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tuberculosis: a disease without boundaries.tuberculosis (tb) is an airborne disease caused by mycobacterium tuberculosis (mtb) that usually affects the lungs leading to severe coughing, fever, and chest pains. although current research in the past four years has provided valuable insight into tb transmission, diagnosis, and treatment, much remains to be discovered to effectively decrease the incidence of and eventually eradicate tb. the disease still puts a strain on public health, being only second to hiv/aids in causing high mortality ...201526198113
deletion of cyp125 confers increased sensitivity to azoles in mycobacterium tuberculosis.mycobacterium tuberculosis is able to utilize cholesterol as a carbon source, and this ability is linked to its virulence in macrophages and in the mouse model of infection. the m. tuberculosis cytochrome p450 cyp125 plays a key role in cholesterol metabolism being involved in the first steps of its degradation. cyp125 is a cholesterol hydroxylase which is essential for cholesterol catabolism in m. bovis bcg and some strains of m. tuberculosis. we generated an unmarked, in-frame deletion of cyp1 ...201526197389
rational design and synthesis of thioridazine analogues as enhancers of the antituberculosis therapy.tuberculosis, caused by mycobacterium tuberculosis, is still one of the leading infectious diseases globally. therefore, novel approaches are needed to face this disease. efflux pumps are known to contribute to the emergence of m. tuberculosis drug resistance. thioridazine has shown good anti-tb properties both in vitro and in vivo, likely due to its capacity to inhibit efflux mechanisms. here we report the design and synthesis of a number of putative efflux inhibitors inspired by the structure ...201526197353
restoration of cd4+ responses to copathogens in hiv-infected individuals on antiretroviral therapy is dependent on t cell memory phenotype.antiretroviral therapy (art) induces rapid suppression of viral replication and a progressive replenishment of cd4(+) t cells in hiv-infected individuals. however, the effect of art on restoring pre-existing memory cd4(+) t cells specific for common copathogens is still unclear. to better understand the dynamics of ag-specific cd4(+) t cells during art, we assessed the frequency, functional capacity, and memory profile of cd4(+) t cells specific for mycobacterium tuberculosis and cmv in 15 hiv-i ...201526195814
heme and i. 201526195628
epidemiologic correlates of pyrazinamide-resistant mycobacterium tuberculosis in new york city.pyrazinamide (pza) has important sterilizing activity in tuberculosis (tb) chemotherapy. we describe trends, risk factors, and molecular epidemiology associated with pza-resistant (pza(r)) mycobacterium tuberculosis in new york city (nyc). from 2001 to 2008, all incident culture-positive tb cases reported by the nyc department of health and mental hygiene (dohmh) were genotyped by is6110-based restriction fragment length polymorphism and spoligotype. multidrug-resistant (mdr) isolates underwent ...201526195530
influence of steric crowding on diastereoselective arabinofuranosylations.the occurrence of arabinofuranosides on the cell surface of mycobacterium tuberculosis (mtb) and their significance in controlling disease spurred interest in developing strategies for their diastereoselective synthesis. mtb uses enzymes to achieve diastereoselectivity through noncovalent interactions. of the two possible glycosidic linkages, chemically, 1,2-trans linkage is relatively easy to synthesize by taking advantage of neighboring group participation, whereas synthesis of the 1,2-cis lin ...201526195010
ph-responsive isoniazid-loaded nanoparticles markedly improve tuberculosis treatment in mice.tuberculosis is a major global health problem for which improved therapeutics are needed to shorten the course of treatment and combat emergence of drug resistance. mycobacterium tuberculosis, the etiologic agent of tuberculosis, is an intracellular pathogen of mononuclear phagocytes. as such, it is an ideal pathogen for nanotherapeutics because macrophages avidly ingest nanoparticles even without specific targeting molecules. hence, a nanoparticle drug delivery system has the potential to targe ...201526193431
