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delayed bactericidal response of mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism.bedaquiline (bdq), an atp synthase inhibitor, is the first drug to be approved for treatment of multidrug-resistant tuberculosis in decades. though bdq has shown excellent efficacy in clinical trials, its early bactericidal activity during the first week of chemotherapy is minimal. here, using microfluidic devices and time-lapse microscopy of mycobacterium tuberculosis, we confirm the absence of significant bacteriolytic activity during the first 3-4 days of exposure to bdq. bdq-induced inhibiti ...201424569628
soluble tnfrp75 regulates host protective immunity against mycobacterium tuberculosis.development of host protective immunity against mycobacterium tuberculosis infection is critically dependent on the inflammatory cytokine tnf. tnf signals through 2 receptors, tnfrp55 and tnfrp75; however, the role of tnfrp75-dependent signaling in immune regulation is poorly defined. here we found that mice lacking tnfrp75 exhibit greater control of m. tuberculosis infection compared with wt mice. tnfrp75-/- mice developed effective bactericidal granulomas and demonstrated increased pulmonary r ...201424569452
[where does the development of new antituberculotics go? part 2 - in vitro evaluation].the present paper is a continuation of a publication of 2012 (čes. a slov. farm. 2012; 31, 150-158). it is oriented at the evaluation of potential antituberculotics in vitro, which is the most widely used approach to testing. the paper is based on the information from chemical abstracts 2011-2013. it is a selection from nearly three thousand items of information intended to help researchers. the greatest attention is paid to the multiresistant strains of mycobacterium tuberculosis. in vitro eval ...201424568332
disseminated tuberculosis manifesting as cholestasis in a patient with aids: a presentation to remember.a 48-year-old man of indian descent and chronic untreated hiv infection presented with a 3-week history of persistent fever, jaundice and a subacute 10-pound weight loss. his presentation was notable for a painless cholestatic jaundice. an extensive evaluation was pursued around cholestasis and liver disease, with a resulting unremarkable workup for viral, bacterial and tick borne infectious aetiologies. a ct scan of the abdomen fortuitously revealed incidental pleural effusions and a subsequent ...201424567181
neurons are host cells for mycobacterium tuberculosis.mycobacterium tuberculosis infection of the central nervous system is thought to be initiated once the bacilli have breached the blood brain barrier and are phagocytosed, primarily by microglial cells. in this study, the interactions of m. tuberculosis with neurons in vitro and in vivo were investigated. the data obtained demonstrate that neurons can act as host cells for m. tuberculosis. m. tuberculosis bacilli were internalized by murine neuronal cultured cells in a time-dependent manner after ...201424566619
molecular characterization of mycobacterium tuberculosis isolates from elephants of nepal.mycobacterium tuberculosis was cultured from the lung tissues of 3 captive elephants in nepal that died with extensive lung lesions. spoligotyping, tbd1 detection and multi-locus variable number of tandem repeat analysis (mlva) results suggested 3 isolates belonged to a specific lineage of indo-oceanic clade, eai5 sit 138. one of the elephant isolates had a new synonymous single nucleotide polymorphism (snp) t231c in the gyra sequence, and the same snp was also found in human isolates in nepal. ...201424566285
mycobacterium tuberculosis-specific polyfunctional cytotoxic cd8+ t cells express cd69.increasing evidences in animals and humans suggest that cd8(+) t cells contribute significantly to immune defenses against mycobacterium tuberculosis (mtb). in the present study, we found that without any stimulation, cd8(+) t cells in pleural fluid cells (pfcs) expressed significantly higher levels of cd69 than pbmcs from patients with tuberculous pleurisy (tbp). cd8(+)cd69(+) t cells expressed significantly higher levels of cd45ro and hla-dr and lower levels of cd45ra than cd8(+)cd69(-) t cell ...201424566284
differentiation of human mononuclear phagocytes increases their innate response to mycobacterium tuberculosis infection.the heterogeneity of mononuclear phagocytes, partially explained by cell differentiation, influences the activation of innate responses. it has been reported that mycobacterium tuberculosis inhibits monocyte differentiation into either dendritic cells or macrophages. to evaluate whether the activation of effector mechanisms against m. tuberculosis differ between less and more differentiated mononuclear phagocytes, we compared monocytes differentiated in vitro for 24 h (mon24) and 120 h (mdm120) ...201424566283
anti-tuberculosis treatment enhances the production of il-22 through reducing the frequencies of regulatory b cell.il-22 has been suggested to play an important role in immune response against mycobacterium tuberculosis infection. however, the exact role of il-22 in human tuberculosis (tb) infection remains unclear and the regulatory mechanism of il-22 response in human tb is unknown. in this study, we observed that successful anti-tuberculosis treatment induced an enhanced and sustained m. tuberculosis antigen-specific il-22 response, correlated with the decrease of the frequencies of cd19(+)cd5(+)cd1d(+) r ...201424566282
development of novel tetrahydrothieno[2,3-c]pyridine-3-carboxamide based mycobacterium tuberculosis pantothenate synthetase inhibitors: molecular hybridization from known antimycobacterial leads.twenty six 2,6-disubstituted 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide derivatives were designed by molecular hybridization approach using and synthesized from piperidin-4-one by five step synthesis. compounds were evaluated for mycobacterium tuberculosis (mtb) pantothenate synthetase (ps) inhibition study, in vitro activities against mtb, cytotoxicity against raw 264.7 cell line. among the compounds, 6-(4-nitrophenylsulfonyl)-2-(5-nitrothiophene-2-carboxamido)-4,5,6,7-tetrahydrothie ...201424565972
direct identification of mycobacteria from culture media using a multiplex real-time pcr assay: report on its application in a clinical laboratory in a region of high tuberculosis endemicity.there are few commercial assays that easily and correctly identify the mycobacteria from culture in a clinical laboratory with a high workload. thus, we developed and evaluated a scheme for the identification of mycobacteria using a multiplex real-time pcr assay and report on its application in our laboratory. the scheme consisted of 3 stepwise pcrs. mycobacterium tuberculosis complex (mtc) and nontuberculous mycobacteria (ntm) were differentially detected in the step 1 pcr, and the ntm species ...201424565848
