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neolignans and phenylpropanoids from the roots of piper taiwanense and their antiplatelet and antitubercular activities.bioassay-guided fractionation of roots from piper taiwanense led to isolation of three neolignans, diallylcatechol (1) and neotaiwanensols a, b (2, 3), two diphenylpropanoid ethers, taiwandimerols a, b (4, 5), with one phenylpropanoid, 2,3-diacetoxy-1-methoxy-5-allylbenzene (6), previously unknown in nature, together with 18 known compounds (7-24). their structures were elucidated by spectroscopic evidence. among the isolates, hydroxychavicol acetate (7), and 4-allylcatechol (8) showed potent in ...201323582215
sternal tuberculosis in a patient with chronic kidney disease.sternum is generally regarded as resistant to infections and thus is an infrequent site of osteomyelitis. involvement of sternum by mycobacterium tuberculosis is rare. sternal tuberculosis in chronic kidney disease (ckd) was not reported till date. we report a 40-year-old patient with stage iv ckd, who presented with sternal and cervical lymphnodal tuberculosis.201323580808
paraspinal abscess secondary to tuberculous spondylitis diagnosed by xpert mtb/rif assay in rural tanzania.a 31-year-old hiv-negative man presented to our clinic with a 6-month history of back pain and a swelling at the back. radiological studies revealed lumbar vertebral destruction. ultrasound of the mass showed a septated cystic mass with turbid fluid. diagnostic aspiration revealed thick pus and smear microscopy detected acid-fast bacilli. xpert mtb/rif assay detected mycobacterium tuberculosis with no rifampicin resistance.201323580687
decline in rates of acquired multidrug-resistant tuberculosis after implementation of the directly observed therapy, short course (dots) and dots-plus programmes in taiwan.to investigate the impact of the directly observed therapy, short course (dots) and dots-plus strategies on changes in resistance profiles among mycobacterium tuberculosis (mtb).201323580558
how to use: interferon γ release assays for tuberculosis.diagnosis and treatment of latent tuberculosis infection (ltbi) is important to reduce risk of progression to active tuberculosis (tb) disease. for the past century the tuberculin skin test (tst) has been used as a measure of exposure to mycobacterium tuberculosis (mtb), but this test has limitations in test performance, sensitivity and specificity. interferon γ release assays (igra), like tst, measure host immune response to mtb. igra are designed to be more specific for the diagnosis of ltbi t ...201323580543
the roles of immune memory and aging in protective immunity and endogenous reactivation of tuberculosis.finding more effective vaccines against tuberculosis (tb) and improved preventive treatments against endogenous reactivation of latent tb is strategic to block transmission and reach the who goal of eliminating tb by 2050. key related open questions in tb research include: i) what are the determinants of a strong memory response upon primary infection? ii) what is the role of cytokines towards protective memory response against a secondary infection? iii) what are the mechanisms responsible for ...201323580062
a population-based study of first and second-line drug-resistant tuberculosis in a high-burden area of the mexico/united states border.the resistance of 139 mycobacterium tuberculosis (mtb) isolates from the city of monterrey, northeast mexico, to first and second-line anti-tb drugs was analysed. a total of 73 isolates were susceptible and 66 were resistant to anti-tb drugs. monoresistance to streptomycin, isoniazid (inh) and ethambutol was observed in 29 cases. resistance to inh was found in 52 cases and in 29 cases inh resistance was combined with resistance to two or three drugs. a total of 24 isolates were multidrug-resista ...201323579794
immunologic evaluation and validation of methods using synthetic peptides derived from mycobacterium tuberculosis for the diagnosis of tuberculosis infection.the goal of this study was to demonstrate the usefulness of an enzyme-linked immunosorbent assay (elisa) for the serodiagnosis of pulmonary tuberculosis (ptb) and extrapulmonary tb (eptb). this assay used 20 amino acid-long, non-overlapped synthetic peptides that spanned the complete mycobacterium tuberculosis esat-6 and ag85a sequences. the validation cohort consisted of 1,102 individuals who were grouped into the following five diagnostic groups: 455 patients with ptb, 60 patients with eptb, 4 ...201323579789
effects of histidine protonation and rotameric states on virtual screening of m. tuberculosis rmlc.while it is well established that protonation and tautomeric states of ligands can significantly affect the results of virtual screening, such effects of ionizable residues of protein receptors are less well understood. in this study, we focus on histidine protonation and rotameric states and their impact on virtual screening of mycobacterium tuberculosis enzyme rmlc. depending on the net charge and the location of proton(s), a histidine can adopt three states: hip (+1 charged, both δ- and ε-nit ...201323579613
mycobacterial ocular inflammation: delay in diagnosis and other factors impacting morbidity.the reported outcomes of ocular mycobacterial infection are commonly unfavorable. this study is among the first to elucidate factors associated with poor outcomes, as well as highlight the continued controversies in therapy, particularly the role of oral corticosteroids.201323579549
foxp3 expression and nitric oxide production in peripheral blood mononuclear cells of communicants with pulmonary tuberculosis.the understanding of the mechanisms involved in the immune response is of significant relevance to the control of tuberculosis (tb), especially in individuals living with patients with tb. to characterize the nitric oxide (no) production and the foxp3 marker expression in this population, peripheral blood mononuclear cells of intradomiciliary contacts of individuals with pulmonary tuberculosis with (ctb, susceptible) and without (stb, resistant) previous history of active infection were stimulat ...201323578109
interaction of mycobacterium tuberculosis cell wall components with the human natural killer cell receptors nkp44 and toll-like receptor 2.we have previously demonstrated that a soluble form of the human nk cell natural cytotoxicity receptor nkp44, binds to the surface of mycobacterium tuberculosis (mtb). herein, we investigated the interaction of mtb cell wall components (cwc) with nkp44 or with toll-like receptor 2 (tlr2) and the role of nkp44 and tlr2 in the direct activation of nk cells upon stimulation with mtb cwc. by using several purified bacterial cwc in an elisa, we demonstrated that nkp44 was able to bind to the mtb cell ...201323578092
community-wide isoniazid preventive therapy drives drug-resistant tuberculosis: a model-based analysis.tuberculosis (tb) control is especially difficult in settings of high hiv prevalence; hiv co-infection erodes host immunity and increases risk of progression to active tb. studies have demonstrated that a 6-month (or longer) course of monotherapy with isoniazid [isoniazid preventive therapy (ipt)] can reduce this risk. the world health organization endorses ipt for symptom-free individuals with hiv/tb co-infection and has recommended expanding ipt to entire communities (community-wide ipt). alth ...201323576815