design, synthesis, and biological evaluation of pyrazolo[1,5-a]pyridine-3-carboxamides as novel antitubercular agents.a series of pyrazolo[1,5-a]pyridine-3-carboxamide derivatives were designed and synthesized as new anti-mycobacterium tuberculosis (mtb) agents. the compounds exhibit promising in vitro potency with nanomolar mic values against the drug susceptive h37rv strain and a panel of clinically isolated multidrug-resistant mtb (mdr-tb) strains. one of the representative compounds (5k) significantly reduces the bacterial burden in an autoluminescent h37ra infected mouse model, suggesting its promising pot ...201526191372
left-hand side exploration of novel bacterial topoisomerase inhibitors to improve selectivity against herg binding.structure-activity relationship (sar) exploration on the left-hand side (lhs) of a novel class of bacterial topoisomerase inhibitors led to a significant improvement in the selectivity against herg cardiac channel binding with concomitant potent antimycobacterial activity. bulky polar substituents at the c-7 position of the naphthyridone ring did not disturb its positioning between two base pairs of dna. further optimization of the polar substituents on the lhs of the naphthyridone ring led to p ...201526191359
detection of mycobacterium tuberculosis in extrapulmonary biopsy samples using pcr targeting is6110, rpob, and nested-rpob pcr cloning.present study was aimed to examine the diagnostic utility of polymerase chain reaction (pcr) and nested pcr techniques for the detection of mycobacterium tuberculosis (mtb) dna in samples from patients with extra pulmonary tuberculosis (eptb). in total 80 formalin-fixed, paraffin-embedded (ffpe) samples comprising 70 samples with definite diagnosis of eptb and 10 samples from known non- eptb on the basis of histopathology examination, were included in the study. pcr amplification targeting is611 ...201526191059
molecular epidemiology of tuberculosis in havana, cuba, 2009.to estimate the proportion of tuberculosis cases attributable to recent transmission and the risk factors possibly associated with tuberculosis clustering.201526211409
solution structure of the phop dna-binding domain from mycobacterium tuberculosis. 201526209027
correction: in vitro activity of rifampicin and verapamil combination in multidrug-resistant mycobacterium tuberculosis. 201526207741
evaluation of dual-color fluorescence in situ hybridization with peptide nucleic acid probes for the detection of mycobacterium tuberculosis and non-tuberculous mycobacteria in clinical specimens.peptide nucleic acid (pna) probes are artificial dna analogues with a hydrophobic nature that can penetrate the mycobacterial cell wall. we evaluated a fish method for simultaneous detection and identification of mycobacterium tuberculosis (mtb) and non-tuberculous mycobacteria (ntm) in clinical respiratory specimens using differentially labeled pna probes.201526206686
phenotypic and genotypic analysis of anti-tuberculosis drug resistance in mycobacterium tuberculosis isolates in myanmar.tuberculosis (tb) is one of the most serious health problems in myanmar. because tb drug resistance is associated with genetic mutation(s) relevant to responses to each drug, genotypic methods for detecting these mutations have been proposed to overcome the limitations of classic phenotypic drug susceptibility testing (dst). we explored the current estimates of drug-resistant tb and evaluated the usefulness of genotypic dst in myanmar.201526206685
detection of first-line anti-tuberculosis drug resistance mutations by allele-specific primer extension on a microsphere-based platform.resistance of mycobacterium tuberculosis to anti-tuberculosis (tb) drugs is almost exclusively due to spontaneous chromosomal mutations in target genes. rapid detection of drug resistance to both first- and second-line anti-tb drugs has become a key component of tb control programs. technologies that allow rapid, cost-effective, and high-throughput detection of specific nucleic acid sequences are needed. this study was to develop a high-throughput assay based on allele-specific primer extension ...201526206684
diagnostic yield and safety of sputum induction with nebulized racemic salbutamol versus hypertonic saline in smear-negative pulmonary tuberculosis.the aim of the study was to compare the diagnostic yield and safety profile of sputum induction (si) with nebulized racemic salbutamol solution versus hypertonic saline in smear-negative pulmonary tuberculosis (tb).201526206666
a time-resolved förster resonance energy transfer assay to measure activity of the deamidase of the prokaryotic ubiquitin-like protein.the modification of proteins in mycobacterium tuberculosis (mtb) by the prokaryotic ubiquitin-like protein (pup) targets them for degradation by mycobacterial proteasomes. although functionally similar to eukaryotic deubiquitylating enzymes, the deamidase of pup, called dop, has no known mammalian homologs. because dop is necessary for persistent infection by mtb, its selective inhibition holds potential for tuberculosis therapy. to facilitate high-throughput screens for dop inhibitors, we devel ...201526205584