minimal diversity of drug-resistant mycobacterium tuberculosis strains, south africa.multidrug- (mdr) and extensively drug-resistant tuberculosis (xdr tb) are commonly associated with beijing strains. however, in kwazulu-natal, south africa, which has among the highest incidence and mortality for mdr and xdr tb, data suggest that non-beijing strains are driving the epidemic. we conducted a retrospective study to characterize the strain prevalence among drug-susceptible, mdr, and xdr tb cases and determine associations between strain type and survival. among 297 isolates from 200 ...201424565645
concomitant multidrug-resistant pulmonary tuberculosis and susceptible tuberculous meningitis. 201424565423
a novel mycobacterial hsp70-containing fusion protein targeting mesothelin augments antitumor immunity and prolongs survival in murine models of ovarian cancer and mesothelioma.although dendritic cell (dc) vaccines are considered to be promising treatments for advanced cancer, their production and administration is costly and labor-intensive. we developed a novel immunotherapeutic agent that links a single-chain antibody variable fragment (scfv) targeting mesothelin (msln), which is overexpressed on ovarian cancer and mesothelioma cells, to mycobacterium tuberculosis (mtb) heat shock protein 70 (hsp70), which is a potent immune activator that stimulates monocytes and d ...201424565018
structural insights into mode of actions of novel natural mycobacterium protein tyrosine phosphatase b inhibitors.tuberculosis has become a major health problem being the second leading cause of death worldwide. mycobacterium tuberculosis secretes a virulence factor, protein tyrosine phosphatase b (mptpb) in the cytoplasm of host macrophage which suppresses its natural innate immune response and helps the pathogen survive and proliferate in the phagosome. the present study aims at indentifying potent inhibitors of mptpb by using computational approaches of ligand based molecular modeling and docking studies ...201424564493
systematic review and meta-analysis on the utility of interferon-gamma release assays for the diagnosis of mycobacterium tuberculosis infection in children: a 2013 update.previous meta-analyses regarding the performance of interferon-gamma release assays (igras) for tuberculosis diagnosis in children yielded contrasting results, probably due to different inclusion/exclusion criteria.201424564486
reflections on the immunology of tuberculosis: will we ever unravel the skein?many and large dumps exist in our knowledge about mycobacterium tuberculosis infection and disease in infants and children. we still do not understand why some individuals do acquire and others do not acquire the infection in the presence of the same risk factors. we do not understand why some individuals convert from latent to active tuberculosis and why other individuals convert from active to inactive tuberculosis even without treatment. as a matter of fact the immune system mounts a bouncing ...201424564297
context-based preprocessing of molecular docking data.data preprocessing is a major step in data mining. in data preprocessing, several known techniques can be applied, or new ones developed, to improve data quality such that the mining results become more accurate and intelligible. bioinformatics is one area with a high demand for generation of comprehensive models from large datasets. in this article, we propose a context-based data preprocessing approach to mine data from molecular docking simulation results. the test cases used a fully-flexible ...201324564276
mature epitope density--a strategy for target selection based on immunoinformatics and exported prokaryotic proteins.current immunological bioinformatic approaches focus on the prediction of allele-specific epitopes capable of triggering immunogenic activity. the prediction of major histocompatibility complex (mhc) class i epitopes is well studied, and various software solutions exist for this purpose. however, currently available tools do not account for the concentration of epitope products in the mature protein product and its relation to the reliability of target selection.201324564223
detection of drug resistant mycobacterium tuberculosis among patients with and without hiv infection in a rural setting.to analyse the sensitivity of mycobacterium tuberculosis by nitrate reductase assay (nra) and the hain molecular line probe assay (lpa) in sputa of tuberculosis (tb)/hiv co-infected patients in guyana.201324564061
bedaquiline - the first atp synthase inhibitor against multi drug resistant tuberculosis.increasing incidence of mdr-tb, long duration of treatment and co-infection with hiv are the significant problems in achieving the eradication of tuberculosis. bedaquiline is an anti-tuberculosis drug with unique mechanism of action. it selectively inhibits the mycobacterial energy metabolism i.e. atp synthesis and found to be effective against all states of mycobacterium tuberculosis like active, dormant, replicating, non-replicating, intracellular and extracellular. preclinical studies have sh ...201324563587
18f-fdg pet/ct in a case of multifocal skeletal tuberculosis without pulmonary disease and potential role for monitoring treatment response.a 39-year-old man presented with left shoulder and interscapular pain. 99mtc-mdp bone scan demonstrated multiple active bone lesions including scapula, spines, ribs, and pelvis. chest x-ray showed no active lung lesion, and mri demonstrated infiltrative enhancing lesions in the t-spines and ribs, indicating skeletal metastasis. 18f-fdg pet/ct performed to search for hidden malignancy revealed multiple osteolytic lesions with intense fdg uptake, supporting metastasis. tissue obtained from the t1 ...201424561689
unconventional surface plasmon resonance signals reveal quantitative inhibition of transcriptional repressor ethr by synthetic ligands.ethr is a mycobacterial repressor that limits the bioactivation of ethionamide, a commonly used anti-tuberculosis second-line drug. several efforts have been deployed to identify ethr inhibitors abolishing the dna-binding activity of the repressor. this led to the demonstration that stimulating the bioactivation of eth through ethr inhibition could be an alternative way to fight mycobacterium tuberculosis. we propose a new surface plasmon resonance (spr) methodology to study the affinity between ...201424561027
diagnosing abdominal tuberculosis in the acute abdomen.despite recent improvements in medical treatments, the incidence of abdominal tuberculosis (atb) in the united kingdom has increased over the past two decades. this case series examined the difficulties encountered in correctly diagnosing this infection.201424560849
empyema necessitatis due to mycobacterium tuberculosis. 201524560698
prevalence and characterization of drug-resistant tuberculosis in a local hospital of northeast china.to investigate the distribution and risk factors associated with drug-resistant tuberculosis (tb) at a local hospital in northeast china.201424556164
