organism. how transcription of th ...201627207833
[evaluation of the diagnostic performance of xpert mtb/rif test for the detection of mycobacterium tuberculosis and rifampin resistance in clinical samples].rapid and accurate detection of active tuberculosis (tb) cases is one of the most important goal of tuberculosis control programme. for this purpose, new methods are being developed to isolate, serotype and determine the drug resistance of the agent. xpert mtb/rif test (cepheidgenexpert® system, usa) that has been recently developed, is a real-time polymerase chain reaction-based method which detects mycobacterium tuberculosis complex and resistance of the strain to rifampicin (rif) from the cli ...201627175492
an automated approach for global identification of srna-encoding regions in rna-seq data from mycobacterium tuberculosis.deep-sequencing of bacterial transcriptomes using rna-seq technology has made it possible to identify small non-coding rnas, rna molecules which regulate gene expression in response to changing environments, on a genome-wide scale in an ever-increasing range of prokaryotes. however, a simple and reliable automated method for identifying srna candidates in these large datasets is lacking. here, after generating a transcriptome from an exponential phase culture of mycobacterium tuberculosis h37rv, ...201627174874
draft genome sequence of branchiibius sp. ny16-3462-2, isolated from a mixed clinical sample.here, we report the release of a draft genome assembly of a gram-positive cocci branchiibius sp. ny16-3462-2 with a high-gc content, sequenced from a mixed clinical sample containing mycobacterium tuberculosis this genome is the first publicly available sequence from a representative of the genus branchiibius.201627174280
antimycobacterial triterpenes from the canadian medicinal plant sarracenia purpurea.the purple pitcher plant, sarracenia purpurea, is a medicinal plant used by the canadian first nations to treat a wide variety of illnesses. the mi'kmaq and wolastoqiyik (maliseet) peoples of eastern canada have traditionally used infusions of s. purpurea for the treatment of tuberculosis-like symptoms. previous investigations have shown methanolic extracts of s. purpurea to possess antimycobacterial activity.201627174081
boosting bcg-primed responses with a subunit apa vaccine during the waning phase improves immunity and imparts protection against mycobacterium tuberculosis.heterologous prime-boosting has emerged as a powerful vaccination approach against tuberculosis. however, optimal timing to boost bcg-immunity using subunit vaccines remains unclear in clinical trials. here, we followed the adhesin apa-specific t-cell responses in bcg-primed mice and investigated its bcg-booster potential. the apa-specific t-cell response peaked 32-52 weeks after parenteral or mucosal bcg-priming but waned significantly by 78 weeks. a subunit-apa-boost during the contraction-pha ...201627173443
antibody detection tests for early diagnosis in tuberculous meningitis.tuberculous meningitis (tbm) is the most severe form of tuberculosis. microbiological confirmation is rare and treatment is often delayed. early diagnosis and immediate initiation of treatment are essential for effective tbm control. a systematic review was performed in this study to assess the diagnostic accuracy of detecting antibodies against mycobacterium tuberculosis in the cerebrospinal fluid (csf), according to standard methods. test performance was summarized using a bivariate random-eff ...201627173078
synthesis and evaluation of the 2-aminothiazoles as anti-tubercular agents.the 2-aminothiazole series has anti-bacterial activity against the important global pathogen mycobacterium tuberculosis. we explored the nature of the activity by designing and synthesizing a large number of analogs and testing these for activity against m. tuberculosis, as well as eukaryotic cells. we determined that the c-2 position of the thiazole can accommodate a range of lipophilic substitutions, while both the c-4 position and the thiazole core are sensitive to change. the series has good ...201627171280
rapid detection of rifampicin- and isoniazid-resistant mycobacterium tuberculosis using taqman allelic discrimination.multidrug-resistant tuberculosis (mdr-tb) is a global problem that many countries are challenged with. rapid and accurate detection of mdr-tb is critical for appropriate treatment and controlling of tb. the aim of the present study was to evaluate the taqman allelic discrimination without minor groove binder (mgb) as a rapid, efficient, and low-cost method for detection of drug resistant strains of mycobacterium tuberculosis.201627169012
prevalence of pulmonary tuberculosis in young adult patients with type 1 diabetes mellitus in india.there is limited information on prevalence of pulmonary tuberculosis (ptb) in patients with type-1-diabetes. we assessed the prevalence of ptb in patients with type-1-diabetes attending the outpatient-clinic in a tertiary-care hospital.201627168934
