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construction of a novel dna vaccine candidate encoding an hspx-ppe44-esxv fusion antigen of mycobacterium tuberculosis.mycobacterium tuberculosis is the causative agent of tuberculosis (tb). bacille calmette-guerin (bcg) vaccine, is not effective in adults, therefore, many efforts have been made to produce an effective adult tb vaccine. the aim of this study was to develop a new tuberculosis dna vaccine candidate encoding a recombinant hspx-ppe44-esxv fusion antigen of m. tuberculosis.201627536702
a case of testicular tuberculosis mimicking malignancy in a healthy young man.genitourinary tuberculosis represents a form of extra-pulmonary tuberculosis that occurs in the kidneys, ureters, seminal vesicles, prostate, testis, vas deferens, and epididymis. isolated testicular involvement is unusual, and differential diagnosis includes testicular tumor, acute infection, infarction, and granulomatous infection. we report a case of a 36-year-old ecuadorian man residing in new york, new york, who presented with a painful scrotal mass, weight loss, and purulent discharge from ...201627536355
drug-resistant tuberculosis in central mozambique: the role of a rapid genotypic susceptibility testing.genotypic molecular testing may be very helpful for tuberculosis (tb) drug-resistance surveillance and for treatment guidance in low resource settings.201627534745
ligand-bound structures and site-directed mutagenesis identify the acceptor and secondary binding sites of streptomyces coelicolor maltosyltransferase glge.glge is a maltosyltransferase involved in α-glucan biosynthesis in bacteria that has been genetically validated as a target for tuberculosis therapies. crystals of the mycobacterium tuberculosis enzyme diffract at low resolution so most structural studies have been with the very similar streptomyces coelicolor glge isoform 1. although the donor binding site for α-maltose 1-phosphate had been previously structurally defined, the acceptor site had not. using mutagenesis, kinetics, and protein crys ...201627531751
mycobacterial carbonic anhydrase inhibition with phenolic acids and esters: kinetic and computational investigations.a series of phenolic acids and some of their esters, derivatives of caffeic, ferulic, and p-coumaric acid, was investigated for the inhibition of three β-carbonic anhydrases (cas, ec 4.2.1.1) from the pathogenic bacterium mycobacterium tuberculosis, rv1248, rv3588 and rv3273 β-cas. some of these compounds were low micromolar inhibitors of the pathogenic enzymes and they did not show inhibitory activity against the human widespread cytosolic isoforms ca i and ii. the binding mode of these inhibit ...201627530867
whole-genome sequencing of multidrug-resistant mycobacterium tuberculosis isolates from myanmar.drug-resistant tuberculosis (tb) is a major health threat in myanmar. an initial study was conducted to explore the potential utility of whole-genome sequencing (wgs) for the diagnosis and management of drug-resistant tb in myanmar. fourteen multidrug-resistant mycobacterium tuberculosis isolates were sequenced. known resistance genes for a total of nine antibiotics commonly used in the treatment of drug-susceptible and multidrug-resistant tb (mdr-tb) in myanmar were interrogated through wgs. al ...201627530852
genetic variation in mycobacterium tuberculosis isolates from a london outbreak associated with isoniazid resistance.the largest outbreak of isoniazid-resistant (inh-r) mycobacterium tuberculosis in western europe is centred in north london, with over 400 cases diagnosed since 1995. in the current study, we evaluated the genetic variation in a subset of clinical samples from the outbreak with the hypothesis that these isolates have unique biological characteristics that have served to prolong the outbreak.201627530812
comment on: delamanid susceptibility testing of mycobacterium tuberculosis using the resazurin microtitre assay and the bactec™ mgit™ 960 system. 201627530753
[reactivation of tuberculosis presenting with empyema due to anticancer chemotherapy for diffuse large b cell lymphoma].a 79-year-old man with a history of tuberculosis was found to have chronic empyema in the right lung and was diagnosed with malignant diffuse large-cell lymphoma (ann arbor stage iie). after completion of one course of rituximab plus cyclophosphamide, pirarubicin, vincristine, and prednisolone (r-chop) chemotherapy, the patient developed lung abscess and sepsis caused by streptococcus intermedius. this condition was treated with antimicrobial agents, and chemotherapy was resumed. after the secon ...201627530021
asymmetric total synthesis of (-)-erogorgiaene and its c-11 epimer and investigation of their antimycobacterial activity.a short, nine-step, highly enantioselective synthesis of (-)-erogorgiaene and its c-11 epimer is reported. the key stereochemistry controlling steps involve catalytic asymmetric crotylation, anionic oxy-cope rearrangement and cationic cyclisation. (-)-erogorgiaene exhibited promising antitubercular activity against multidrug-resistant strains of mycobacterium tuberculosis.201627529822
tuberculous cellulitis: diseases behind cellulitislike erythema.an 89-year-old man presented with an inflammatory erythematous plaque on the left thigh that closely mimicked cellulitis. empiric therapies with ordinary antibiotics were not effective. a skin biopsy showed epithelioid cell granulomas throughout the dermis and subcutis. ziehl-neelsen stain revealed numerous acid-fast bacilli. additionally, mycobacterium tuberculosis was isolated from a skin biopsy specimen as well as gastric fluid and sputum cultures. he was diagnosed with tuberculous cellulitis ...201627529716
immunotherapy for tuberculosis: future prospects.tuberculosis (tb) is still a major global health problem. a third of the world's population is infected with mycobacterium tuberculosis. only ~10% of infected individuals develop tb but there are 9 million tb cases with 1.5 million deaths annually. the standard prophylactic treatment regimens for latent tb infection take 3-9 months, and new cases of tb require at least 6 months of treatment with multiple drugs. the management of latent tb infection and tb has become more challenging because of t ...201627529060
in vitro mycobacterial growth inhibition assays: a tool for the assessment of protective immunity and evaluation of tuberculosis vaccine efficacy.tuberculosis (tb) continues to pose a serious global health threat, and the current vaccine, bcg, has variable efficacy. however, the development of a more effective vaccine is severely hampered by the lack of an immune correlate of protection. candidate vaccines are currently evaluated using preclinical animal models, but experiments are long and costly and it is unclear whether the outcomes are predictive of efficacy in humans. unlike measurements of single immunological parameters, mycobacter ...201627527814
stringent response factors ppx1 and ppk2 play an important role in mycobacterium tuberculosis metabolism, biofilm formation, and sensitivity to isoniazid in vivo.mycobacterium tuberculosis remains a global health threat largely due to the lengthy duration of curative antibiotic treatment, contributing to medical nonadherence and the emergence of drug resistance. this prolonged therapy is likely due to the presence of m. tuberculosis persisters, which exhibit antibiotic tolerance. inorganic polyphosphate [poly(p)] is a key regulatory molecule in the m. tuberculosis stringent response mediating antibiotic tolerance. the polyphosphate kinase ppk1 is respons ...201627527086