multifunctional essentiality of succinate metabolism in adaptation to hypoxia in mycobacterium tuberculosis.mycobacterium tuberculosis is a chronic, facultative intracellular pathogen that spends the majority of its decades-long life cycle in a non- or slowly replicating state. however, the bacterium remains poised to resume replicating so that it can transmit itself to a new host. knowledge of the metabolic adaptations used to facilitate entry into and exit from nonreplicative states remains incomplete. here, we apply (13)c-based metabolomic profiling to characterize the activity of m. tuberculosis t ...201323576728
modulation of mycobacterial-specific th1 and th17 cells in latent tuberculosis by coincident hookworm infection.hookworm infections and tuberculosis (tb) are coendemic in many parts of the world. it has been suggested that infection with helminth parasites could suppress the predominant th1 (ifn-γ-mediated) response needed to control mycobacterium tuberculosis infection and enhance susceptibility to infection and/or disease. to determine the role of coincident hookworm infection on responses at steady-state and on m. tuberculosis-specific immune responses in latent tb (ltb), we examined the cellular respo ...201323576678
changes in the major cell envelope components of mycobacterium tuberculosis during in vitro growth.one-third of the world's population is infected with mycobacterium tuberculosis (m.tb), which causes tuberculosis. mycobacterium tuberculosis cell envelope components such as glycolipids, lipoglycans and polysaccharides play important roles in bacteria-host cell interactions that dictate the host immune response. however, little is known about the changes in the amounts and types of these cell envelope components as the bacillus divides during in vitro culture. to shed light on these phenomena, ...201323576535
genetic profile of tuberculosis among the migrant population in fujian province, china.the fujian district in china has a high migrant worker population. although tuberculosis (tb) among migrants is a serious threat to public health in fujian, little is known about the molecular characteristics of tb isolates in this population.201323575332
completing treatment for latent tuberculosis: patient background matters.treatment of latent infection with mycobacterium tuberculosis effectively reduces future activation and transmission of tuberculosis. however, patient adherence to preventive treatment influences its effectiveness. treatment completion is commonly considered as a proxy for adherence.201323575323
serious treatment related adverse drug reactions amongst anti-retroviral naïve mdr-tb patients.globally treatment outcomes for multidrug-resistant mycobacterium tuberculosis (mdr-tb) remain poor and this is compounded by high drug toxicity. little is known about the influence of adverse drug reactions (adrs) on treatment outcomes in south africa.201323573193
selected culture and drug-susceptibility testing methods for drug-resistant mycobacterium tuberculosis screening in resource-constrained settings.evaluation of: adikaram cp, perera j, wijesundera ss. the manual mycobacteria growth indicator tube and the nitrate reductase assay for the rapid detection of rifampicin resistance of m. tuberculosis in low resource settings. bmc infect. dis. 12, 326 (2012). the control of drug-resistant tuberculosis (tb) requires an accurate and a rapid diagnostic for the detection of critical patterns of drug resistance. rifampicin resistance is a good predictor of the presence of multidrug-resistant tb. tradi ...201323570402
tuberculous and non-tuberculous granulomatous lymphadenitis in patients receiving imatinib mesylate (glivec) for metastatic gastrointestinal stromal tumor.imatinib mesylate (im) is the standard treatment for bcr-abl-positive chronic myelogenous leukemia (cml) and is the first-line adjuvant and palliative treatment for metastatic and inoperable gastrointestinal stromal tumor (gist). im is not known to be associated with an increased risk for development of granulomatous diseases.201323569448
a facile hydroxyindole carboxylic acid based focused library approach for potent and selective inhibitors of mycobacterium protein tyrosine phosphatase b.focused on mtb: a facile hydroxyindole carboxylic acid based focused amide library was designed to target both the ptp active site and a unique nearby pocket for enhanced affinity and selectivity. hts of the library led to the identification of a highly potent and selective inhibitor, 11 a, of mptpb, an essential virulence factor for mycobacterium tuberculosis. compound 11 a shows high cellular activity and is capable of reversing the altered immune responses induced by mptpb in macrophages.201323568546
computational models for tuberculosis drug discovery.the search for small molecules with activity against mycobacterium tuberculosis increasingly uses -high-throughput screening and computational methods. previously, we have analyzed recent studies in which computational tools were used for cheminformatics. we have now updated this analysis to illustrate how they may assist in finding desirable leads for tuberculosis drug discovery. we provide our thoughts on strategies for drug discovery efforts for neglected diseases.201323568475
synthesis and identification of β-aryloxyquinoline based diversely fluorine substituted n-aryl quinolone derivatives as a new class of antimicrobial, antituberculosis and antioxidant agents.a new class of β-aryloxyquinoline based diversely fluorine substituted n-aryl quinolone derivatives 8a-x have been synthesized via a one-pot multicomponent reaction. in vitro antimicrobial activity of the synthesized compounds was investigated against a representative panel of pathogenic strains. compounds 8g, 8h, 8m, 8q and 8v exhibited excellent antimicrobial activity compared with first line drugs. in vitro antituberculosis activity was evaluated against mycobacterium tuberculosis h37rv and c ...201323567957
a novel approach to automated genotyping of mycobacterium tuberculosis using a panel of 15 miru vntrs.in this study, we present a new approach to variable number tandem repeats (vntr) analysis using the qiaxcel capillary electrophoresis system and a software-integrated peak calling function. allelic ladders representing 15 mycobacterial interspersed repetitive units (miru)-vntr loci were used to define peak calling tables thereby enabling high precision mycobacterium tuberculosis strain identification.201323566824
a robust and efficient method for the isolation of dna-free, pure and intact rna from mycobacterium tuberculosis.we describe a robust method for the isolation of pure, intact rna suitable for transcriptome studies from mycobacteria with consistent yields of 1 μg to 3 μg total rna per 10(7) cells. the method reduces the use of hazardous chemicals and incorporates protocols for efficient removal of gdna and rrna.201323566823