childhood tuberculosis: an overview. 201526205109
genetic markers, genotyping methods & next generation sequencing in mycobacterium tuberculosis.molecular epidemiology (me) is one of the main areas in tuberculosis research which is widely used to study the transmission epidemics and outbreaks of tubercle bacilli. it exploits the presence of various polymorphisms in the genome of the bacteria that can be widely used as genetic markers. many dna typing methods apply these genetic markers to differentiate various strains and to study the evolutionary relationships between them. the three widely used genotyping tools to differentiate mycobac ...201526205019
lung necrosis and neutrophils reflect common pathways of susceptibility to mycobacterium tuberculosis in genetically diverse, immune-competent mice.pulmonary tuberculosis (tb) is caused by mycobacterium tuberculosis in susceptible humans. here, we infected diversity outbred (do) mice with ∼100 bacilli by aerosol to model responses in a highly heterogeneous population. following infection, 'supersusceptible', 'susceptible' and 'resistant' phenotypes emerged. tb disease (reduced survival, weight loss, high bacterial load) correlated strongly with neutrophils, neutrophil chemokines, tumor necrosis factor (tnf) and cell death. by contrast, immu ...201526204894
aromatic amine n-oxide organometallic compounds: searching for prospective agents against infectious diseases.in search of prospective agents against infectious diseases, 1,1'-bis(diphenylphosphino)ferrocene pyridine-2-thiolato-1-oxide m(ii) hexafluorophosphate compounds [m(mpo)(dppf)](pf6), where m = palladium or platinum, were synthesized and fully characterized in the solid state and in solution using experimental and dft computational techniques. the compounds are isomorphous and the m(ii) transition metal ions are in a nearly planar trapezoidal cis-coordination bound to the pyridine-2-thiolato-1-ox ...201526203896
tuberculous meningitis in children and adults: a 10-year retrospective comparative analysis.tuberculous meningitis (tbm) is the most lethal form of mycobacterium tuberculosis infection, which has a high rate of neurological complications and sequelae.201526186004
towards host-directed therapies for tuberculosis.the treatment of tuberculosis is based on combinations of drugs that directly target mycobacterium tuberculosis. a new global initiative is now focusing on a complementary approach of developing adjunct host-directed therapies.201526184493
laboratory evaluation of a specimen transport medium for downstream molecular processing of sputum samples to detect mycobacterium tuberculosis.modern molecular-based approaches for the detection of mycobacterium tuberculosis in sputum samples promise quicker and more accurate detection of cases. however, processing sputum samples at central diagnostic facilities provides a diagnostic approach, but requires a safe and efficient system that is not affected by transport delays and ambient temperature to be feasible. we evaluated the technical properties of primestore®-molecular transport medium (ps-mtm) for its ability to inactivate mycob ...201526183764
colistin as a potentiator of anti-tb drug activity against mycobacterium tuberculosis.the mycobacterial cell wall is an effective permeability barrier that limits intracellular concentrations of anti-tb drugs and hampers the success of treatment. we hypothesized that colistin might enhance the efficacy of anti-tb drugs by increasing mycobacterial cell wall permeability. in this study, we investigated the additional effect of colistin on the activity of anti-tb drugs against mycobacterium tuberculosis in vitro.201526183185
inhalation of recombinant adenovirus expressing granulysin protects mice infected with mycobacterium tuberculosis.granulysin is a cytolytic molecule with perforin and granzymes that is expressed by activated human ctls, nk and γδ t cells, and it has broad antimicrobial activity, including to drug-sensitive and drug-resistant mycobacterium tuberculosis. we hypothesized that approaches facilitating the expression of granulysin in m. tuberculosis-infected host cells in the lung may provide a novel treatment strategy for pulmonary tb. in this study, a recombinant replication-deficient adenovirus serotype 5-base ...201526181627