characterization of dpre1-mediated benzothiazinone resistance in mycobacterium tuberculosis.benzothiazinones (btzs) are a class of compounds found to be extremely potent against both drug-susceptible and drug-resistant mycobacterium tuberculosis strains. the potency of btzs is explained by their specificity for their target decaprenylphosphoryl-d-ribose oxidase (dpre1), in particular by covalent binding of the activated form of the compound to the critical cysteine 387 residue of the enzyme. to probe the role of c387, we used promiscuous site-directed mutagenesis to introduce other cod ...201627527085
evaluation of a whole-blood chemiluminescent immunoassay of ifn-γ, ip-10, and mcp-1 for diagnosis of active pulmonary tuberculosis and tuberculous pleurisy patients.the study explored the use of ip-10, mcp-1, and ifn-γ as biomarkers to improve the diagnoses of active pulmonary tuberculosis and tuberculous pleurisy. we enrolled 267 individuals, including 134 tb patients, 93 patients with non-tuberculous pulmonary diseases, and 40 healthy controls. whole bloods were stimulated in vitro with rcfp-10/esat-6 protein antigen of mycobacterium tuberculosis. the levels of ifn-γ, ip-10, and mcp-1 in cultured supernatants of whole bloods were detected by a chemilumine ...201627523388
rifampicin resistance mutations in the 81 bp rrdr of rpob gene in mycobacterium tuberculosis clinical isolates using xpert mtb/rif in khyber pakhtunkhwa, pakistan: a retrospective study.multi-drug resistant tuberculosis (mdr-tb) is a major public health problem especially in developing countries. world health organization (who) recommends use of xpert mtb/rif assay to simultaneously detecting mycobacterium tuberculosis (mtb) and rifampicin (rif) resistance. the primary objective of this study was to determine the frequency of mdr-tb in patients suspected to have drug resistance in khyber pakhtunkhwa. the frequency of probes for various rpob gene mutations using xpert mtb/rif as ...201627519406
whole-genome sequencing analysis of serially isolated multi-drug and extensively drug resistant mycobacterium tuberculosis from thai patients.multi-drug and extensively drug-resistant tuberculosis (mdr and xdr-tb) are problems that threaten public health worldwide. only some genetic markers associated with drug-resistant tb are known. whole-genome sequencing (wgs) is a promising tool for distinguishing between re-infection and persistent infection in isolates taken at different times from a single patient, but has not yet been applied in mdr and xdr-tb. we aim to detect genetic markers associated with drug resistance and distinguish b ...201627518818
analysis of mycobacterium tuberculosis genotypic lineage distribution in chile and neighboring countries.tuberculosis (tb), caused by the pathogen mycobacterium tuberculosis (mtb), remains a disease of high importance to global public health. studies into the population structure of mtb have become vital to monitoring possible outbreaks and also to develop strategies regarding disease control. although chile has a low incidence of mtb, the current rates of migration have the potential to change this scenario. we collected and analyzed a total of 458 m. tuberculosis isolates (1 isolate per patient) ...201627518286
molecular detection of mycobacterium tuberculosis in cattle and buffaloes: a cause for public health concern.tuberculosis is a re-emerging disease causing a growing public health burden. the current study was conducted to investigate the occurrence of mycobacterium tuberculosis among cattle and buffaloes with tuberculous lesions. typical tuberculous lesions were collected from 34 cattle and 34 buffaloes (bubalus bubalis) through postmortem examination of slaughtered animals in abattoirs. dnas were extracted from samples, and m. tuberculosis was identified by pcr. positive samples were examined for resi ...201627517579
first-line anti-tubercular drug resistance of mycobacterium tuberculosis in iran: a systematic review.the spread of drug-resistant tuberculosis (tb) is one of the major public health problems through the world. surveillance of anti-tb drug resistance is essential for monitoring of tb control strategies. the occurrence of drug resistance, particularly multi-drug resistance mycobacterium tuberculosis (mdr), defined as resistance to at least rifampicin (rif) and isoniazid (inh), has become a significant public health dilemma. the status of drug-resistance tb in iran, one of the eastern mediterranea ...201627516756
official american thoracic society/centers for disease control and prevention/infectious diseases society of america clinical practice guidelines: treatment of drug-susceptible tuberculosis.the american thoracic society, centers for disease control and prevention, and infectious diseases society of america jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the european respiratory society and the us national tuberculosis controllers association. representatives from the american academy of pediatrics, the canadian thoracic society, the international union against tuberculosis and lung disease, and the wo ...201627516382
[analysis on drug resistance of mycobacterium tuberculosis and influencing factors in six provinces of china].to analyze the drug-resistance of clinical mycobacterium tuberculosis strains isolated from the tuberculosis(tb)patients in six provinces in china and related risk factors, and provide evidences for the effective prevention and treatment of drug resistant tb.201627453102
comparison of cortisol and thyroid hormones between tuberculosis-suspect and healthy elephants of nepal.we compared cortisol and thyroid hormone (t3 and t4) concentrations between tuberculosis (tb)-suspected (n=10) and healthy (n=10) elephants of nepal. whole blood was collected from captive elephants throughout nepal, and tb testing was performed using the elephanttb stat-pak(®) and dpp vettb(®) serological assays that detect antibodies against mycobacterium tuberculosis and m. bovis in elephant serum. cortisol, t3 and t4 were quantified by competitive enzyme immunoassays, and the results showed ...201627452878
microfold cells actively translocate mycobacterium tuberculosis to initiate infection.the prevailing paradigm is that tuberculosis infection is initiated when patrolling alveolar macrophages and dendritic cells within the terminal alveolus ingest inhaled mycobacterium tuberculosis (mtb). however, definitive data for this model are lacking. among the epithelial cells of the upper airway, a specialized epithelial cell known as a microfold cell (m cell) overlies various components of mucosa-associated lymphatic tissue. here, using multiple mouse models, we show that mtb invades via ...201627452467