recycling and refurbishing old antitubercular drugs: the encouraging case of inhibitors of mycolic acid biosynthesis.one of the first approaches undertaken in the quest for antitubercular compounds was that of understanding the mechanism of action of old drugs and proposing chemical modifications or other strategies to improve their activity, generally lost to the mechanisms of resistance developed by mycobacterium tuberculosis. a leading case was the work carried out on a set of compounds with proven activity on the essential pathway of the synthesis of mycolic acids. as a result, different solutions were pre ...201323566152
molecular identification of falciparum malaria and human tuberculosis co-infections in mummies from the fayum depression (lower egypt).due to the presence of the lake quarun and to the particular nature of its irrigation system, it has been speculated that the fayum, a large depression 80 kilometers south-west of modern cairo, was exposed to the hazards of malaria in historic times. similarly, it has been speculated that, in the same area, also human tuberculosis might have been far more widespread in the antiquity than in its recent past. if these hypotheses were confirmed, it would imply that frequent cases of co-infection be ...201323565222
ibuprofen therapy resulted in significantly decreased tissue bacillary loads and increased survival in a new murine experimental model of active tuberculosis.c3heb/fej mice infected with mycobacterium tuberculosis were used in an experimental animal model mimicking active tuberculosis in humans to evaluate the effect of antiinflammatory agents. no other treatment but ibuprofen was given, and it was administered when the animals' health started to deteriorate. animals treated with ibuprofen had statistically significant decreases in the size and number of lung lesions, decreases in the bacillary load, and improvements in survival, compared with findin ...201323564636
biochemical and structural studies of the mycobacterium tuberculosis o6-methylguanine methyltransferase and mutated variants.mycobacterium tuberculosis displays remarkable genetic stability despite continuous exposure to the hostile environment represented by the host's infected macrophages. similarly to other organisms, m. tuberculosis possesses multiple systems to counteract the harmful potential of dna alkylation. in particular, the suicidal enzyme o(6)-methylguanine-dna methyltransferase (ogt) is responsible for the direct repair of o(6)-alkylguanine in double-stranded dna and is therefore supposed to play a centr ...201323564173
disseminated tuberculosis presenting with secondary haemophagocytic lymphohistiocytosis and poncet's disease in an immunocompetent individual.we report a 27-year-old previously healthy man, who presented with fever and painful swelling of both ankles for 6 months, and who had been jaundiced for 1 week. clinical examination revealed diffuse macular rash, severe pallor, deep icterus, generalised lymphadenopathy and hepatosplenomegaly. detailed evaluation revealed granulomata in bone marrow aspirate, and numerous acid fast bacilli in lymph node biopsy. bone marrow pcr was also positive for mycobacterium tuberculosis. a diagnosis of disse ...201323563676
immunogenicity of mycobacterial vesicles in humans: identification of a new tuberculosis antibody biomarker.biomarkers for active tuberculosis (tb) are urgently needed. mycobacteria produce membrane vesicles (mvs) that contain concentrated immune-modulatory factors that are released into the host. we evaluated the human immune responses to bcg and mycobacterium tuberculosis mvs to characterize the antibody responses and identify potentially novel tb biomarkers. serological responses to mvs were evaluated by elisas and immunoblots with sera from 16 sputum smear-positive, 12 smear-negative hiv uninfecte ...201323562367
inhalable microparticles of nitric oxide donors induce phagosome maturation and kill mycobacterium tuberculosis.nitric oxide (no) kills mycobacterium tuberculosis (mtb) in vitro, but gaseous no is difficult to administer to patients. we evaluated the consequences of intracellular delivery of no using inhalable microparticles (mp) containing no donors. mp containing 10% w/w of no donors alone, or in addition to 25% each of isoniazid (inh) and rifabutin (rfb) in a polylactide-co-glycolide (plga) matrix were prepared by spray drying. thp-1-derived macrophages infected with mtb h37rv were exposed to mp or sol ...201323562366
the lpqs knockout mutant of mycobacterium tuberculosis is attenuated in macrophages.lipoproteins of mycobacterium tuberculosis (m. tuberculosis) represent an important class of cell envelop proteins. on the whole, 99 putative lipoproteins have been identified in the genome of m. tuberculosis. earlier investigations on individual mycobacterial lipoproteins demonstrate that some lipoproteins elicit a strong immune response, while others are virulence factors in different models of infection. lpqs is an uncharacterized lipoprotein encoded by the open reading frame rv0847 of m. tub ...201323562345
isoniazid: radical-induced oxidation and reduction chemistry.isoniazid is a potent and selective therapeutic prodrug agent used to treat infections by mycobacterium tuberculosis. although it has been used clinically for over five decades its full mechanism of action is still being elucidated. essential to its mechanism of action is the activation of isoniazid to a reactive intermediate, the isonicotinyl acyl radical, by the catalase-peroxidase katg. the isonicotinyl acyl radical then reacts with nad producing an inhibitor of the nadh-dependent enoyl acp r ...201323562055
characterization of mutations in multi- and extensive drug resistance among strains of mycobacterium tuberculosis clinical isolates in republic of korea.in order to characterize molecular mechanisms of first- and second-line drug resistance in mycobacterium tuberculosis and to evaluate the use of molecular markers of resistance, we analyzed 62 multidrug-resistant, 100 extensively drug-resistant, and 30 pan-susceptible isolates from korean tuberculosis patients. twelve genome regions associated with drug resistance, including katg, ahpc, and inha promoter for isoniazid (inh); embb for ethambutol (emb), rpob for rifampin (rif), pnca for pyrazinami ...201323561273
expression analysis of efflux pump genes among drug-susceptible and multidrug-resistant mycobacterium tuberculosis clinical isolates and reference strains.finding a gene or genes that are involved with multidrug resistance will be useful for finding a new target for the treatment of drug resistant tuberculosis. in this study, we aimed to compare the differences of the expression of 15 putative multidrug efflux pump genes in clinically isolated drug sensitive and multidrug resistant (mdr) mycobacterium tuberculosis isolates, and reference strains. we found that these genes in the drug-sensitive and mdr m. tuberculosis isolates have similar rates of ...201323561272
association between embb mutations and ethambutol resistance in mycobacterium tuberculosis isolates from cuba and the dominican republic: reproducible patterns and problems.the relation of ethambutol resistance to embb mutations remains unclear, and there are no reports on ethambutol resistance from the caribbean. we examined the sequence of embb in 57 distinct multi-drug resistant (mdr) and non-mdr strains of mycobacterium tuberculosis, mostly from cuba and the dominican republic. embb306 codon mutations were found exclusively in mdr-tb, but in both ethambutol sensitive and resistant strains. valine substitutions predominated in ethambutol resistant strains, while ...201323560784