benzimidazole-based compounds kill mycobacterium tuberculosis.tuberculosis remains one of the deadliest infectious diseases, killing 1.4 million people annually and showing a rapid increase in cases resistant to multiple drugs. new antibiotics against tuberculosis are urgently needed. here we describe the design, synthesis and structure-activity relationships of a series of benzimidazole-based compounds with activity against mycobacterium tuberculosis (mtb) in a replicating state, a physiologically-induced non-replicating state, or both. compounds 49, 67, ...201424556148
functional analysis of mce4a gene of mycobacterium tuberculosis h37rv using antisense approach.antisense strategy is an attractive substitute for knockout mutations created for gene silencing. mce genes have been shown to be involved in mycobacterial uptake and intracellular survival. here we report reduced expression of mce4a and mce1a genes of mycobacterium tuberculosis using antisense technology. for this, 1.1 kb region of mce4a and mce1a was cloned in reverse orientation in psd5 shuttle vector, resulting into antisense constructs psd5-4as and psd5-1as, respectively. in m. tuberculosis ...201424556072
a novel molecular typing method of mycobacteria based on dna barcoding visualization.different subtypes of mycobacterium tuberculosis (mtb) may induce diverse severe human infections, and some of their symptoms are similar to other pathogenes, e.g. nontuberculosis mycobacteria (ntm). so determination of mycobacterium subtypes facilitates the effective control of mtb infection and proliferation. this study exploits a novel dna barcoding visualization method for molecular typing of 17 mycobacteria genomes published in the ncbi prokaryotic genome database. three mycobacterium genes ...201424555538
isolation of the plant hormone (+)-abscisic acid as an antimycobacterial constituent of the medicinal plant endophyte nigrospora sp.an extract of the endophytic fungus nigropsora sp. (isolate tc2-054) from the canadian medicinal plant fragaria virginiana exhibited significant antimycobacterial activity against mycobacterium tuberculosis h37ra. bioassay guided fractionation revealed that linoleic acid derivatives and the plant hormone (+)-abscisic acid (aba) were responsible for the observed antimycobacterial activity. this activity of aba has not been previously reported.201324555269
potential for use of the seegene anyplex mtb/ntm real-time detection assay in a regional reference laboratory.requests for direct molecular diagnosis of mycobacterial disease are increasingly warranted. the anyplex mtb/ntm assay demonstrates sensitivities, specificities, and positive and negative predictive values of 1.00, 0.96, 0.93, and 1.00 for mycobacterium tuberculosis complex (mtbc) and 1.00, 0.97, 0.75, and 1.00 for nontuberculous mycobacteria (ntm) detection, respectively, making it a suitable screening test for mycobacterial detection.201424554748
design, synthesis and antimycobacterial activity of some new pyridazine derivatives: bis-pyridazine. part iv.the design, synthesis, structure and the antimycobacterial activities of a new class of nitrogen heterocycles, namely n1-substituted-diphenyl ether-bis-pyridazine (bp), is presented. an efficient, facile and straight applicable method for preparation of bp derivatives is described. the primary cycle high throughput screening reveals that two bp compounds, 2a and 3b, are potent inhibitors against mycobacterium tuberculosis (mtb), with their antitubercular activity being superior to the second-lin ...201324552228
mechanism of action of 5-nitrothiophenes against mycobacterium tuberculosis.on using the streptomycin-starved 18b strain as a model for nonreplicating mycobacterium tuberculosis, we identified a 5-nitrothiophene compound as highly active but not cytotoxic. mutants resistant to 5-nitrothiophenes were found be cross-resistant to the nitroimidazole pa-824 and unable to produce the f420 cofactor. furthermore, 5-nitrothiophenes were shown to be activated by the f420-dependent nitroreductase ddn and to release nitric oxide, a mechanism of action identical to that described fo ...201424550336
systems biology-based identification of mycobacterium tuberculosis persistence genes in mouse lungs.identifying mycobacterium tuberculosis persistence genes is important for developing novel drugs to shorten the duration of tuberculosis (tb) treatment. we developed computational algorithms that predict m. tuberculosis genes required for long-term survival in mouse lungs. as the input, we used high-throughput m. tuberculosis mutant library screen data, mycobacterial global transcriptional profiles in mice and macrophages, and functional interaction networks. we selected 57 unique, genetically d ...201424549847
the copper-responsive ricr regulon contributes to mycobacterium tuberculosis virulence.as with most life on earth, the transition metal copper (cu) is essential for the viability of the human pathogen mycobacterium tuberculosis. however, infected hosts can also use cu to control microbial growth. several cu-responsive pathways are present in m. tuberculosis, including the regulated in copper repressor (ricr) regulon, which is unique to pathogenic mycobacteria. in this work, we describe the contribution of each ricr-regulated gene to cu resistance in vitro and to virulence in anima ...201424549843
sequence analysis of the drug‑resistant rpob gene in the mycobacterium tuberculosis l‑form among patients with pneumoconiosis complicated by tuberculosis.the aim of the present study was to investigate the mutational characteristics of the drug‑resistant mycobacterium tuberculosis l‑form of the rpob gene isolated from patients with pneumoconiosis complicated by tuberculosis, in order to reduce the occurrence of the drug resistance of patients and gain a more complete information on the resistance of the mycobacterium tuberculosis l‑form. a total of 42 clinically isolated strains of mycobacterium tuberculosis l‑form were collected, including 31 dr ...201424535137
inhalable particles containing rapamycin for induction of autophagy in macrophages infected with mycobacterium tuberculosis.we investigated whether particles suitable for delivery to alveolar macrophages may provide a means of targeting rapamycin, an inducer of autophagy, to alveolar macrophages as a host-directed antituberculosis agent. inhalable particles were prepared by spray-drying and characterized using laser scattering and electron microscopy. their aerodynamic diameter was calculated from bulk and tapped densities. in vitro drug release was studied in pbs containing 1% sds. in vitro uptake of particles by th ...201424533458
verapamil, and its metabolite norverapamil, inhibit macrophage-induced, bacterial efflux pump-mediated tolerance to multiple anti-tubercular drugs.drug tolerance likely represents an important barrier to tuberculosis treatment shortening. we previously implicated the mycobacterium tuberculosis efflux pump rv1258c as mediating macrophage-induced tolerance to rifampicin and intracellular growth. in this study, we infected the human macrophage-like cell line thp-1 with drug-sensitive and drug-resistant m. tuberculosis strains and found that tolerance developed to most antituberculosis drugs, including the newer agents moxifloxacin, pa-824, li ...201424532601