diagnostic usefulness of ifn-gamma releasing assays compared with conventional tests in patients with disseminated tuberculosis.ifn-gamma releasing assays (igras) such as t-spot.tb assay and quantiferon-tb in-tube (qft-git) have yielded promising results for the diagnosis of tuberculosis (tb). however, little is known about the usefulness of these assays for diagnosing disseminated tb. we therefore compared their usefulness with traditional tests in patients with disseminated tb. all adult patients with suspected disseminated tb were prospectively enrolled at a tertiary hospital in an intermediate tb-burden country durin ...201526181542
intestinal tuberculosis previously mistreated as crohn's disease and complicated with perforation: a case report and literature review.tuberculosis is known as a notorious mimicker and distinguishing between intestinal tuberculosis and crohn's disease is a huge diagnostic challenge.201526180746
differential expression of putative drug resistance genes in mycobacterium tuberculosis clinical isolates.understanding drug resistance in mycobacterium tuberculosis requires an integrated analysis of strain lineages, mutations and gene expression. previously, we reported the differential expression of esxg, esxh, infa, groes, rpmi, rpsa and lipf genes in a sensitive m. tuberculosis strain and in a multidrug-resistant clinical isolate. here, we have evaluated the expression of these genes in 24 clinical isolates that belong to different lineages and have different drug resistance profiles. in vitro, ...201526454220
the xpert® mtb/rif assay in routine diagnosis of pulmonary tuberculosis: a multicentre study in lithuania.drug-resistant tuberculosis (tb) is an important public health problem in lithuania with mdr rates in new cases reaching 11% in 2012. currently available diagnostic tools are not fully adequate for an accurate and rapid result for diagnosis of tb and mdr-tb.201526403251
vitamin d deficiency and tb disease phenotype.extrapulmonary tb is increasingly common, yet the determinants of the wide clinical spectrum of tb are poorly understood.201526400877
rapid, single-cell electrochemical detection of mycobacterium tuberculosis using colloidal gold nanoparticles.tuberculosis (tb) remains a global health threat, with over a third of the world population suffering from the disease, and 1.5 million deaths due to the disease in 2013 alone. despite significant advances in tb detection strategies in recent years, a bigger push toward detecting tb in the shortest and easiest way possible at the point-of-care (poc) is still in demand. to this end, we have designed a simple yet rapid and sensitive bioassay that detects mtb dna electrochemically using colloidal g ...201526382883
mycobacterium tuberculosis is resistant to isoniazid at a slow growth rate by single nucleotide polymorphisms in katg codon ser315.an important aim for improving tb treatment is to shorten the period of antibiotic therapy without increasing relapse rates or encouraging the development of antibiotic-resistant strains. in any m. tuberculosis population there is a proportion of bacteria that are drug-tolerant; this might be because of pre-existing populations of slow growing/non replicating bacteria that are protected from antibiotic action due to the expression of a phenotype that limits drug activity. we addressed this quest ...201526382066
morphological changes in the overall mycobacterium tuberculosis h37ra cell shape and cytoplasm homogeneity due to mutellina purpurea l. essential oil and its main constituents.the aim of this study was to evaluate the antimycobacterial activity of the essential oil (eo) of mutellina purpurea l. and its main constituents against the m. tuberculosis h37ra strain.201526381133
mtb-dr-rif 9g test: detection and discrimination of tuberculosis and multi-drug resistant tuberculosis strains.this report describes the evaluation of the novel mtb-dr-rif 9g test for the accurate detection and discrimination of mycobacterium tuberculosis (mtb) and rifampicin-resistant m. tuberculosis (mtb-dr-rif) in the clinical samples. the procedure included the amplification of a nucleotide fragment of the rpob gene of the mtb and mtb-dr-rif strains and their hybridization with the immobilized probes. the mtb-dr-rif 9g test was evaluated for its ability to detect and discriminate mtb and mtb-dr-rif s ...201526381057
perianal tuberculosis: a case report and review of the literature.tuberculosis (tb) is still a major health problem worldwide. we present a rare case of an immuno-competent patient with perianal tb. a 38-year-old man visited a clinic with pain, swelling, and redness in the perineum. he had been persistently coughing for the past 6 mo. the abscess had formed a fistula to the perianal region, indicating perianal abscess. mycobacterium tuberculosis was found in sputum and perianal abscess. surgical drainage was performed, and oral anti-tuberculous drugs were admi ...201526380834