practical approaches for mining frequent patterns in molecular datasets.pattern detection is an inherent task in the analysis and interpretation of complex and continuously accumulating biological data. numerous itemset mining algorithms have been developed in the last decade to efficiently detect specific pattern classes in data. although many of these have proven their value for addressing bioinformatics problems, several factors still slow down promising algorithms from gaining popularity in the life science community. many of these issues stem from the low user- ...201627168722
characterization of the in vitro assembly of ftsz in arthrobacter strain a3 using light scattering.the self-assembly of ftsz, the bacterial homolog of tubulin, plays an essential role in cell division. light scattering technique is applied to real-time monitor the in vitro assembly of ftsz in arthrobacter strain a3, a newly isolated psychrotrophic bacterium. the critical concentration needed for the assembly is estimated as 6.7μm. the polymerization of ftsz in arthrobacter strain a3 requires both gtp and divalent metal ions, while salt is an unfavorable condition for the assembly. the ftsz po ...201627164494
methods and clinical development of adenovirus-vectored vaccines against mucosal pathogens.adenoviruses represent the most widely used viral-vectored platform for vaccine design, showing a great potential in the fight against intracellular infectious diseases to which either there is a lack of effective vaccines or the traditional vaccination strategy is suboptimal. the extensive understanding of the molecular biology of adenoviruses has made the new technologies and reagents available to efficient generation of adenoviral-vectored vaccines for both preclinical and clinical evaluation ...201627162933
antibiotic resistance mechanisms in m. tuberculosis: an update.treatment of tuberculosis (tb) has been a therapeutic challenge because of not only the naturally high resistance level of mycobacterium tuberculosis to antibiotics but also the newly acquired mutations that confer further resistance. currently standardized regimens require patients to daily ingest up to four drugs under direct observation of a healthcare worker for a period of 6-9 months. although they are quite effective in treating drug susceptible tb, these lengthy treatments often lead to p ...201627161440
protocol for a population-based molecular epidemiology study of tuberculosis transmission in a high hiv-burden setting: the botswana kopanyo study.mycobacterium tuberculosis (mtb) is transmitted from person to person via airborne droplet nuclei. at the community level, mtb transmission depends on the exposure venue, infectiousness of the tuberculosis (tb) index case and the susceptibility of the index case's social network. people living with hiv infection are at high risk of tb, yet the factors associated with tb transmission within communities with high rates of tb and hiv are largely undocumented. the primary aim of the kopanyo study is ...201627160840
unraveling methylation changes of host macrophages in mycobacterium tuberculosis infection.to characterize at high resolution dna methylation changes of cytokines which occur in the genome of macrophages in association with mycobacterium tuberculosis (mtb) infection201627156630
strategies of genome editing in mycobacteria: achievements and challenges.tremendous amount of physiological and functional complexities acquired through decades of evolutionary pressure makes mycobacterium tuberculosis (mtb) one of the most dreadful microorganisms infecting humans from centuries. astonishing advances in genomics and genome editing tools substantially grew our knowledge about mtb as an organism but dramatically failed to completely understand it as a pathogen. though conventional tools based on homologous recombination, antisense, controlled proteolys ...201627156629
functional polymorphisms of the tlr7 and tlr8 genes contribute to mycobacterium tuberculosis infection.tuberculosis (tb) has recently re-emerged as a major global public health threat and mycobacterium tuberculosis (mtb) is a highly successful pathogen that evolved remarkable strategies to establish persistent infection. there is strong evidence that host genetic factors influence individual susceptibility to tb. in this study, we evaluated the associations between the tlr7 and tlr8 genetic polymorphisms and tb susceptibility in chinese individuals. the results demonstrated that the frequency of ...201627156628
molecular characterization of mycobacterium tuberculosis isolates from tanga, tanzania: first insight of miru-vntr and microarray-based spoligotyping in a high burden country.molecular typing of mycobacterium tuberculosis(mtb) has greatly enhanced the understanding of the population structure of mtb isolates and epidemiology of tuberculosis (tb). to characterize prevalent genotypes of mtb, microarrays‑based spoligotyping and mycobacterial interspersed repetitive unit‑variable number of tandem repeats (miru‑vntr) were applied on 80 isolates collected from primary health care facilities in tanga, north‑eastern tanzania. a total of 18 distinct spoligotypes were identifi ...201627156627