primary application of ppe68 of mycobacterium tuberculosis.ppe68 protein is absent from bcg and the attenuated strains of mycobacterium tuberculosis (mtb). in this study, the shuttle plasmid pbudce4.1/ppe68/orim was constructed and transformed into bcg to obtain ppe68 recombination bcg (ppe68-rbcg), and balb/c mice were immunized with ppe68-rbcg to evaluate the immunological characterization of ppe68-rbcg. the level of lgg2a, ifn-γ, il-12 and il-4 in serum of immunized mice were detected, the proliferation response of spleen lymphocyte were measured, th ...201424530747
design, synthesis and antitubercular evaluation of novel series of n-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives.the analogs of n-[4-(piperazin-1-yl)phenyl]cinnamamide were designed and synthesized by molecular hybridization approach in which part c of the designed molecule was linked through amide and carbamate functionality that improves the physicochemical properties and govern the pharmacokinetic and pharmacodynamic behavior. the systematic modification was done around the part c to explore the structure activity relationship of antitubercular cinnamamide. all 52 compounds were evaluated for its antitu ...201424530490
disseminated tuberculosis presenting as tuberculous peritonitis and sepsis tuberculosa gravissima in a patient with cirrhosis of the liver: a diagnosis of challenge.we report the case of an 81-year-old man diagnosed with liver cirrhosis complicated by spontaneous bacterial peritonitis and septic shock. mycobacterium tuberculosis complex was isolated from the ascites, sputum, and blood culture 1 month after the patient died. clinicians should be aware of the unusual diagnosis of sepsis tuberculosa gravissima presenting with tuberculous peritonitis, which is easily misdiagnosed as spontaneous bacterial peritonitis and gram-negative bacillus sepsis in patients ...201624530253
a hydrolase of trehalose dimycolate induces nutrient influx and stress sensitivity to balance intracellular growth of mycobacterium tuberculosis.chronic tuberculosis in an immunocompetent host is a consequence of the delicately balanced growth of mycobacterium tuberculosis (mtb) in the face of host defense mechanisms. we identify an mtb enzyme (tdmhmtb) that hydrolyzes the mycobacterial glycolipid trehalose dimycolate and plays a critical role in balancing the intracellular growth of the pathogen. tdmhmtb is induced under nutrient-limiting conditions and remodels the mtb envelope to increase nutrient influx but concomitantly sensitizes m ...201424528862
multi-functional flow cytometry analysis of cd4+ t cells as an immune biomarker for latent tuberculosis status in patients treated with tumour necrosis factor (tnf) antagonists.although monitoring tuberculosis (tb) infection during long-term treatment with tumour necrosis factor (tnf) antagonists is of great importance, no monitoring strategy has yet proved successful. indeed, even the newly proposed interferon-gamma release assays (igras) are known to produce dynamic changes in ifn-γ plasma levels, making them unreliable indicators of patients' pathological/clinical status. we used intracellular cytokine flow cytometry (iccfc) to investigate the performance of multi-f ...201424528189
current methods in the molecular typing of mycobacterium tuberculosis and other mycobacteria.in the epidemiology of tuberculosis (tb) and nontuberculous mycobacterial (ntm) diseases, as in all infectious diseases, the key issue is to define the source of infection and to disclose its routes of transmission and dissemination in the environment. for this to be accomplished, the ability of discerning and tracking individual mycobacterium strains is of critical importance. molecular typing methods have greatly improved our understanding of the biology of mycobacteria and provide powerful to ...201424527454
in vitro and intracellular activity of 4-substituted piperazinyl phenyl oxazolidinone analogues against mycobacterium tuberculosis. 201424526515
application of cox proportional hazards model in case of tuberculosis patients in selected addis ababa health centres, ethiopia.introduction. tuberculosis (tb) is a chronic infectious disease and mainly caused by mycobacterium tuberculosis (mtb). it has been one of the major causes of mortality in ethiopia. the objective of the study was to identify factors that affect the survival of the patients with tuberculosis who started treatment for tuberculosis. methods. this was a retrospective study in six randomly selected health centres in addis ababa, ethiopia. the data were obtained from medical records of tb patients regi ...201424523962
real-time pcr assay for rapid detection of epidemiologically and clinically significant mycobacterium tuberculosis beijing genotype isolates.mycobacterium tuberculosis beijing genotype strains are rapidly disseminating, frequently hypervirulent, and multidrug resistant. here, we describe a method for their rapid detection by real-time pcr that targets the specific is6110 insertion in the dnaa-dnan genome region. the method was evaluated with a geographically and genetically diverse collection representing areas in east asia and the former soviet union in which the beijing genotype is endemic and epidemic (i.e., major foci of its glob ...201424523461
a low cost, safe, disposable, rapid and self-sustainable paper-based platform for diagnostic testing: lab-on-paper.there is a strong interest in the use of biopolymers in the electronic and biomedical industries, mainly towards low-cost applications. the possibility of developing entirely new kinds of products based on cellulose is of current interest, in order to enhance and to add new functionalities to conventional paper-based products. we present our results towards the development of paper-based microfluidics for molecular diagnostic testing. paper properties were evaluated and compared to nitrocellulos ...201424521980
identification of latent tuberculosis infection-related micrornas in human u937 macrophages expressing mycobacterium tuberculosis hsp16.3.latent tuberculosis infection (ltbi) relies on a homeostasis of macrophages and mycobacterium tuberculosis (mtb). the small heat shock protein, mtb hsp16.3 (also known as latency-associated antigen), plays an important role in mtb persistence within macrophages. however, the mechanism of ltbi remains elusive. the aim of this study was to delineate ltbi-related mirna expression in u937 macrophages expressing mtb hsp16.3 protein. u937 macrophages were infected with an integrase-deficient lentiviru ...201424521422
different subsets of macrophages in patients with new onset tuberculous pleural effusion.macrophages are the infiltrate components of tuberculous pleural effusion (tpe). this study is aimed at examining the role of different subsets of macrophages in pleural fluid (pf) and peripheral blood (pb) from patients with new onset tpe.201424520370