expression and purification of the recombinant cytochrome p450 cyp141 protein of mycobacterium tuberculosis as a diagnostic tool and vaccine production.tuberculosis (tb) is regarded as a health problem worldwide, particularly in developing countries. mycobacterium tuberculosis (m. tuberculosis) is the cause of this disease. approximately two billion people worldwide are infected by m. tuberculosis and annually about two million individuals die in consequence. forty million people are estimated to die because of m. tuberculosis over the next 25 years if the measures for controlling this infection are not extensively developed. in the vaccination ...201526380105
pyrosequencing analysis for mutations in embb codon306 among clinical mycobacterium tuberculosis isolates from qingdao, china.in this study, our objectives was to analyze the molecular characteristics of mutation at embb codon306 in mycobacterium tuberculosis in qingdao by pyrosequencing technology, and to assess the value of embb codon306 used as a molecular marker to diagnose multidrug resistant (mdr) tb strains. pyrosequencing was used to detect mutations at embb codon306 among m. tuberculosis isolates from tuberculosis (tb) patients in qingdao. the correlation between embb306 mutation and mdr phenotype was evaluate ...201526379935
b cells and programmed death-ligand 2 signaling are required for maximal interferon-γ recall response by splenic cd4⁺ memory t cells of mice vaccinated with mycobacterium tuberculosis ag85b.cd4+ t cells producing interferon-γ are crucial for protection against mycobacterium tuberculosis infection and are the cornerstone of tuberculosis vaccination and immunological diagnostic assays. since emerging evidence indicates that b cells can modulate t cell responses to m. tuberculosis infection, we investigated the contribution of b cells in regulating interferon-γ recall response by memory thelper1 cells specific for ag85b, a leading candidate for tuberculosis sub-unit vaccines. we found ...201526379242
efficient calculation of enzyme reaction free energy profiles using a hybrid differential relaxation algorithm: application to mycobacterial zinc hydrolases.determination of the free energy profile for an enzyme reaction mechanism is of primordial relevance, paving the way for our understanding of the enzyme's catalytic power at the molecular level. although hybrid, mostly dft-based, qm/mm methods have been extensively applied to this type of studies, achieving accurate and statistically converged results at a moderate computational cost is still an open challenge. recently, we have shown that accurate results can be achieved in less computational t ...201526415840
phenothiazines as a solution for multidrug resistant tuberculosis: from the origin to present.historically, multiplicity of actions in synthetic compounds is a rule rather than exception. the science of non-antibiotics evolved in this background. from the antimalarial and antitrypanosomial dye methylene blue, chemically similar compounds, the phenothiazines, were developed. the phenothiazines were first recognised for their antipsychotic properties, but soon after their antimicrobial functions came to be known and then such compounds were designated as non-antibiotics. the emergence of h ...201526415662
identification of 13 blood-based gene expression signatures to accurately distinguish tuberculosis from other pulmonary diseases and healthy controls.tuberculosis (tb), caused by infection with mycobacterium tuberculosis, is still a major threat to human health worldwide. current diagnostic methods encounter some limitations, such as sample collection problem or unsatisfied sensitivity and specificity issue. moreover, it is hard to identify tb from some of other lung diseases without invasive biopsy. in this paper, the logistic models with three representative regularization approaches including lasso (the most popular regularization method), ...201526405955
comparison of samples obtained from bronchoscopy of patients with and without bronchial anthracosis for investigating the prevalence of mycobacterium tuberculosis.bronchial anthracosis is caused by the deposition of carbon, silica or asbestos particles in mucosal and submucosal cells and macrophages, and it can lead to chronic bronchial obstruction. certain studies have reported an association between bronchial anthracosis and infection with mycobacterium tuberculosis. this study aimed to compare the samples obtained from bronchoscopy of patients with and without bronchial anthracosis for investigating the prevalence of mycobacterium tuberculosis.201526405675