development of potent chemical antituberculosis agents targeting mycobacterium tuberculosis acetohydroxyacid synthase.mycobacterium tuberculosis acetohydroxyacid synthase (mtb-ahas) has been suggested as a crucial target for antibacterial agents. high-throughput screening of a chemical library was performed to identify potent new inhibitors of mtb-ahas. among the 6800 tested compounds, 15 were identified as potent inhibitors, exhibiting >80-90% inhibition of in vitro mtb-ahas activity at a fixed concentration of 20 µm. five compounds belonging to the triazolopyrimidine structural class showed greater inhibition ...201627451857
an outbreak of multidrug-resistant tuberculosis among a family.tuberculosis is a major public health problem and it may be complicated by multidrug-resistant tuberculosis (mdr-tb). wide transmission among immunocompetent contacts of the index case is possible. if you detect tuberculosis in two contacts of the index case, it is called an outbreak. the aim of our paper is to evaluate the characteristics of a mdr-tb outbreak affecting 7 people in a family treated during 2012-2014 in istanbul yedikule training and research hospital for chest disease and thoraci ...201627451825
defining dormancy in mycobacterial disease.tuberculosis remains a threat to global health and recent attempts to shorten therapy have not succeeded mainly due to cases of clinical relapse. this has focussed attention on the importance of "dormancy" in tuberculosis. there are a number of different definitions of the term and a similar multiplicity of different in vitro and in vivo models. the danger with this is the implicit assumption of equivalence between the terms and models, which will make even more difficult to unravel this complex ...201627450015
prevalence of pyrazinamide resistance across the spectrum of drug resistant phenotypes of mycobacterium tuberculosis.pyrazinamide resistance is largely unknown in the spectrum of drug resistant phenotypes. we summarize data on pza resistance in clinical isolates from south africa. pza dst should be performed when considering its inclusion in treatment of patients with rifampicin-resistant tb or mdr-tb.201627450014
evaluation of il-2, il-10, il-17 and ip-10 as potent discriminative markers for active tuberculosis among pulmonary tuberculosis suspects.although interferon gamma release assays (igras) are useful for specifically detecting mycobacterium tuberculosis, they are limited by their inability to differentiate between active tuberculosis (active tb), latent tuberculosis infection (ltbi), and patients with prior tb infection. the purpose of this study was to rapidly and accurately identify active tb patients among patients with suspected respiratory tb by combining interferon-gamma (ifn-γ) with additional cytokines.201627450011
remap: operon map of m. tuberculosis based on rna sequence data.a map of the transcriptional organization of genes of an organism is a basic tool that is necessary to understand and facilitate a more accurate genetic manipulation of the organism. operon maps are largely generated by computational prediction programs that rely on gene conservation and genome architecture and may not be physiologically relevant. with the widespread use of rna sequencing (rnaseq), the prediction of operons based on actual transcriptome sequencing rather than computational genom ...201627450008
mycobacterium tuberculosis strain 18b, a useful non-virulent streptomycin dependent mutant to study latent tuberculosis as well as for in vivo and in vitro testing of anti-tuberculosis drugs. 201627450005
digital pcr assay detection of circulating mycobacterium tuberculosis dna in pulmonary tuberculosis patient plasma.nucleic acid amplification tests are a major diagnostic tool for pulmonary tuberculosis (ptb). recently, digital pcr (dpcr) assay has improved sensitivity for the detection of small copy numbers of target molecules. the aim of this study is to explore the utility of dpcr for detecting mycobacterium tuberculosis (mtb) dna in ptb patient plasma. total dna was purified from plasma samples of newly diagnosed sputum smear-positive ptb patients. copy numbers of mtb-specific genes in the samples were q ...201627450004
a quantitative adaptation of the wayne test for pyrazinamide resistance.pyrazinamide (pza) is the most important drug against the latent stage of tuberculosis (tb) and is used in both first and second line treatment regimens. the continued increase in multi-drug resistant tb and the prevalence of pza resistance makes the development of alternative assays for prompt identification of pza resistance all the more important.201627450003
influence of phthiocerol dimycocerosate on cd4(+) t cell priming and persistence during mycobacterium tuberculosis infection.the characterisation of mycobacterial factors that influence or modulate the host immune response may aid the development of more efficacious tb vaccines. we have previously reported that mycobacterium tuberculosis deficient in export of phthiocerol dimycocerosates (dim) (mt103(δdrrc)) is more attenuated than wild type m. tuberculosis and provides sustained protective immunity compared to the existing bcg vaccine. here we sought to define the correlates of immunity associated with dim deficiency ...201627450001
gender biased immune-biomarkers in active tuberculosis and correlation of their profiles to efficacy of therapy.active pulmonary tb is an inflammatory disease and is increasingly viewed as an imbalance of immune responses to mycobacterium tuberculosis (m. tb.) infection. in addition, this immune imbalance may be gender biased (males have a higher prevalence of tb) but reasons for such bias are uncertain. we hypothesized that studies on profiles of immune-biomarkers will not only provide insight into molecular basis of gender bias but may also help identify biomarkers to monitor efficacy of tb therapy. we ...201627450000
antimycobacterial activity of pyrazinoate prodrugs in replicating and non-replicating mycobacterium tuberculosis.tuberculosis (tb) is an important infectious disease caused by mycobacterium tuberculosis (mtb) and responsible for thousands of deaths every year. although there are antimycobacterial drugs available in therapeutics, just few new chemical entities have reached clinical trials, and in fact, since introduction of rifampin only two important drugs had reached the market. pyrazinoic acid (poa), the active agent of pyrazinamide, has been explored through prodrug approach to achieve novel molecules w ...201627449999
role of il-10 and tnf-α during mycobacterium tuberculosis infection in murine alveolar macrophages.mycobacterium tuberculosis (mtb) is known to be responsible for tuberculosis (tb), but the pathogenesis of this disease and the host defense mechanisms involved are, for the most part, poorly understood. in this study, we divided 30 male c57bl/6 mice into control and infection groups, and following injection with physiological saline or mtb, respectively, euthanized five mice from each group on days 1, 3, and 7. tnf-α and il-10 levels were measured by enzyme-linked immunosorbent assay and flow c ...201627706765
the transcriptional signature of active tuberculosis reflects symptom status in extra-pulmonary and pulmonary tuberculosis.mycobacterium tuberculosis infection is a leading cause of infectious death worldwide. gene-expression microarray studies profiling the blood transcriptional response of tuberculosis (tb) patients have been undertaken in order to better understand the host immune response as well as to identify potential biomarkers of disease. to date most of these studies have focused on pulmonary tb patients with gene-expression profiles of extra-pulmonary tb patients yet to be compared to those of patients wi ...201627706152