exploiting protein symmetry to design light-controllable enzyme inhibitors.the activity of the metabolic branch-point enzyme pria from mycobacterium tuberculosis (mtpria) can be controlled reversibly by light. two-pronged inhibitors based on the dithienylethene scaffold were designed utilizing mtpria's natural rotational symmetry. switching from the flexible, ring-open to the rigid, ring-closed isomer reduces inhibition activity by one order of magnitude.201424520030
restoration of innate immune activation accelerates th1-cell priming and protection following pulmonary mycobacterial infection.the immune mechanisms underlying delayed induction of th1-type immunity in the lungs following pulmonary mycobacterial infection remain poorly understood. we have herein investigated the underlying immune mechanisms for such delayed responses and whether a selected innate immune-modulating strategy can accelerate th1-type responses. we have found that, in the early stage of pulmonary infection with attenuated mycobacterium tuberculosis (m.tb h37ra), the levels of infection in the lung continue t ...201424519467
fluorescent quantitative pcr of mycobacterium tuberculosis for differentiating intestinal tuberculosis from crohn's disease.intestinal tuberculosis (itb) and crohn's disease (cd) are granulomatous disorders with similar clinical manifestations and pathological features that are often difficult to differentiate. this study evaluated the value of fluorescent quantitative polymerase chain reaction (fq-pcr) for mycobacterium tuberculosis (mtb) in fecal samples and biopsy specimens to differentiate itb from cd. from june 2010 to march 2013, 86 consecutive patients (38 females and 48 males, median age 31.3 years) with prov ...201424519133
assessing the essentiality of the decaprenyl-phospho-d-arabinofuranose pathway in mycobacterium tuberculosis using conditional mutants.in mycobacterium tuberculosis the decaprenyl-phospho-d-arabinofuranose (dpa) pathway is a validated target for the drugs ethambutol and benzothiazinones. to identify other potential drug targets in the pathway, we generated conditional knock-down mutants of each gene involved using the tet-pip off system. dpre1, dpre2, ubia, prsa, rv2361c, tkt and rpib were confirmed to be essential under non-permissive conditions, whereas rv3807c was not required for survival. in the most vulnerable group, dpre ...201424517327
non-replicating mycobacterium tuberculosis elicits a reduced infectivity profile with corresponding modifications to the cell wall and extracellular matrix.a key feature of mycobacterium tuberculosis is its ability to become dormant in the host. little is known of the mechanisms by which these bacilli are able to persist in this state. therefore, the focus of this study was to emulate environmental conditions encountered by m. tuberculosis in the granuloma, and determine the effect of such conditions on the physiology and infectivity of the organism. non-replicating persistent (nrp) m. tuberculosis was established by the gradual depletion of nutrie ...201424516549
moxifloxacin retains antimycobacterial activity in the presence of gyra mutations.moxifloxacin-resistant mycobacterium tuberculosis mutants were selected in vitro using different concentrations of moxifloxacin. gyra mutations at codons 88 and 94 were associated with resistance (defined as an mic of ≥2 μg/ml) (p < 0.0001 and p = 0.0053, respectively). despite the presence of gyra mutations, moxifloxacin significantly impedes bacterial growth, supporting its use for the treatment of ofloxacin-resistant m. tuberculosis.201424514091
atp synthase in mycobacteria: special features and implications for a function as drug target.atp synthase is a ubiquitous enzyme that is largely conserved across the kingdoms of life. this conservation is in accordance with its central role in chemiosmotic energy conversion, a pathway utilized by far by most living cells. on the other hand, in particular pathogenic bacteria whilst employing atp synthase have to deal with energetically unfavorable conditions such as low oxygen tensions in the human host, e.g. mycobacterium tuberculosis can survive in human macrophages for an extended tim ...201424513197
histopathological findings in immunohistological staining of the granulomatous tissue reaction associated with tuberculosis.purpose. the histological diagnosis of mycobacterium tuberculosis (mtb) remains a diagnostic challenge despite different methods. immunohistochemistry (ihc) not only could confirm granulomatous tissue involvement but also can demonstrate mtb antigen immunolocalization. this study tries to clarify the details of immunohistochemical staining for mtb with pabbcg. materials/methods. twenty-three confirmed tb granulomatous tissue samples were studied by ziehl-neelsen and immunohistochemistry (ihc) st ...201424511393
disseminated tuberculosis following liver transplant presenting with an axillary abscess.four years after an orthoptic liver transplant for hepatocellular carcinoma secondary to alcoholic liver disease, the patient presented in a crescendo manner with skin infections and finally a septic right arm wound. the abscess was drained and cultures grew mycobacterium tuberculosis. the patient reported a previous episode of 'pneumonia' and subsequent hospitalisations for recurrent chest infections, and following further investigation, he was diagnosed with disseminated tuberculosis. the infe ...201424510698
assignment of oriented sample nmr resonances from a three transmembrane helix protein.oriented sample solid state nmr techniques have been routinely employed to determine the structures of membrane proteins with one or two transmembrane helices. for larger proteins the technique has been limited by spectral resolution and lack of assignment strategies. here, a strategy for resonance assignment is devised and applied to a three transmembrane helix protein. sequence specific assignments for all labeled transmembrane amino acid sites are obtained, which provide a set of orientationa ...201424509383
mycobacterium tuberculosis as cause of therapeutic failure in prosthetic joint infections. 201424508372
drug resistance pattern of mycobacterium tuberculosis isolates from patients of five provinces of iran.to determine the patterns of resistance to first line anti-tuberculosis (tb) drugs among a collection of mycobacterium tuberculosis (mtb) isolates from 5 provinces of iran.201424507638
a case of multidrug-resistant monoarticular joint tuberculosis in a renal transplant recipient.tuberculosis (tb) is a common opportunistic infection after renal transplantation. the risk of tb in renal transplant recipients is reported to be 20 to 74 times higher than in the general population. although extrapulmonary tb occurs frequently, isolated ankle joint tb is a rare form of extrapulmonary tb infection. it is often difficult to diagnose because of its atypical presentation; management is complex, especially with multidrug-resistant tb, the need for a prolonged course of therapy, and ...201424507066