serial image analysis of mycobacterium tuberculosis colony growth reveals a persistent subpopulation in sputum during treatment of pulmonary tb.faster elimination of drug tolerant 'persister' bacteria may shorten treatment of tuberculosis (tb) but no method exists to quantify persisters in clinical samples. we used automated image analysis to assess whether studying growth characteristics of individual mycobacterium tuberculosis colonies from sputum on solid media during early tb treatment facilitates 'persister' phenotyping. as time to detection (ttd) in liquid culture inversely correlates with total bacterial load we also evaluated th ...201627156626
activity of nitazoxanide and tizoxanide against mycobacterium tuberculosis in vitro and in whole blood culture.nitazoxanide (ntz) and its metabolite tizoxanide (tiz) were studied as antimycobacterial agents in vitro (in mycobacterial growth indicator tube [mgit] cultures) and in a whole blood bactericidal assay. both ntz and tiz show high protein binding. in mgit cultures (albumin concentration = 78 μm), inhibition of mycobacterium tuberculosis growth occurred at total drug concentrations of ≥16 μg/ml, whereas in whole blood cultures (albumin concentration = 350 μm), ≥128 μg/ml was required. free drug fr ...201627156623
elevated serum 25-hydroxy (oh) vitamin d levels are associated with risk of tb progression in gambian adults.vitamin d is essential in the host defence against tuberculosis (tb) as an immune modulator. the aim of this study was to determine the level of 25-hydroxyvitamin d (25 (oh) d) from adult tb index cases before and after treatment and their exposed household contacts (hhc) in the gambia.201627156622
whole genome sequencing of mycobacterium tuberculosis for detection of recent transmission and tracing outbreaks: a systematic review.contact tracing complemented with genotyping is considered an important means of understanding person-to-person transmission of tuberculosis (tb). it still remains unclear whether whole genome sequencing (wgs) of mycobacterium tuberculosis can rule in transmission and how it performs in different human populations, risk groups and across tb lineages. this systematic review aimed to determine the sensitivity and specificity of wgs for detection of recent transmission using conventional epidemiolo ...201627156621
hiv-1 and the mycobacterium tuberculosis granuloma: a systematic review and meta-analysis.infection with hiv-1 greatly increases the risk of active tuberculosis (tb). although hypotheses suggest hiv-1 disrupts mycobacterium tuberculosis (mtb) granuloma function, few studies have examined this directly. the objective of this study was to determine what evidence exists about the effect hiv-1 co-infection has upon mtb granulomas. a systematic search of pubmed, web of science, and medline up to 20 march 2015 was conducted, to identify studies comparing mtb-infected tissue from hiv-1 infe ...201627156620
prevalence and transmission of pyrazinamide resistant mycobacterium tuberculosis in china.pyrazinamide (pza) is an important first-line anti-tuberculosis drug, however, there are relatively few available data on pza resistant (pza-r) rate in china. from june 2009 to june 2012, we selected 493 isolates from five field settings in china to investigate pza-r by pnca gene sequencing. the result showed that pza-r rate was 1.0% (2/196) among pan-susceptible isolates, 3.1% (4/130) among isoniazid (inh) mono-resistant isolates, 14.0% (6/43) among rifampin (rif) mono-resistant isolates and 43 ...201627156619
longitudinal whole genome analysis of pre and post drug treatment mycobacterium tuberculosis isolates reveals progressive steps to drug resistance.tuberculosis (tb) is one of the leading causes of death due to an infectious disease in the world. understanding the mechanisms of drug resistance has become pivotal in the detection and treatment of newly emerging resistant tb cases. we have analyzed three pairs of mycobacterium tuberculosis strains pre- and post-drug treatment to identify mutations involved in the progression of resistance to the drugs rifampicin and isoniazid. in the rifampicin resistant strain, we confirmed a mutation in rpo ...201627156618
cloning, expression and characterization of histidine-tagged biotin synthase of mycobacterium tuberculosis.the emergence of mycobacterium tuberculosis strains that are resistant to the current anti-tuberculosis (tb) drugs necessitates a need to develop a new class of drugs whose targets are different from the current ones. m. tuberculosis biotin synthase (mtbbs) is one such target that is essential for the survival of the bacteria. in this study, mtbbs was cloned, overexpressed and purified to homogeneity for biochemical characterization. it is likely to be a dimer in its native form. its ph and temp ...201627156617
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