metformin: candidate host-directed therapy for tuberculosis in diabetes and non-diabetes patients.despite major advances in tuberculosis (tb) control, tb continues to be a leading cause of death worldwide. the discovery of new anti-tb treatment drugs and regimens that target drug-sensitive and drug-resistant tb are being complemented with a search for adjunct host-directed therapies that synergize for mycobacterium tuberculosis (mtb) elimination. the goal of host-directed therapies is to boost immune mechanisms that diminish excess inflammation to reduce lung tissue damage and limit mtb grow ...201627720378
predictive value of serum bradykinin and desarg(9)-bradykinin levels for chemotherapeutic responses in active tuberculosis patients: a retrospective case series.there is an urgent need for methods that can rapidly and accurately assess therapeutic responses in patients with active tuberculosis (tb) in order to predict treatment outcomes. exposure to bacterial pathogens can rapidly activate the plasma contact system, triggering the release of bradykinin (bk) and its metabolite desarg(9)-bradykinin (dabk) to induce inflammation and innate immune responses. we hypothesized that serum bk and dabk levels might act as sensitive immune response signatures for ...201627720377
pulmonary artery invasion caused by mycobacterium tuberculosis.extrapulmonary tuberculosis refers to mycobacterium tuberculosis involving organs other than the lungs (eg, pleura, lymph nodes, genitourinary tract, abdomen, skin, joints and bones, or meninges). in non-hiv-endemic areas, where reactivation is the predominant mechanism of tuberculosis, pleural involvement occurs in 4% of cases. we present an extremely rare case of a 62-year-old immunocompetent patient with pleural tuberculosis confirmed by surgical pleural biopsies, who presented with a large m ...201627719830
first characterization of the cd4 and cd8 t-cell responses to quantiferon-tb plus.quantiferon(®)-tb gold plus (qft-plus) is the new generation of quantiferon-tb gold in-tube test to identify latent tuberculosis infection (ltbi). qft-plus includes tb1 and tb2 tubes which contain selected mycobacterium tuberculosis (mtb) peptides designed to stimulate both cd4 and cd8 t-cells. aim of this study is the flow cytometric characterization of the specific cd4 and cd8 t-cell responses to mtb antigens contained within qft-plus.201627717779
chronic tuberculous otomastoiditis: a case report.worldwide, tuberculosis is a widespread disease, with 8.7 million new cases occurring annually. its etiologic agent, mycobacterium tuberculosis, essentially causes pneumonia. however, this organism affects the middle ear in rare cases, accounting for 0.04-0.09% of all chronic middle ear otitis cases in western countries. in this report, we describe the case of a young woman affected by tuberculosis of the middle ear. in our experience, empiric therapy was not beneficial. adequate treatment was p ...201627716611
to be or not be a (functional) antibody against tb.in this issue of cell, lu et al. provide important insights on the efficacy of human antibodies to mycobacterium tuberculosis and on how functional heterogeneity of the antibody response may explain a century of contradictory evidence for the role of humoral immunity in defense against tuberculosis.201627716502
raman spectroscopic identification of mycobacterium tuberculosis.in this study, raman microspectroscopy has been utilized to identify mycobacteria to the species level. because of the slow growth of mycobacteria, the per se cultivation-independent raman microspectroscopy emerges as a perfect tool for a rapid on-the-spot mycobacterial diagnostic test. special focus was laid upon the identification of mycobacterium tuberculosis complex (mtc) strains, as the main causative agent of pulmonary tuberculosis worldwide, and the differentiation between pathogenic and ...201627714969
lipid structure influences the ability of glucose monocorynomycolate to signal through mincle.mincle (macrophage-inducible c-type lectin) is a c-type lectin receptor that provides the capacity for immune sensing of a range of pathogen- and commensal-derived glycolipids. mincle can recognize mycolic and/or corynomycolic acid esters of trehalose, glycerol and glucose from mycobacteria and corynebacteria. while simple straight-chain long fatty acids (e.g. behenic acid) can substitute for mycolic acid on trehalose and glycerol and maintain robust signalling through mincle, glucose monobehena ...201627714279
ethionamide biomimetic activation and an unprecedented mechanism for its conversion into active and non-active metabolites.ethionamide (eth), a second-line anti-tubercular drug that is regaining a lot of interest due to the increasing cases of drug-resistant tuberculosis, is a pro-drug that requires an enzymatic activation step to become active and to exert its therapeutic effect. the enzyme responsible for eth bioactivation in mycobacterium tuberculosis is a monooxygenase (etha) that uses flavin adenine dinucleotide (fad) as a cofactor and is nadph- and o2-dependant to exert its catalytic activity. in this work, we ...201627714216
mycobacterium tuberculosis rv2882c protein induces activation of macrophages through tlr4 and exhibits vaccine potential.macrophages constitute the first line of defense against mycobacterium tuberculosis and are critical in linking innate and adaptive immunity. therefore, the identification and characterization of mycobacterial proteins that modulate macrophage function are essential for understanding tuberculosis pathogenesis. in this study, we identified the novel macrophage-activating protein, rv2882c, from m. tuberculosis culture filtrate proteins. recombinant rv2882c protein activated macrophages to secrete ...201627711141
prevalence of drug resistance mycobacterium tuberculosis among patients seen in coast provincial general hospital, mombasa, kenya.although prevention and control of spread of multi-drug resistant tuberculosis strains is a global challenge, there is paucity of data on the prevalence of dr-tb in patients diagnosed with tb in referral hospitals in kenya. the present study assessed patients' characteristics and prevalence of drug resistant tb in sputa smear positive tb patients presenting to coast provincial general hospital (cpgh) in mombasa, kenya.201627711122
molecular strain typing of mycobacterium tuberculosis: a review of frequently used methods.tuberculosis, caused by the bacterium mycobacterium tuberculosis, remains one of the most serious global health problems. molecular typing of m. tuberculosis has been used for various epidemiologic purposes as well as for clinical management. currently, many techniques are available to type m. tuberculosis. choosing the most appropriate technique in accordance with the existing laboratory conditions and the specific features of the geographic region is important. insertion sequence is6110-based ...201627709842