evidence for a role for interleukin-17, th17 cells and iron homeostasis in protective immunity against tuberculosis in cynomolgus macaques.tuberculosis (tb) remains a major global public health problem. the only vaccine, bcg, gives variable protection, especially in adults, so several new vaccines are in clinical trials. there are no correlates of protective immunity to tb; therefore vaccines progress through lengthy and expensive pre-clinical assessments and human trials. correlates of protection could act as early end-points during clinical trials, accelerating vaccine development and reducing costs. a genome-wide microarray was ...201424505407
pentacyclic nitrofurans with in vivo efficacy and activity against nonreplicating mycobacterium tuberculosis.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 pen ...201424505329
use of ancillary techniques in improving the yield of samples obtained at endoscopic ultrasound-guided fine needle aspiration of thoracic and abdominal lymph nodes.thoracic and abdominal lymph nodes may be enlarged in a variety of disorders. endoscopic ultrasound-guided fine needle aspiration (eus-fna) is a well-established technique for sampling such nodes, but samples obtained are small, which may make definitive diagnosis difficult. we conducted a retrospective review to determine the contribution of ancillary techniques, such as special histochemistry (shc), immunohistochemistry (ihc) and flow cytometry, in increasing the diagnostic yield of eus-fna ca ...201424503737
commercial nucleic acid amplification tests in tuberculous meningitis--a meta-analysis.although nucleic acid amplification tests (naats) promise a rapid, definitive diagnosis of tuberculous meningitis, the performance of first-generation naats was suboptimal and variable. we conducted a meta-analysis of studies published between 2003 and 2013, using the quality assessment of diagnostic accuracy studies-2 (quadas-2) tool to evaluate methodological quality. the diagnostic accuracy of newer commercial naats was assessed. pooled estimates of diagnostic accuracy for commercial naats me ...201424503504
autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial.novel treatment options are urgently needed for multidrug-resistant (mdr) and extensively drug-resistant (xdr) tuberculosis, which are associated with immune dysfunction and poor treatment outcomes. mesenchymal stromal cells (mscs) are immunomodulatory and adjunct autologous treatment with bone marrow-derived mscs might improve clinical outcome by transforming chronic inflammation into productive immune responses. our aim was to assess the safety of infusion of autologous mscs as an adjunct trea ...201424503266
inventory study of non-tuberculous mycobacteria in the european union.since non-tuberculous mycobacteria (ntm) disease is not notifiable in most european union (eu) and european economic area (eea) countries, the epidemiological situation of the >150 ntm species is largely unknown. we aimed to collect data on the frequency of ntm detection and ntm species types in eu/eea countries.201424502462
[the dependence of the inflammatory reaction on the properties of mycobacterium tuberculosis and the course of specific pulmonary process].the systemic analysis of the inflammatory process in untreated patients with newly diagnosed infiltrative-destructive tuberculosis has been performed in the context of host mycobacterium interaction. variability of acute phase proteins (app) reflecting mobilization of nonspecific protective systems of the body did not depend on cytotoxicity of mycobacterium tuberculosis (mbt). in 87.5% of patients the dependence between effectiveness of antitubercular chemotherapy (for three months) and combinat ...201424502145
all-trans retinoic acid-triggered antimicrobial activity against mycobacterium tuberculosis is dependent on npc2.a role for vitamin a in host defense against mycobacterium tuberculosis has been suggested through epidemiological and in vitro studies; however, the mechanism is unclear. in this study, we demonstrate that vitamin a-triggered antimicrobial activity against m. tuberculosis requires expression of npc2. comparison of monocytes stimulated with all-trans retinoic acid (atra) or 1,25-dihydroxyvitamin d3 (1,25d3), the biologically active forms of vitamin a and vitamin d, respectively, indicates that a ...201424501203
optimization of standard in-house 24-locus variable-number tandem-repeat typing for mycobacterium tuberculosis and its direct application to clinical material.variable-number tandem-repeat (vntr) typing with a panel of 24 loci is the current gold standard in the molecular typing of mycobacterium tuberculosis complex isolates. however, because of technical problems, a part of the loci often cannot be amplified by multiplex pcrs. therefore, a considerable number of single-locus pcrs have to be performed for the loci with missing results, which impairs the laboratory work flow. therefore, the original in-house method described by supply et al. in 2006 wa ...201424501023
towards a new combination therapy for tuberculosis with next generation benzothiazinones.the benzothiazinone lead compound, btz043, kills mycobacterium tuberculosis by inhibiting the essential flavo-enzyme dpre1, decaprenylphosphoryl-beta-d-ribose 2-epimerase. here, we synthesized a new series of piperazine-containing benzothiazinones (pbtz) and show that, like btz043, the preclinical candidate pbtz169 binds covalently to dpre1. the crystal structure of the dpre1-pbtz169 complex reveals formation of a semimercaptal adduct with cys387 in the active site and explains the irreversible ...201424500695
dynamic evolution and immunoreactivity of aptamers binding to polyclonal antibodies against mpt64 antigen of mycobacterium tuberculosis.antibody responses can be useful markers of tuberculosis infection. however, the established immunoassay diagnostic method is limited by antigenic variability. replacing the recombinant proteins with aptamers may overcome these antigenic challenges. in this study, we systematically monitored the selection process of aptamers against anti-mpt64 antibodies of mycobacterium tuberculosis to obtain more aptamers for developing a multisite system to increase the sensitivity of tb serological diagnosis ...201424500599
evaluation of fluorotype mtb for detection of mycobacterium tuberculosis complex dna in clinical specimens from a low-incidence country.with fluorotype mtb (ft mtb, hain lifesciences, germany) a new semi-automated assay for detection of m. tuberculosis complex (mtbc) in clinical specimens has been introduced. in a prospective study, we evaluated the diagnostic performance of ft mtb in a routine diagnostic setting in a low-incidence country.201424498967
construction and immunogenicity of the dna vaccine of mycobacterium tuberculosis dormancy antigen rv1733c.we aimed to construct the dna vaccine encoding mycobacterium tuberculosis (mtb) dormancy antigen rv1733c and investigate its immunogenicity in mice. the recombinant plasmid pcdna-rv1733c was transfected into p815 cells and its product was detected by indirect immunofluorescence. the mice were immunized once every 2 weeks by intramuscular injection of pcdna-rv1733c plasmid for a total of three times. the specific antibodies in the serum of the immunized mice were detected by enzyme-linked immunos ...201424498941