mycobacterium tuberculosis utilizes a unique heterotetrameric structure for dehydrogenation of the cholesterol side chain.compounding evidence supports the important role in pathogenesis that the metabolism of cholesterol by mycobacterium tuberculosis plays. elucidating the pathway by which cholesterol is catabolized is necessary to understand the molecular mechanism by which this pathway contributes to infection. on the basis of early metabolite identification studies in multiple actinomycetes, it has been proposed that cholesterol side chain metabolism requires one or more acyl-coa dehydrogenases (acads). there a ...201323560677
mycobacterium tuberculosis clpp proteases are co-transcribed but exhibit different substrate specificities.caseinolytic (clp) proteases are widespread energy-dependent proteases; the functional atp-dependent protease is comprised of multimers of proteolytic and regulatory subunits. mycobacterium tuberculosis has two clpp proteolytic subunits (clpp1 and clpp2), with both being essential for growth in vitro. clpp1 and clpp2 are arranged in an apparent operon; we demonstrated that the two genes are co-expressed under normal growth conditions. we identified a single promoter region for the clpp1p2 operon ...201323560081
pupylation as a signal for proteasomal degradation in bacteria.posttranslational modifications in the form of covalently attached proteins like ubiquitin (ub), were long considered an exclusive feature of eukaryotic organisms. the discovery of pupylation, the modification of lysine residues with a prokaryotic, ubiquitin-like protein (pup), demonstrated that certain bacteria use a tagging pathway functionally related to ubiquitination in order to target proteins for proteasomal degradation. however, functional analogies do not translate into structural or me ...201423557784
hla-drb1*1501 and vdr polymorphisms and survival of mycobacterium tuberculosis in human macrophages exposed to inhalable microparticles.we examined whether hla-drb1*1501 and four vdr snps influence the macrophage response to infection with mycobacterium tuberculosis (mtb) via innate immune versus drug treatment or drug delivery mechanisms.201323556450
ability of innate defence regulator peptides idr-1002, idr-hh2 and idr-1018 to protect against mycobacterium tuberculosis infections in animal models.tuberculosis is an ongoing threat to global health, especially with the emergence of multi drug-resistant (mdr) and extremely drug-resistant strains that are motivating the search for new treatment strategies. one potential strategy is immunotherapy using innate defence regulator (idr) peptides that selectively modulate innate immunity, enhancing chemokine induction and cell recruitment while suppressing potentially harmful inflammatory responses. idr peptides possess only modest antimicrobial a ...201323555622
bayesian estimation of mixture models with prespecified elements to compare drug resistance in treatment-naïve and experienced tuberculosis cases.we propose a bayesian approach for estimating branching tree mixture models to compare drug-resistance pathways (i.e. patterns of sequential acquisition of resistance to individual antibiotics) that are observed among mycobacterium tuberculosis isolates collected from treatment-naïve and treatment-experienced patients. resistant pathogens collected from treatment-naïve patients are strains for which fitness costs of resistance were not sufficient to prevent transmission, whereas those collected ...201323555210
detection of mycobacterium tuberculosis by using loop-mediated isothermal amplification combined with a lateral flow dipstick in clinical samples.tuberculosis (tb) is a communicable disease caused by the bacterium mycobacterium tuberculosis (mtb) and is a persistent problem in the developing countries. loop-mediated isothermal amplification (lamp) allows dna to be amplified rapidly at a constant temperature. here, a lamp method was combined with a chromatographic lateral-flow dipstick (lfd) to detect is6110 gene of m. tuberculosis specifically and rapidly. the reaction was optimized at 63°c for 60 min, and the amplified dna hybridized to ...201323555102
insights into the origin, emergence, and current spread of a successful russian clone of mycobacterium tuberculosis.mycobacterium tuberculosis variant beijing b0/w148 is regarded as a successful clone of m. tuberculosis that is widespread in the former soviet union and respective immigrant communities. understanding the pathobiology and phylogeography of this notorious strain may help to clarify its origin and evolutionary history and the driving forces behind its emergence and current dissemination. i present the first review and analysis of all available data on the subject. in spite of the common perceptio ...201323554420
epidemic spread of multidrug-resistant tuberculosis in johannesburg, south africa.numerous reports have documented isolated transmission events or clonal outbreaks of multidrug-resistant mycobacterium tuberculosis strains, but knowledge of their epidemic spread remains limited. in this study, we evaluated drug resistance, strain diversity, and clustering rates in patients diagnosed with multidrug-resistant (mdr) tuberculosis (tb) at the national health laboratory service (nhls) central tb laboratory in johannesburg, south africa, between march 2004 and december 2007. phenotyp ...201323554196
fabrication of autoclavable bacteriologic loops for handling mycobacterium tuberculosis isolates from recycled materials in a resource poor setting.in resource limited settings, the appropriation of scarce resources during research efforts can be daunting. sourcing for disposable plastic bacteriological loops for manipulating m. tuberculosis had been eating into the research budget. in an attempt to reduce cost, an alternative and more cost effective way of obtaining autoclavable bacteriologic inoculation loops from used materials in the laboratory was employed. autoclave resistant loops were prepared from polypropylene automatic pipette ti ...201323550202
kinetics of ifn-gamma and tnf-alpha gene expression and their relationship with disease progression after infection with mycobacterium tuberculosis in guinea pigs.guinea pig is one of the most suitable animal models for mycobacterium tuberculosis (m. tb) infection since it shows similarities to pulmonary infection in humans. although guinea pig shows hematogenous spread of m. tb infection into the whole body, immunological studies have mainly focused on granulomatous tissues in lungs and spleens. in order to investigate the time-course of disease pathogenesis and immunological profiles in each infected organ, we performed the following approaches with gui ...201323549819