adult pulmonary tuberculosis as a pathological manifestation of hyperactive antimycobacterial immune response.the intricate relationship between tuberculosis (tb) and immune system remains poorly understood. it is generally believed that weakening of the immune response against mycobacterium tuberculosis leads to reactivation of latent infection into the active pulmonary disease. however, heterogeneous nature of tb and failure of rationally designed vaccines in clinical trials raises serious questions against the simplistic view of tb as an outcome of weakened immunity. in the wake of accumulating human ...201627709522
micrornas play big roles in modulating macrophages response toward mycobacteria infection.macrophages are crucial player in the defense against multiple intracellular pathogens. mycobacterium tuberculosis, the causative agent of tuberculosis which inflicted around one third of global population, can replicate and persist within macrophages. micrornas, endogenous, small noncoding rna, can regulate the expression of macrophages genes required for appropriate signaling. mycobacteria can manipulate the expression of macrophages micrornas to subvert cell response for its survival and pers ...201627693402
two infants with tuberculid associated with kawasaki disease.bacille de calmette et guerin (bcg) is the only licensed tuberculosis vaccine to prevent severe tuberculosis. the adverse events of bcg vaccination, including local reactions, lymphadenitis, osteomyelitis, tuberculid, and disseminated infection, have been reported. two infants presented erythema at the inoculation site of bcg after the resolution of kawasaki disease (kd). they received bcg vaccination 1 week and 6 weeks before the kd onset, respectively. intravenous immunoglobulin improved the k ...201627435523
hiv interferes with mycobacterium tuberculosis antigen presentation in human dendritic cells.hiv coinfection is the most prominent risk factor for progression of mycobacterium tuberculosis (mtb) infection into active tuberculosis (tb) disease. the mechanisms behind the increased transition from latent to active tb in coinfected individuals have not been well elucidated at the cellular level. we hypothesized that hiv infection contributes to mtb pathogenesis by interfering with the dendritic cell (dc)-mediated immune control. mtb-antigen processing and presentation are key events in the ...201627746182
the early secreted antigenic target of 6 kd of mycobacterium tuberculosis inhibits the proliferation and differentiation of human peripheral blood cd34(+) cells.abnormalities in hematopoiesis are common in tuberculosis patients and highly prevalent in aids patients with tuberculosis coinfection. to explore the potential role of the early secreted antigenic target of 6-kd (esat-6) of mycobacterium tuberculosis (mtb) in abnormal hematopoiesis in tuberculosis, we studied the effect of esat-6 on proliferation and differentiation of in vitro-expanded cd34(+) cells isolated from the peripheral blood of the healthy donors. esat-6 but not control protein antige ...201627745787
cord factor as an invisibility cloak? a hypothesis for asymptomatic tb persistence.mycobacterium tuberculosis (mtb) has long been known to persist in grossly normal tissues even in people with active lesions and granulomas in other parts of the body. we recently reported that post-primary tb begins as an asymptomatic infection that slowly progresses, accumulating materials for a massive necrotizing reaction that results in cavitation. this paper explores the possible roles of trehalose 6,6' dimycolate (tdm) or cord factor in the ability of mtb to persist in such lesions withou ...201627743706
emerging role of mesenchymal stem cells during tuberculosis: the fifth element in cell mediated immunity.mesenchymal stem cells (mscs) are non-hematopoietic cells that occur in almost all human tissues and can be cultured and expanded to large numbers in vitro. they secrete growth factors, cytokines, and chemokines and express toll-like receptors on their surface, although multiple cell biological mechanisms remain unclear. mscs are multi-potent and can differentiate into many cell types including adipocytes, neuronal cells and osteoclasts. despite gaps in cell biology, because of their immunomodul ...201627743705
defensins: the case for their use against mycobacterial infections.human tuberculosis remains a huge global public health problem with an estimated 1/3rd of the population being infected. defensins are antibacterial cationic peptides produced by a number of cell types, most notably neutrophil granulocytes and epithelial cells. all three defensin types (α-, β-, and θ-defensins) have antibacterial activities, mainly through bacterial membrane permeabilization. defensins are effective against gram-negative and gram-positive bacteria including mycobacteria and are ...201627725944
high correlation of clinical criteria in the diagnosis of drug-resistant tb and prevalence of ofloxacin resistance.to study the drug resistance profile of patients with suspected multidrug-resistant tuberculosis (mdr-tb).201627725047
the mycobacterium tuberculosis transcriptional landscape under genotoxic stress.as an intracellular human pathogen, mycobacterium tuberculosis (mtb) is facing multiple stressful stimuli inside the macrophage and the granuloma. understanding mtb responses to stress is essential to identify new virulence factors and pathways that play a role in the survival of the tubercle bacillus. the main goal of this study was to map the regulatory networks of differentially expressed (de) transcripts in mtb upon various forms of genotoxic stress. we exposed mtb cells to oxidative (h2o2 o ...201627724857
the type vii secretion system of staphylococcus aureus secretes a nuclease toxin that targets competitor bacteria.the type vii protein secretion system (t7ss) plays a critical role in the virulence of human pathogens including mycobacterium tuberculosis and staphylococcus aureus. here, we report that the s. aureus t7ss secretes a large nuclease toxin, esad. the toxic activity of esad is neutralized during its biosynthesis through complex formation with an antitoxin, esag, which binds to its c-terminal nuclease domain. the secretion of esad is dependent on a further accessory protein, esae, that does not int ...201627723728
a high-throughput assay for developing inhibitors of phop, a virulence factor of mycobacterium tuberculosis.tuberculosis (tb) still kills over 1.5 million people per year despite available anti-tb drugs. the emergence of drug-resistant tb poses a major threat to public health and prompts for an urgent need for new and more effective drugs. the long duration needed to treat tb by the current tb drugs, which target the essential cellular activities, inevitably leads to the emergence of drug-resistance. phop of mycobacterium tuberculosis (mtb), an essential virulence factor, is a novel target for drug de ...201627748178
evaluation of interleukin17and interleukin 23 expression in patients with active and latent tuberculosis infection.tuberculosis is one of the most important infectious diseases with high mortality rates worldwide, especially in developing countries. interleukin17 (il-17) is an important acquired immunity cytokine, which is mainly produced by cd4(+)th17 cells. it can recruit neutrophils and macrophages to the infected site in the lungs. il-23 is one of the most important inducers of il-17. in the present study, the expressions of il-23 and il-17 were examined in the pathogenesis of tuberculosis.201627746865