the candidate tb vaccine, mva85a, induces highly durable th1 responses.vaccination against tuberculosis (tb) should provide long-term protective immunity against mycobacterium tuberculosis (m.tb). the current tb vaccine, bacille calmette-guerin (bcg), protects against disseminated childhood tb, but protection against lung tb in adolescents and adults is variable and mostly poor. one potential reason for the limited durability of protection may be waning of immunity through gradual attrition of bcg-induced t cells. we determined if a mva85a viral-vector boost could ...201424498312
high tuberculosis prevalence in a south african prison: the need for routine tuberculosis screening.tuberculosis is a major health concern in prisons, particularly where hiv prevalence is high. our objective was to determine the undiagnosed pulmonary tuberculosis ("undiagnosed tuberculosis") prevalence in a representative sample of prisoners in a south african prison. in addition we investigated risk factors for undiagnosed tuberculosis, to explore if screening strategies could be targeted to high risk groups, and, the performance of screening tools for tuberculosis.201424498059
reengineering redox sensitive gfp to measure mycothiol redox potential of mycobacterium tuberculosis during infection.mycobacterium tuberculosis (mtb) survives under oxidatively hostile environments encountered inside host phagocytes. to protect itself from oxidative stress, mtb produces millimolar concentrations of mycothiol (msh), which functions as a major cytoplasmic redox buffer. here, we introduce a novel system for real-time imaging of mycothiol redox potential (emsh ) within mtb cells during infection. we demonstrate that coupling of mtb msh-dependent oxidoreductase (mycoredoxin-1; mrx1) to redox-sensit ...201424497832
tlr2 engagement on cd4(+) t cells enhances effector functions and protective responses to mycobacterium tuberculosis.we have previously demonstrated that mycobacterial lipoproteins engage tlr2 on human cd4(+) t cells and upregulate tcr-triggered ifn-γ secretion and cell proliferation in vitro. here we examined the role of cd4(+) t-cell-expressed tlr2 in mycobacterium tuberculosis (mtb) ag-specific t-cell priming and in protection against mtb infection in vivo. like their human counterparts, mouse cd4(+) t cells express tlr2 and respond to tlr2 costimulation in vitro. this th1-like response was observed in the ...201424497180
catalytic regioselective synthesis of pyrazole based pyrido[2,3-d]pyrimidine-diones and their biological evaluation.a new type of biopolymer-based heterogeneous catalyst, cellulose supported acidic ionic liquid (cell-il), which was developed earlier in our lab, has been found to be very effective for the regioselective synthesis of pyrazole based pyrido[2,3-d]pyrimidine-diones. its regioselectivity was confirmed by (1)h nmr spectroscopy. all the newly synthesized compounds were characterized by lc-ms, (1)h nmr, (13)c nmr, ir spectroscopy and elemental analysis. the newly synthesized compounds were evaluated f ...201424496121
exact vs. approximate computation: reconciling different estimates of mycobacterium tuberculosis epidemiological parameters.exact computational methods for inference in population genetics are intuitively preferable to approximate analyses. we reconcile two starkly different estimates of the reproductive number of tuberculosis from previous studies that used the same genotyping data and underlying model. this demonstrates the value of approximate analyses in validating exact methods.201424496011
transcriptional regulation of bacterial virulence gene expression by molecular oxygen and nitric oxide.molecular oxygen (o 2) and nitric oxide (no) are diatomic gases that play major roles in infection. the host innate immune system generates reactive oxygen species and no as bacteriocidal agents and both require o 2 for their production. furthermore, the ability to adapt to changes in o 2 availability is crucial for many bacterial pathogens, as many niches within a host are hypoxic. pathogenic bacteria have evolved transcriptional regulatory systems that perceive these gases and respond by repro ...201424495931
challenges and solutions for a rational vaccine design for tb-endemic regions.vaccines have been successful for global eradication or control of dreaded diseases such as smallpox, diphtheria, tetanus, yellow fever, whooping cough, polio, and measles. unfortunately, this success has not been achieved for controlling tuberculosis (tb) worldwide. bacillus calmette guérin (bcg) is the only available vaccine against tb. paradoxically, bcg has deciphered success in the western world but has failed in tb-endemic areas. in this article, we highlight and discuss the aspects of imm ...201524495096
adjuvanted poly(lactic-co-glycolic) acid nanoparticle-entrapped inactivated porcine reproductive and respiratory syndrome virus vaccine elicits cross-protective immune response in pigs.porcine reproductive and respiratory syndrome (prrs), caused by the prrs virus (prrsv), is an economically devastating disease, causing daily losses of approximately $3 million to the us pork industry. current vaccines have failed to completely prevent prrs outbreaks. recently, we have shown that poly(lactic-co-glycolic) acid (plga) nanoparticle-entrapped inactivated prrsv vaccine (np-kag) induces a cross-protective immune response in pigs. to further improve its cross-protective efficacy, the n ...201424493925
increased severity of tuberculosis in guinea pigs with type 2 diabetes: a model of diabetes-tuberculosis comorbidity.impaired glucose tolerance and type 2 diabetes were induced in guinea pigs to model the emerging comorbidity of mycobacterium tuberculosis infection in diabetic patients. type 2 diabetes mellitus was induced by low-dose streptozotocin in guinea pigs rendered glucose intolerant by first feeding a high-fat, high-carbohydrate diet before m. tuberculosis exposure. m. tuberculosis infection of diabetic guinea pigs resulted in severe and rapidly progressive tuberculosis (tb) with a shortened survival ...201424492198
serine 83 in dosr, a response regulator from mycobacterium tuberculosis, promotes its transition from an activated, phosphorylated state to an inactive, unphosphorylated state.a sensor kinase, doss, and its corresponding response regulator, dosr, constitute a two component system for regulating gene expression under hypoxic conditions in mycobacterium tuberculosis. among response regulators in m. tuberculosis, narl has high sequence similarity to dosr, and autophosphorylated doss transfers its phosphate group not only to dosr but also to narl. phosphorylated dosr is more rapidly dephosphorylated than phosphorylated narl. dosr and narl differ with respect to the amino ...201424491537
single nucleotide polymorphism (snp) analysis used for the phylogeny of the mycobacterium tuberculosis complex based on a pyrosequencing assay.different polymorphisms have been described as markers to classify the lineages of the mycobacterium tuberculosis complex. the analysis of nine single nucleotide polymorphisms (snps) was used to describe seven snps cluster groups (scgs). we attempted to classify those strains that could not been categorized into lineages by the genotyping methods used in the routine testing.201424491224