division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections.the lung is highly exposed to the external environment. for this reason, the lung needs to handle a number of potential threats present in inhaled air such as viruses or bacteria. dendritic cells (dcs) and macrophages (mfs) play an important role in orchestrating the immune responses to these challenges. the severe lung inflammation caused by some pathogens poses a unique challenge to the immune system: the potential insult must be eliminated rapidly whereas tissue inflammation must be controlle ...201323549447
molecular investigation of multiple strain infections in patients with tuberculosis in mubende district, uganda.multiple strain tuberculosis (tb) infections are now an acceptable facet of tuberculosis epidemiology. identification of patients infected with more than one strain gives an insight in disease dynamics at individual and population level. this study therefore aimed at identifying multiple strain infections among tb infected patients. furthermore, to determine factors associated with multiple strain infections in mubende district of uganda. a total of 72 mycobacterium tuberculosis isolates from pa ...201323548804
host genomics and control of tuberculosis infection.tuberculosis (tb), caused by the human pathogenic bacterium mycobacterium tuberculosis, poses a major global health problem. the tubercle bacillus is transmitted from person to person by aerosol, but only a proportion of those in contact with infectious aerosol particles will become infected. if infection occurs, less than 10% of those infected will develop clinical signs of tb, while the majority will develop latent tb infection (ltbi). the identification and treatment of ltbi persons is a majo ...201323548717
key targets and relevant inhibitors for the drug discovery of tuberculosis.tuberculosis (tb) is an infectious disease caused by the pathogen mycobacterium tuberculosis (m. tuberculosis), killing about two million people worldwide each year. an increase in the prevalence of drug-resistant strains of m. tuberculosis in the past decades has renewed focus on the development of new drugs that can treat both drug-sensitive and resistant tb infections. m. tuberculosis evades the host immune system and drug regimes by entering dormant phase within macrophage. as a consequence, ...201323547780
inoculation dose of mycobacterium tuberculosis does not influence priming of t cell responses in lymph nodes.the effect of mycobacterium tuberculosis inocula size on t cell priming in the lymph node and effector t cells in the lung remains controversial. in this study, we used a naive mouse model, without the transfer of transgenic t cells, in conjunction with mathematical model to test whether infection with higher aerosolized inocula would lead to increased priming of m. tuberculosis-specific t cells in the lung-draining lymph node. our data do not support that inoculum size has a measurable influenc ...201323547119
a bronchoesophageal fistula that developed shortly after the initiation of antituberculous chemotherapy.a 26-year-old man visited our clinic because of a persistent cough. although his chest roentgenography showed no abnormalities, a sputum culture revealed a positive result for mycobacterium tuberculosis. computed tomography (ct) prior to antituberculous chemotherapy demonstrated an esophagomediastinal fistula with subcarinal lymphadenopathy. one week after the treatment, he complained of a severe cough exacerbated by swallowing liquid. the development of a bronchoesophageal fistula (bef) was sug ...201323545678
sample preparation, crystallization and structure solution of hisc from mycobacterium tuberculosis.histidinolphosphate aminotransferase (hisc; rv1600) from mycobacterium tuberculosis was overexpressed in m. smegmatis and purified to homogeneity using nickel-nitrilotriacetic acid metal-affinity and gel-filtration chromatography. diffraction-quality crystals suitable for x-ray analysis were grown by the hanging-drop vapour-diffusion technique using 30% polyethylene glycol monomethyl ether 2000 as the precipitant. the crystals belonged to the hexagonal space group p3221, with an unusual high sol ...201323545656
immunohistological characterization of spinal tb granulomas from hiv-negative and -positive patients.tuberculosis (tb) is mainly a disease of the lungs, but mycobacterium tuberculosis (mtb) can establish infection in virtually any organ in the body. rising rates of extrapulmonary (ep) tb have been largely associated with the hiv epidemic, as patients co-infected with hiv show a four-fold higher risk of eptb. spinal tb (pott's disease), one of the most debilitating extrapulmonary forms of disease, is difficult to diagnose and can cause deformity and/or neurological deficits. this study examined ...201323541388
pyrosequencing for the rapid detection of rifampicin resistance in mycobacterium tuberculosis: a meta-analysis.multidrug-resistant tuberculosis is a major threat to the control of tuberculosis and to public health. whereas most conventional methods of drug susceptibility testing (dst) are precise but time consuming, pyrosequencing is a rapid, high-throughput technique.201323541177
[new tuberculosis drugs in resistant and multiresistant tuberculosis].drug-resistant tuberculosis is a globally emerging problem with a rising incidence. according to the who in 2008, 17% of strains of mycobacterium tuberculosis, in untreated cases were resistant to at least one drug and 3.6% were resistant to rifampicin and isoniazid, which is called multidrug-resistant tuberculosis. the problem is greater in patients previously treated and in some countries, where rates of multidrug resistance reach 60%. approximately 5% of multidrug-resistant tuberculosis patie ...201323540388
an overview and mapping of childhood tuberculosis: prevalence, scientific production and citation analysis.the study aimed to analyze publications in the field of "pediatric tuberculosis" and associate them with regional tuberculosis (tb) profile.201323540086
high-level resistance to isoniazid and ethionamide in multidrug-resistant mycobacterium tuberculosis of the lisboa family is associated with inha double mutations.the purpose of this study was to determine the levels of isoniazid and ethionamide resistance and to identify associated mutations in endemic multidrug-resistant (mdr) strains of mycobacterium tuberculosis from the lisbon metropolitan area, portugal.201323539241
co-occurrence of amikacin-resistant and -susceptible mycobacterium tuberculosis isolates in clinical samples from beijing, china.this study examined the phenomenon of heteroresistance in mycobacterium tuberculosis clinical isolates obtained from retreated patients in beijing, china between 2006 and 2011.201323539239
transmission of mycobacterium tuberculosis from an asian elephant (elephas maximus) to a chimpanzee (pan troglodytes) and humans in an australian zoo.mycobacterium tuberculosis is primarily a pathogen of humans. infections have been reported in animal species and it is emerging as a significant disease of elephants in the care of humans. with the close association between humans and animals, transmission can occur. in november 2010, a clinically healthy asian elephant in an australian zoo was found to be shedding m. tuberculosis; in september 2011, a sick chimpanzee at the same zoo was diagnosed with tuberculosis caused by an indistinguishabl ...201323537562