conjugation with an inulin-chitosan adjuvant markedly improves the immunogenicity of mycobacterium tuberculosis cfp10-tb10.4 fusion protein.protein-based vaccines are of potential to deal with the severe situations posed by mycobacterium tuberculosis (mtb). due to inherently poor immunogenicity of mtb protein antigens, a potent immunostimulatory adjuvant is needed to enhance the cellular and humoral immune response to mtb protein antigens. inulin and chitosan (cs) are polysaccharide adjuvants that can be used to achieve such an objective. the inulin-cs conjugate (inulin-cs) acted as a potent adjuvant through a synergistic interactio ...201627723352
genomics study of mycobacterium tuberculosis strains from different ethnic populations in taiwan.to better understand the transmission and evolution of mycobacterium tuberculosis (mtb) in taiwan, six different mtb isolates (representatives of the beijing ancient sublineage, beijing modern sublineage, haarlem, east-african indian, t1, and latin-american mediterranean (lam)) were characterized and their genomes were sequenced. discriminating among large sequence polymorphisms (lsps) that occur once versus those that occur repeatedly in a genomic region may help to elucidate the biological rol ...201627721649
development, validation and application of a 96-well enzymatic assay based on lc-esi-ms/ms quantification for the screening of selective inhibitors against mycobacterium tuberculosis purine nucleoside phosphorylase.mycobacterium tuberculosis (mtb) purine nucleoside phosphorylase (pnp, ec 2.4.2.1) has been identified as a target for the development of specific inhibitors with potential antimycobacterial activity. we hereby described the development and validation of a new 96-well lc-esi-ms/ms method to assess the inhibition activity of nucleoside analogues towards mtbpnp and the human pnp (hspnp). enzyme activity was determined by monitoring the phosphorolysis of inosine (ino) to hypoxanthine (hpx). the enz ...201627769382
validation of genotype cluster investigations for mycobacterium tuberculosis: application results for 44 clusters from four heterogeneous united states jurisdictions.tracking the dissemination of specific mycobacterium tuberculosis (mtb) strains using genotyped mtb isolates from tuberculosis patients is a routine public health practice in the united states. the present study proposes a standardized cluster investigation method to identify epidemiologic-linked patients in mtb genotype clusters. the study also attempts to determine the proportion of epidemiologic-linked patients the proposed method would identify beyond the outcome of the conventional contact ...201627769182
turkish and japanese mycobacterium tuberculosis sublineages share a remote common ancestor.two geographically distant m. tuberculosis sublineages, tur from turkey and t3-osaka from japan, exhibit partially identical genotypic signatures (identical 12-loci miru-vntr profiles, distinct spoligotyping patterns). we investigated t3-osaka and tur sublineages characteristics and potential genetic relatedness, first using miru-vntr locus analysis on 21 and 25 samples of each sublineage respectively, and second comparing whole genome sequences of 8 new samples to public data from 45 samples un ...201627746295
bioinformatics tools and databases for whole genome sequence analysis of mycobacterium tuberculosis.tuberculosis (tb) is an infectious disease of global public health importance caused by mycobacterium tuberculosis complex (mtc) in which m. tuberculosis (mtb) is the major causative agent. recent advancements in genomic technologies such as next generation sequencing have enabled high throughput cost-effective generation of whole genome sequence information from mtb clinical isolates, providing new insights into the evolution, genomic diversity and transmission of the mtb bacteria, including mo ...201627637931
rnaseq reveals hypervirulence-specific host responses to m. tuberculosis infection.the distinguishing factors that characterize the host response to infection with virulent mycobacterium tuberculosis (m.tb) are largely confounding. we present an infection study with 2 genetically closely related m.tb strains that have vastly different pathogenic characteristics. the early host response to infection with these detergent-free cultured strains was analyzed through rnaseq in an attempt to provide information on the subtleties which may ultimately contribute to the virulent phenoty ...201627763806
latent mycobacterium tuberculosis infection and interferon-gamma release assays.the identification of individuals with latent tuberculosis infection (ltbi) is useful for both fundamental understanding of the pathogenesis of disease and for clinical and public health interventions (i.e., to prevent progression to disease). basic research suggests there is a pathogenetic continuum from exposure to infection to disease, and individuals may advance or reverse positions within the spectrum, depending on changes in the host immunity. unfortunately, there is no diagnostic test tha ...201627763261
cytokines and chemokines in mycobacterium tuberculosis infection.chemokines and cytokines are critical for initiating and coordinating the organized and sequential recruitment and activation of cells into mycobacterium tuberculosis-infected lungs. correct mononuclear cellular recruitment and localization are essential to ensure control of bacterial growth without the development of diffuse and damaging granulocytic inflammation. an important block to our understanding of tb pathogenesis lies in dissecting the critical aspects of the cytokine/chemokine interpl ...201627763255
draft genome sequence of mycobacterium tuberculosis strain b9741 of beijing b0/w lineage from hiv positive patient from siberia.we report a draft genome sequence of mycobacterium tuberculosis strain b9741 belonging to beijing b0/w lineage isolated from a hiv patient from siberia, russia. this clinical isolate showed mdr phenotype and resistance to isoniazid, rifampin, streptomycin and pyrazinamide. we analyzed snps associated with virulence and resistance. the draft genome sequence and annotation have been deposited at genbank under the accession nz_lvjj00000000.201627761405
mr1-restricted mucosal-associated invariant t (mait) cells respond to mycobacterial vaccination and infection in nonhuman primates.studies on mucosal-associated invariant t cells (maits) in nonhuman primates (nhp), a physiologically relevant model of human immunity, are handicapped due to a lack of macaque mait-specific reagents. here we show that while mr1 ligand-contact residues are conserved between human and multiple nhp species, three t-cell receptor contact-residue mutations in nhp mr1 diminish binding of human mr1 tetramers to macaque maits. construction of naturally loaded macaque mr1 tetramers facilitated identific ...201627759023
serine/threonine protein phosphatase pstp of mycobacterium tuberculosis is necessary for accurate cell division and survival of pathogen.protein phosphatases play vital roles in phosphorylation-mediated cellular signaling. although there are 11 serine/threonine protein kinases in mycobacterium tuberculosis, only one serine/threonine phosphatase, pstp, has been identified. although pstp has been biochemically characterized and multiple in vitro substrates have been identified, its physiological role has not yet been elucidated. in this study, we have investigated the impact of pstp on cell growth and survival of the pathogen in th ...201627758870