lichen scrofulosorum presenting as pyrexia of unknown origin.cutaneous tuberculosis forms a subset of extra pulmonary tuberculosis. it accounts for about 1.5% of all the cases of extrapulmonary tuberculosis. lichen scrofulosorum is a rare form of cutaneous tuberculosis. it is usually seen in children or young adults and an important marker of occult tuberculosis. usually, the eruption appears in children and adolescents with strong immune sensitivity to mycobacterium tuberculosis and consists of tiny follicular papules. underlying systemic involvement is ...201424491013
cd4+ t cells contain early extrapulmonary tuberculosis (tb) dissemination and rapid tb progression and sustain multieffector functions of cd8+ t and cd3- lymphocytes: mechanisms of cd4+ t cell immunity.the possibility that cd4(+) t cells can act as "innate-like" cells to contain very early mycobacterium tuberculosis dissemination and function as master helpers to sustain multiple effector functions of cd8(+) t cells and cd3(-) lymphocytes during development of adaptive immunity against primary tuberculosis (tb) has not been demonstrated. we showed that pulmonary m. tuberculosis infection of cd4-depleted macaques surprisingly led to very early extrapulmonary m. tuberculosis dissemination, where ...201424489088
application of peripheral blood mycobacterium tuberculosis pcr for diagnosis of tuberculosis patients.mycobacterium tuberculosis (mtb) infection is a global health problem. failure to accurately identify cases of active mtb has serious effects on both patients and the community. acid-fast bacilli (afb) smear has poor sensitivity and culture methods have a delay ranging from 1 to 8 weeks for diagnosis. nucleic acid amplification assays may be suitable candidates for this purpose.201424488906
synthesis and evaluation of anti-tubercular activity of 6-(4-substitutedpiperazin-1-yl) phenanthridine analogues.a series of seventeen new 6-(4-substitutedpiperazin-1-yl)phenanthridine derivatives were designed, synthesized, and evaluated for their anti-tubercular activity against mycobacterium tuberculosis h37rv by microplate alamar blue assay and most active compounds were tested for cytotoxicity studies against mouse macrophage cell lines (raw264.7). among the tested compounds, ten compounds exhibited significant activity against the growth of m. tuberculosis (mic ranging from 1.56 to 6.25 μg/ml). in pa ...201424486416
degree, duration, and causes of visual impairment in eyes affected with ocular tuberculosis.ocular tuberculosis (tb) can affect nearly every ocular tissue, leading to a variety of vision-threatening clinical manifestations. the goal of this study is to estimate the degree, duration, and causes of visual impairment in eyes affected by ocular tb.201424485195
comparative evaluation of three immunochromatographic identification tests for culture confirmation of mycobacterium tuberculosis complex.the rapid identification of acid-fast bacilli recovered from patient specimens as mycobacterium tuberculosis complex (mtc) is critically important for accurate diagnosis and treatment. a thin-layer immunochromatographic (tlc) assay using anti-mpb64 or anti-mpt64 monoclonal antibodies was developed to discriminate between mtc and non-tuberculosis mycobacteria (ntm). capilia tb-neo, which is the improved version of capilia tb, is recently developed and needs to be evaluated.201424484470
a metabolic biosignature of early response to anti-tuberculosis treatment.the successful treatment of tuberculosis (tb) requires long-term multidrug chemotherapy. clinical trials to evaluate new drugs and regimens for tb treatment are protracted due to the slow clearance of mycobacterium tuberculosis (mtb) infection and the lack of early biomarkers to predict treatment outcome. advancements in the field of metabolomics make it possible to identify metabolic profiles that correlate with disease states or successful chemotherapy. however, proof-of-concept of this approa ...201424484441
serum complement c4b, fibronectin, and prolidase are associated with the pathological changes of pulmonary tuberculosis.mycobacterium tuberculosis infection can activate the immune system, leading to characteristic pathological changes such as inflammatory granuloma, caseous necrosis, and cavity formation.201424484408
salivary sig-a response against the recombinant ag38 antigen of mycobacterium tuberculosis indonesian strain.an evaluation of the humoral response based on secretory immunoglobulin a levels in the saliva of pulmonary tuberculosis (tb) acid-fast bacillus-positive (tb-afb+) patients against a recombinant 38 kda antigen (ag38-rec) is reported. a total of 60 saliva samples consist of 30 tb-afb+ patients and 30 healthy controls were tested against 500 ng of semi-purified antigen using the dot blot method. results showed that the protein antigen could differentiate between healthy individuals and tb-afb(+) p ...201424482698
a genomic portrait of the genetic architecture and regulatory impact of microrna expression in response to infection.micrornas (mirnas) are critical regulators of gene expression, and their role in a wide variety of biological processes, including host antimicrobial defense, is increasingly well described. consistent with their diverse functional effects, mirna expression is highly context dependent and shows marked changes upon cellular activation. however, the genetic control of mirna expression in response to external stimuli and the impact of such perturbations on mirna-mediated regulatory networks at the ...201424482540
inhibition of mycobacterium tuberculosis transaminase bioa by aryl hydrazines and hydrazides.7,8-diaminopelargonic acid synthase (bioa) of mycobacterium tuberculosis is a recently validated target for therapeutic intervention in the treatment of tuberculosis (tb). using biophysical fragment screening and structural characterization of compounds, we have identified a potent aryl hydrazine inhibitor of bioa that reversibly modifies the pyridoxal-5'-phosphate (plp) cofactor, forming a stable quinonoid. analogous hydrazides also form covalent adducts that can be observed crystallographicall ...201424482078
an indeterminate result of quantiferon-tb gold in-tube for miliary tuberculosis due to a high level of ifn-γ production.the quantiferon-tb gold in-tube(®) test has excellent specificity for mycobacterium tuberculosis. however, diagnosis of miliary tuberculosis remains challenging, and the interpretation of quantiferon(®) results in immunocompromised individuals has not been fully established. here, we present a patient with military tuberculosis who showed an indeterminate quantiferon(®) result. a 76-year-old male presented with fever and pancytopenia. radiological tests did not show the classical miliary pattern ...201424481938
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