functional characterisation of three o-methyltransferases involved in the biosynthesis of phenolglycolipids in mycobacterium tuberculosis.phenolic glycolipids are produced by a very limited number of slow-growing mycobacterial species, most of which are pathogen for humans. in mycobacterium tuberculosis, the etiologic agent of tuberculosis, these molecules play a role in the pathogenicity by modulating the host immune response during infection. the major variant of phenolic glycolipids produced by m. tuberculosis, named pgl-tb, consists of a large lipid core terminated by a glycosylated aromatic nucleus. the carbohydrate part is c ...201323536839
does neutralization of gastric aspirates from children with suspected intrathoracic tuberculosis affect mycobacterial yields on mgit culture?the microbiological confirmation of pulmonary tuberculosis in children relies on cultures of gastric aspirate (ga) specimens. conventionally, gas are neutralized to improve culture yields of mycobacteria. however, there are limited data to support this practice. to study the utility of neutralization of gas with sodium bicarbonate in children with intrathoracic tuberculosis, a total of 116 children of either sex, aged 6 months to 14 years (median age, 120 months; interquartile range [iqr], 7 to ...201323536406
novel semisynthetic antibiotics from caprazamycins a-g: caprazene derivatives and their antibacterial activity.acidic treatment of a mixture of caprazamycins (cpzs) a-g isolated from a screen of novel antimycobacterial agents gave caprazene, a core structure of cpzs, in high yield. chemical modification of the resulting caprazene was performed to give its various derivatives. the structure-activity relationships of the caprazene derivatives against several mycobacterial species and pathogenic gram-positive and gram-negative bacteria were studied. although caprazene showed no antibacterial activity, the a ...201323532021
tuberculosis in cba/j mice.tuberculosis (tb) develops in 5% to 10% of people infected with mycobacterium tuberculosis (m.tb), but we do not understand how tb develops. cba/j mice may model these events, as sick mice share features with tb patients, including weight loss, m.tb growth, extensive granulomatous infiltrates, neutrophils, necrosis, and fibrosis. here, m.tb-infected cba/j mice were categorized clinically: those with no signs or those with 10% weight loss to determine whether clinical state was associated with lu ...201323531875
drug-resistant tuberculosis: time for visionary political leadership.two decades ago, who declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. at that time, most strains of mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. however, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (mdr) tuberculosis rising. who estimates roughly ...201323531391
tuberculosis biomarkers discovery: developments, needs, and challenges.biomarkers are indispensable to the development of new tuberculosis therapeutics and vaccines. the most robust biomarkers measure factors that are essential to the underlying pathological process of the disease being treated, and thus can capture the full effects of many types of interventions on clinical outcomes in multiple prospective, randomised clinical trials. many mycobacterium tuberculosis and human biomarkers have been studied over the past decade. present research focuses on three area ...201323531389
advances in tuberculosis diagnostics: the xpert mtb/rif assay and future prospects for a point-of-care test.rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. new technologies have been developed and assessed, and are now being implemented. the xpert mtb/rif assay, which enables simultaneous detection of mycobacterium tuberculosis (mtb) and rifampicin (rif) resistance, was endorsed by who in december, 2010. this assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or hiv-associated pulmonary tuber ...201323531388
phase i, single-dose, dose-escalating study of inhaled dry powder capreomycin: a new approach to therapy of drug-resistant tuberculosis.multidrug-resistant tuberculosis (mdr-tb) threatens global tb control. the lengthy treatment includes one of the injectable drugs kanamycin, amikacin, and capreomycin, usually for the first 6 months. these drugs have potentially serious toxicities, and when given as intramuscular injections, dosing can be painful. advances in particulate drug delivery have led to the formulation of capreomycin as the first antituberculosis drug available as a microparticle dry powder for inhalation and clinical ...201323529740
antibacterial activity of salicylanilide 4-(trifluoromethyl)-benzoates.the development of novel antimicrobial agents represents a timely research topic. eighteen salicylanilide 4-(trifluoromethyl)benzoates were evaluated against mycobacterium tuberculosis, m. avium and m. kansasii, eight bacterial strains including methicillin-resistant staphylococcus aureus (mrsa) and for the inhibition of mycobacterial isocitrate lyase. some compounds were further screened against drug-resistant m. tuberculosis and for their cytotoxicity. minimum inhibitory concentrations (mics) ...201323529028
probing the structure of mycobacterium tuberculosis mbta: model validation using molecular dynamics simulations and docking studies.multidrug resistance capacity of mycobacterium tuberculosis demands urgent need for developing new antitubercular drugs. the present work is on m. tuberculosis-mbta, an enzyme involved in the biosynthesis of siderophores, having a critical role in bacterial growth and virulence. the molecular models of both holo and apo forms of m. tuberculosis-mbta have been constructed and validated. a docking study with a series of 42 5'-o-[n-(salicyl) sulfamoyl] adenosine derivatives, using gold software, re ...201423527569
increased production of il-4 and il-12p40 from bronchoalveolar lavage cells are biomarkers of mycobacterium tuberculosis in the sputum.tuberculosis (tb) causes 1.45 million deaths annually world wide, the majority of which occur in the developing world. active tb disease represents immune failure to control latent infection from airborne spread. acid-fast bacillus (afb) seen on sputum smear is a biomarker for contagiousness.201323527200
the rationale for using rifabutin in the treatment of mdr and xdr tuberculosis outbreaks.genetically related mycobacterium tuberculosis strains with alterations at codon 516 in the rpob gene were observed amongst a substantial number of patients with drug resistant tuberculosis in the eastern cape province (ecp) of south africa. mutations at codon 516 are usually associated with lower level rifampicin (rif) resistance, while susceptibility to rifabutin (rfb) remains intact. this study was conducted to assess the rationale for using rfb as a substitution for rif in the treatment of m ...201323527189
continuous and discontinuous cigarette smoke exposure differentially affects protective th1 immunity against pulmonary tuberculosis.pulmonary tuberculosis (tb), caused by mycobacterium tuberculosis, is the leading cause of death due to a bacterial pathogen. emerging epidemiologic evidence suggests that the leading risk factor associated with tb mortality is cigarette smoke exposure. despite this, it remains poorly understood what is the effect of cigarette smoke exposure on anti-tb immunity and whether its potential detrimental effect can be reversed by cigarette smoking cessation. in our current study, we have investigated ...201323527127