drug susceptibility profiles of pulmonary mycobacterium tuberculosis isolates from patients in informal urban settlements in nairobi, kenya.anti-tuberculosis drug resistance is an emerging health problem in kenya and especially in slums. slum environments create a conducive environment for the spread of tuberculosis (tb) due to high population density and lack of basic amenities such as decent housing, access to clean water, lack of drainage and basic sanitation. furthermore, ineffective health services in crowded and poorer populations, poor patient compliance, a large pool of untreated cases, delayed diagnosis and inappropriate tr ...201627756241
circulating granulysin levels in healthcare workers and latent tuberculosis infection estimated using interferon-gamma release assays.granulysin (gnly) is produced by human lymphocyte subpopulations and exhibits antimicrobial activity against mycobacterium tuberculosis. we examined the association between gnly levels in blood and latent tuberculosis (tb) infection.201627756230
the mycobacterium tuberculosis desaturase desa1 (rv0824c) is a ca(2+) binding protein.the hallmark feature of mycobacterium tuberculosis (m.tb) the causative agent of human tuberculosis, is its complex lipid rich cell wall comprised primarily of mycolic acids, long chain fatty acids that play a key role in structural stability and permeability of the cell wall. in addition, they are involved in inhibiting phagosome-lysosome fusion and aid in granuloma formation during the pathogenic process. m.tb desa1 is an essential acyl-acyl carrier protein desaturase predicted to catalyze the ...201627721064
gold nanorods as drug delivery vehicles for rifampicin greatly improve the efficacy of combating mycobacterium tuberculosis with good biocompatibility with the host cells.tb remains a challenging disease to control worldwide. nanoparticles have been used as drug carriers to deliver high concentrations of antibiotics directly to the site of infection, reducing the duration of treatment along with any side effects of off-target toxicities after systemic exposure to the antibiotics. herein we have developed a drug delivery platform where gold nanorods (aunrs) are conjugated to rifampicin (rf), which is released after uptake into macrophage cells (raw264.7). due to t ...201627595304
thalidomide in refractory tuberculomas and pseudoabscesses.paradoxical immune reconstitution inflammatory syndrome is a well-described entity even in immunocompetent children, principally in association with mycobacterium tuberculosis infections. central nervous system involvement is a potential life-threatening form, sometimes refractory to standard treatment. we report the case of an hiv-negative refugee teenager, who presented with brain tuberculomas and pseudoabscesses responsive only to thalidomide.201627753773
intravital excitation increases detection sensitivity for pulmonary tuberculosis by whole-body imaging with β-lactamase reporter enzyme fluorescence.tuberculosis is a pulmonary disease with an especially high mortality rate in immuno-compromised populations, specifically children and hiv positive individuals. the causative agent, mycobacterium tuberculosis (mtb), is a very slow growing and difficult organism to work with, making both diagnosis and development of effective treatments cumbersome. we utilize a fiber-optic fluorescence microendoscope integrated with a whole-body imaging system for in vivo mtb detection. the system exploits an en ...201627753271
antiretroviral therapy improves survival among tb-hiv co-infected patients who have cd4+ t-cell count above 350cells/mm(3).co-infection with mycobacterium tuberculosis remains a leading cause of morbidity and mortality among hiv infected individuals especially in developing countries. early initiation of cart in these patients when cd4+ t cell count is less than 200cells/mm(3) has reduced disease progression and mortality. however for patients with higher cd4+ t cell counts greater than 350cells/mm(3) evidence is conflicting. in this study we seek to evaluate the effectiveness of cart in reducing mortality among tb- ...201627751168
modeling the permeability of drug-like molecules through the cell wall of mycobacterium tuberculosis: an analogue based approach.the emergence of drug resistant strains of mycobacterium tuberculosis (mtb) accentuates the urgent need for the development of novel antitubercular drugs. the major causes of drug resistance are genetic mutations, the influx-efflux transporter system, and the complex cell wall system of mtb, which can function as permeability barriers. the driving force for permeability of small molecules through a biological system depends on various physicochemical factors. to understand the permeability of sm ...201627604290
optimal clinical doses of faropenem, linezolid, and moxifloxacin in children with disseminated tuberculosis: goldilocks.when treated with the same antibiotic dose, children achieve different 0- to 24-hour area under the concentration-time curves (auc0-24) because of maturation and between-child physiological variability on drug clearance. children are also infected by mycobacterium tuberculosis isolates with different antibiotic minimum inhibitory concentrations (mics). thus, each child will achieve different auc0-24/mic ratios when treated with the same dose.201627742641
a faropenem, linezolid, and moxifloxacin regimen for both drug-susceptible and multidrug-resistant tuberculosis in children: flame path on the milky way.the regimen of linezolid and moxifloxacin was found to be efficacious in the hollow fiber system model of pediatric intracellular tuberculosis. however, its kill rate was slower than the standard 3-drug regimen of isoniazid, rifampin, and pyrazinamide. we wanted to examine the effect of adding a third oral agent, faropenem, to this dual combination.201627742640
concentration-dependent synergy and antagonism of linezolid and moxifloxacin in the treatment of childhood tuberculosis: the dynamic duo.no treatment regimens have been specifically designed for children, in whom tuberculosis is predominantly intracellular. given their activity as monotherapy and their ability to penetrate many diseased anatomic sites that characterize disseminated tuberculosis, linezolid and moxifloxacin could be combined to form a regimen for this need.201627742639
linezolid for infants and toddlers with disseminated tuberculosis: first steps.infants and toddlers often present with disseminated and lymph node tuberculosis, in which mycobacterium tuberculosis (mtb) is predominantly intracellular. linezolid, used to treat tuberculosis in adults, has not been formally studied in infants. infants clear linezolid 5 times faster than adults and achieve lower 0- to 24-hour area under the concentration-time curves (auc0-24).201627742638
modulation of human t cell cytokines by the mycobacterium tuberculosis-secreted protein wag31.mycobacterium tuberculosis secretes a number of proteins into the extracellular milieu during growth. several of these proteins have been associated with modulation of the host immune response. antigen 84, or wag31, is one such protein that is conserved among all mycobacterial species and is recognized by the sera from tuberculosis and leprosy patients. here, we examined the effect of wag31 on the ability of activated human t cells to produce cytokines such as il-10, il-17 and ifn-γ in response ...201627742462
association of pellicle growth morphological characteristics and clinical presentation of mycobacterium tuberculosis isolates.trehalose 6,6'dimycolate (tdm) is a glycolipid found in nearly pure form on the surface of virulent mycobacterium tuberculosis (mtb). this manuscript investigated the production of tdm, growth rate and colony morphology of multiple strains of mtb, each of which had been isolated from both pulmonary (sputum) and extrapulmonary sites of multiple patients. since sputum contains mtb primarily from cavities and extrapulmonary biopsies are typically granulomas, this provided an opportunity to compare ...201627742461
human immunology of tuberculosis.immunology is a central theme when it comes to tuberculosis (tb). the outcome of human infection with mycobacterium tuberculosis is dependent on the ability of the immune response to clear or contain the infection.in cases where this fails, the bacterium replicates, disseminates within the host, and elicits a pathologic inflammatory response, and disease ensues. clinical presentation of tb disease is remarkably heterogenous, and the disease phenotype is largely dependent on host immune status. o ...201627740453
design of selective substrates and activity-based probes for hydrolase important for pathogenesis 1 (hip1) from mycobacterium tuberculosis.although serine proteases are important mediators of mycobacterium tuberculosis (mtb) virulence, there are currently no tools to selectively block or visualize members of this family of enzymes. selective reporter substrates or activity-based probes (abps) could provide a means to monitor infection and response to therapy using imaging methods. here, we use a combination of substrate selectivity profiling and focused screening to identify optimized reporter substrates and abps for the mtb "hydro ...201627739665
strategies for the discovery and development of new antibiotics from natural products: three case studies.natural products continue to be a predominant source for new anti-infective agents. research at the helmholtz institute for pharmaceutical research saarland (hips) and the helmholtz centre for infection research (hzi) is dedicated to the development of new lead structures against infectious diseases and, in particular, new antibiotics against hard-to-treat and multidrug-resistant bacterial pathogens. in this chapter, we introduce some of the concepts currently being employed in the field of anti ...201627738913
mycobacterium tuberculosis malate synthase structures with fragments reveal a portal for substrate/product exchange.fragment screening and high throughput screening are complementary approaches that combine with structural biology to explore the binding capabilities of an active site. we have used a fragment-based approach on malate synthase (glcb) from mycobacterium tuberculosis and discovered several novel binding chemotypes. in addition, the crystal structures of glcb in complex with these fragments indicated conformational changes in the active site that represent the enzyme conformations during catalysis ...201627738104
structure-function profile of mmpl3, the essential mycolic acid transporter from mycobacterium tuberculosis.the mmpl family of proteins translocates complex (glyco)lipids and siderophores across the cell envelope of mycobacteria and closely related corynebacteriaceae and plays important roles in the biogenesis of the outer membrane of these organisms. despite their significance in the physiology and virulence of mycobacterium tuberculosis, and from the perspective of developing novel antituberculosis agents, little is known about their structure and mechanism of translocation. in this study, the essen ...201627737557
design, synthesis, and evaluation of novel hybrid efflux pump inhibitors for use against mycobacterium tuberculosis.efflux pumps are considered a major potential contributor to the development of various forms of resistance in mycobacterium tuberculosis leading to the emergence of multidrug-resistant tuberculosis (tb). verapamil (ver) and tricyclic chemosensitizers such as the phenothiazines are known to possess efflux pump inhibition properties and have demonstrated significant efficacy in various tb disease models. novel hybrid molecules based on fusion of the ver substructure with various tricyclic, as wel ...201627737555
whole genome sequencing demonstrates limited transmission within identified mycobacterium tuberculosis clusters in new south wales, australia.australia has a low tuberculosis incidence rate with most cases occurring among recent immigrants. given suboptimal cluster resolution achieved with 24-locus mycobacterium interspersed repetitive unit (miru-24) genotyping, the added value of whole genome sequencing was explored. miru-24 profiles of all mycobacterium tuberculosis culture-confirmed tuberculosis cases diagnosed between 2009 and 2013 in new south wales (nsw), australia, were examined and clusters identified. the relatedness of cases ...201627737005
development of a one-pot assay for screening and identification of mur pathway inhibitors in mycobacterium tuberculosis.the cell wall of mycobacterium tuberculosis (mtb) consists of peptidoglycan, arabinogalactan and mycolic acids. the cytoplasmic steps in the peptidoglycan biosynthetic pathway, catalyzed by the mur (a-f) enzymes, involve the synthesis of udp-n-acetylmuramyl pentapeptide, a key precursor molecule required for the formation of the peptidoglycan monomeric building blocks. mur enzymes are indispensable for cell integrity and their lack of counterparts in eukaryotes suggests them to be promising mtb ...201627734910
the progress of therapeutic vaccination with regard to tuberculosis.a major problem with tuberculosis (tb) control is the long duration of drug therapy-both for latent and for active tb. therapeutic vaccination has been postulated to improve this situation, and to this end there are several candidates already in clinical phases of development. these candidates follow two main designs, namely bacilli-directed therapy based on inactivated -whole or -fragmented bacillus (mycobacterium w and ruti) or fusion proteins that integrate non-replicating bacilli -related an ...201627733848
comparison of characteristics of culture-negative pyogenic spondylitis and tuberculous spondylitis: a retrospective study.differences between the characteristics of culture positive pyogenic spondylitis (cpps) and tuberculous spondylitis (ts) are well known. however, differences between the characteristics of culture negative pyogenic spondylitis (cnps) and ts have not been reported; these would be more helpful in clinical practice especially when initial microbiologic examination of blood and/or biopsy tissue did not reveal the causative bacteria in patients with infectious spondylitis.201627733126
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