intersubunit ionic interactions stabilize the nucleoside diphosphate kinase of mycobacterium tuberculosis.most nucleoside diphosphate kinases (ndpks) are hexamers. the c-terminal tail interacting with the neighboring subunits is crucial for hexamer stability. in the ndpk from mycobacterium tuberculosis (mt) this tail is missing. the quaternary structure of mt-ndpk is essential for full enzymatic activity and for protein stability to thermal and chemical denaturation. we identified the intersubunit salt bridge arg(80)-asp(93) as essential for hexamer stability, compensating for the decreased intersub ...201323526954
extraction, derivatization, and determination of metabolome in human macrophages.a gc/tof-ms was applied to the determination of metabolites in human macrophages. the extraction conditions and quenching conditions were investigated and optimized. the results indicated that 0.9% w/v sodium chloride at 4°c was the most favorable condition to quench macrophage, 1 ml 50% acn for 2 min in ice bath was the optimal condition to extract 5 × 10(6) cells. two hundred six peaks could be detectable with peak area over 50 using this method. among these peaks, 45 peaks with the similarity ...201323526673
spectrum of urogenital tuberculosis.urogenital tuberculosis (ugtb) plays an important role because its complications may be fatal, it significantly reduces quality of life, and it is often associated with aids. diagnosis of ugtb is often delayed. we analyzed 131 case histories of ugtb patients from the years 2009-2011. gender, age, and the clinical form and main features of the disease were taken into account. the most common form was kidney tuberculosis (74.8%). isolated kidney tuberculosis (ktb) more often occurs in women: 56.8% ...201323526041
optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model.the dosage of 10 mg/kg/d rifampin, as currently used in the treatment of tuberculosis (tb), is not an optimal dose. shortening of treatment duration might be achievable using an increased rifampin dose.201323525933
incidence of tuberculous and non-tuberculous mycobacteria, differentiated by multiplex pcr, in clinical specimens of a large general hospital.to determine the incidence of mycobacterium tuberculosis complex and non-tuberculous mycobacterial isolates in the routine setting of a large general hospital using an "in-house" multiplex polymerase chain reaction method and to establish a paradigm for the definitive identification of mycobacteria isolated using semi-automated equipment.201323525313
efficient synthesis of new (r)-2-amino-1-butanol derived ureas, thioureas and acylthioureas and in vitro evaluation of their antimycobacterial activity.the synthesis of 22 structurally diverse urea, thiourea and acylthiourea derivatives containing the (r)-2-amino-1-butanol motif has been performed. the evaluation of their in vitro activity against mycobacterium tuberculosis (h37rv and strain 43) showed promising results in the case of the acylthiourea derivatives (mic range 0.36-7.46 μm for h37rv strain).201323524112
new fluoroquinolones active against fluoroquinolones-resistant mycobacterium tuberculosis strains.a set of 21 new fluoroquinolones bearing an aromatic or heteroaromatic moiety at c-7 and an alkyl group at n-1 were synthesized based on the lead structure of pirfloxacin and tested in vitro against mycobacterium tuberculosis (m. tuberculosis) h37rv by mic determination in liquid medium. among the synthesized compounds, 1-(tert-butyl)-6-fluoro-7-(4-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2o) and 1-(tert-butyl)-6-fluoro-7-(pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic ...201323523640
current trends of mycobacterium tuberculosis molecular epidemiology in saudi arabia and associated demographical factors.data are scarce on demographical factors related to the population structure of mycobacterium tuberculosis in saudi arabia. a study was conducted on 902 clinical isolates to explore current trends in the phylogeography and associated demographical factors of tuberculosis by using spoligotyping and 24 loci based miru-vntr typing. young male patients (aged 16-29 and 30-44) were predominant in this cohort. the phylogenetic diversity among m. tuberculosis isolates was found high, as almost all known ...201323523599
a rare cause of blindness.mycobacterium tuberculosis (tb) infection remains a serious problem in many underdeveloped countries. tb is largely perceived as a disease affecting the pulmonary system, yet despite declining cases of pulmonary tb in the united states (us), extrapulmonary infections are being reported at an increasing proportion of total tb cases. moreover, due to the insidious nature of extrapulmonary tb (eptb), it may not be readily recognized by emergency physicians, as it masquerades as more commonly encoun ...201323522955
co-infection of tuberculosis and parasitic diseases in humans: a systematic review.co-infection of tuberculosis and parasitic diseases in humans is an important public problem in co-endemic areas in developing countries. however, there is a paucity of studies on co-infection and even fewer reviews. this review examines 44 appropriate papers by prisma from 289 papers searched in pubmed via the ncbi entrez system (no grey literature) up to december 2012 in order to analyze the factors that influence epidemic and host's immunity of co-infection. the limited evidence in this revie ...201323522098
detection of mycobacterium tuberculosis using a capillary-array microsystem with integrated dna extraction, loop-mediated isothermal amplification, and fluorescence detection.this article reports for the first time a high-throughput microfluidic system with fully integrated loop-mediated isothermal amplification (lamp) analysis. with the developed system, parallel mycobacterium tuberculosis detections were implemented in polytetrafluoroethylene capillaries through the utilization of droplet technology coupled with magnetic beads. during the analysis, liquid plugs containing different types of sample or reagents are sequentially introduced into the capillaries and mad ...201323521496
amplicon dna melting analysis for the simultaneous detection of brucella spp and mycobacterium tuberculosis complex. potential use in rapid differential diagnosis between extrapulmonary tuberculosis and focal complications of brucellosis.some sites of extrapulmonary tuberculosis and focal complications of brucellosis are very difficult to differentiate clinically, radiologically, and even histopathologically. conventional microbiological methods for the diagnosis of extrapulmonary tuberculosis and complicated brucellosis not only lack adequate sensitivity, they are also time consuming, which could lead to an unfavourable prognosis. the aim of this work was to develop a multiplex real-time pcr assay based on sybr green i to simul ...201323520501
sputum induction to aid diagnosis of smear-negative or sputum-scarce tuberculosis in adults in hiv-endemic settings.sputum induction can aid tuberculosis (tb) diagnosis, but adult data from hiv-endemic environments are limited, and it is unclear how performance varies depending on the clinical context (in-patient versus outpatient), hiv status and whether patients are smear-negative or sputum-scarce. 696 adults with suspected smear-negative or sputum-scarce tb from cape town (south africa) were referred for routine sputum induction. liquid culture for mycobacterium tuberculosis served as the reference standar ...201423520317
expression, purification, crystallization and preliminary x-ray crystallographic analysis of the l,d-transpeptidase ldtmt1 from mycobacterium tuberculosis.mycobacterium tuberculosis is capable of adapting to prolonged periods of dormancy, a state which is resistant to killing by antimycobacterial agents. the l,d-transpeptidation reaction catalysed by the l,d-transpeptidase ldtmt1 is likely to play an essential role in the adaptation of m. tuberculosis to its dormant state. ldtmt1 has been successfully crystallized using vapour-diffusion methods. the crystals of this protein belonged to space group p6₅22, with unit-cell parameters a=57.25, b=57.25, ...201323519798
structural basis for the inhibition of mycobacterium tuberculosis l,d-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains.difficulty in the treatment of tuberculosis and growing drug resistance in mycobacterium tuberculosis (mtb) are a global health issue. carbapenems inactivate l,d-transpeptidases; meropenem, when administered with clavulanate, showed in vivo activity against extensively drug-resistant mtb strains. ldtmt2 (rv2518c), one of two functional l,d-transpeptidases in mtb, is predominantly expressed over ldtmt1 (rv0116c). here, the crystal structure of n-terminally truncated ldtmt2 (residues leu131-ala408 ...201323519417
resistome analysis of mycobacterium tuberculosis: identification of aminoglycoside 2'-nacetyltransferase (aac) as co-target for drug desigining.: the emergence of multidrug resistant tuberculosis (mdrtb) highlights the urgent need to understand the mechanisms of resistance to the drugs and to develop a new arena of therapeutics to treat the disease. ethambutol, isonazid, pyrazinamide, rifampicin are first line of drugs against tb, whereas aminoglycoside, polypeptides, fluoroquinolone, ethionamide are important second line of bactericidal drugs used to treat mdrtb, and resistance to one or both of these drugs are defining characteristic ...201323519100
design, synthesis and structure-activity relationships of 3,5-diaryl-1h-pyrazoles as inhibitors of arylamine n-acetyltransferase.the synthesis and inhibitory potencies of a novel series of 3,5-diaryl-1h-pyrazoles as specific inhibitors of prokaryotic arylamine n-acetyltransferase enzymes is described. the series is based on hit compound 1 3,5-diaryl-1h-pyrazole identified from a high-throughout screen that has been carried out previously and found to inhibit the growth of mycobacterium tuberculosis.201323518278
the immune response in tuberculosis.there are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with mycobacterium tuberculosis and remains asymptomatic. of these latent individuals, only 5-10% will develop active tuberculosis disease in their lifetime. cd4(+) t cells, as well as the cytokines il-12, ifn-γ, and tnf, are critical in the control of mycobacterium tuberculosis infection, but the host factors that determine why some individuals are protected ...201323516984
mycobacterium tuberculosis spoligotypes circulating in the lebanese population: a retrospective study.genotyping mycobacterium tuberculosis in lebanon on the national level may be beneficial for assessing patients and monitoring the therapeutic response to dots. this study aimed to characterize the spoligotypes of clinical isolates of m. tuberculosis patients collected between april 2004 and october 2005 from all lebanese provinces. isolates (n = 60) were cultured and identified by their biochemical characteristics. dna extracts of these samples were amplified by pcr and genotyped by spoligotypi ...201323516820
multicenter evaluation of genechip for detection of multidrug-resistant mycobacterium tuberculosis.drug-resistant tuberculosis (tb), especially multidrug-resistant tb (mdr-tb), is still one of the most serious threats to tb control worldwide. early diagnosis of mdr-tb is important for effectively blocking transmission and establishing an effective protocol for chemotherapy. genechip is a rapid diagnostic method based on molecular biology that overcomes the poor biosafety, time consumption, and other drawbacks of traditional drug sensitivity testing (dst) that can detect mdr-tb. however, the g ...201323515537
a reduction in anti-tuberculosis drug resistance after the implementation of the national "stop tb" program in central taiwan, 2003-2007.the aim of this study was to determine the performance of the national "stop tb" program in central taiwan during 2003-2007 by examining trends in the combined drug resistance to first-line anti-tuberculosis (tb) drugs among clinical mycobacterium tuberculosis isolates. using 4,819 clinical m. tuberculosis isolates obtained from two mycobacteriology referral laboratories, the resistance to drugs was measured and analyzed along with the treatment outcomes in notified tb patients. the proportion o ...201323514903
evaluation of a membrane array for detection of mycobacterium tuberculosis complex and nontuberculous mycobacteria in positive liquid cultures.molecular identification of mycobacteria in positive mycobacteria growth indicator tube (mgit) cultures can accelerate mycobacterial diagnosis. a membrane hybridization array (blue point) was evaluated for this purpose in 284 positive mgit cultures. discrepant results were resolved by testing with the genotype mycobacterium kit, tbc id test, sequencing of the 16s rrna gene and internal transcribed spacer. total recovery from culture and the array (if confirmed) was considered 100%. the sensitivi ...201323514755
eales' disease - current concepts in diagnosis and management.eales' disease, first described by the british ophthalmologist henry eales in 1880, is characterized by three overlapping stages of venous inflammation (vasculitis), occlusion, and retinal neovascularization. diagnosis is mostly clinical and requires exclusion of other systemic or ocular conditions that could present with similar retinal features. in recent years, immunological, molecular biological, and biochemical studies have indicated the role of human leukocyte antigen, retinal autoimmunity ...201323514227
antimycobacterial effect of extract and its components from rheum rhaponticum.the global threat of tuberculosis demands the search for alternative antimycobacterial drugs. the present study examined roots and petioles from rheum rhaponticum for antimycobacterial activity. crude methanol extracts and eight phenolic compounds isolated by preparative column chromatography were tested against mycobacterium tuberculosis h37ra and m. bovis using the broth dilution method. the extract from roots and its components, such as rhaponticin, deoxyrhaponticin, resveratrol, barbaloin, a ...201323513971
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