management of latent mycobacterium tuberculosis infection: who guidelines for low tuberculosis burden countries.latent tuberculosis infection (ltbi) is characterised by the presence of immune responses to previously acquired mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (tb). here we report evidence-based guidelines from the world health organization for a public health approach to the management of ltbi in high risk individuals in countries with high or middle upper income and tb incidence of <100 per 100 000 per year. the guidelines strongly recommend systematic t ...201526405286
countrywide roll-out of xpert(®) mtb/rif in swaziland: the first three years of implementation.all 19 public health laboratories in swaziland that had xpert(®) mtb/rif machines installed as part of a countrywide roll-out between june 2011 and june 2014.201526400386
high-dose vitamin d3 in adults with pulmonary tuberculosis: a double-blind randomized controlled trial.tuberculosis, including multidrug-resistant tuberculosis (mdr-tb), is a major global health problem. individuals with tuberculosis disease commonly exhibit vitamin d deficiency, which may adversely affect immunity and the response to therapy.201526399865
identification and characterization of lipase activity and immunogenicity of lipl from mycobacterium tuberculosis.lipids and lipid-metabolizing esterases/lipases are highly important for the mycobacterial life cycle and, possibly, for mycobacterial virulence. in this study, we expressed 10 members of the lip family of mycobacterium tuberculosis. among the 10 proteins, lipl displayed a significantly high enzymatic activity for the hydrolysis of long-chain lipids. the optimal temperature for the lipase activity of lipl was demonstrated to be 37°c, and the optimal ph was 8.0. the lipase active center was not t ...201526398213
glpx gene in mycobacterium tuberculosis is required for in vitro gluconeogenic growth and in vivo survival.several enzymes involved in central carbon metabolism and gluconeogenesis play a critical role in survival and pathogenesis of mycobacterium tuberculosis (mtb). the only known functional fructose 1,6-bisphosphatase (fbpase) in mtb is encoded by the glpx gene and belongs to the class ii sub-family of fbpase. we describe herein the generation of a δglpx strain using homologous recombination. although the growth profile of δglpx is comparable to that of wild type mtb when grown on the standard enri ...201526397812
molecular epidemiology of mycobacterium tuberculosis isolates in 100 patients with tuberculosis using pulsed field gel electrophoresis.tuberculosis (tb) is a widespread infectious disease. today, tb has created a public health crisis in the world. genotyping of mycobacterium tuberculosis isolates is useful for surveying the dynamics of tb infection, identifying new outbreaks, and preventing the disease. different molecular methods for clustering of m. tuberculosis isolates have been used.201526396714
core component eccb1 of the mycobacterium tuberculosis type vii secretion system is a periplasmic atpase.pathogenic mycobacteria transport virulence factors across their complex cell wall via a type vii secretion system (t7ss)/early secreted antigenic target-6 of kda secretion system (esx). esx conserved component (ecc) b, a core component of the t7ss architecture, is predicted to be a membrane bound protein, but little is known about its structure and function. here, we characterize eccb1, showing that it is an atpase with no sequence or structural homology to other atpases located in the cell env ...201526396239
structural basis for the regulation of the mmpl transporters of mycobacterium tuberculosis.the mycobacterial cell wall is critical to the virulence of these pathogens. recent work shows that the mmpl (mycobacterial membrane protein large) family of transporters contributes to cell wall biosynthesis by exporting fatty acids and lipidic elements of the cell wall. the expression of the mycobacterium tuberculosis mmpl proteins is controlled by a complex regulatory network, including the tetr family transcriptional regulators rv3249c and rv1816. here we report the crystal structures of the ...201526396194
determination of in vitro synergy between linezolid and other antimicrobial agents against mycobacterium tuberculosis isolates.in this study, our objective was to explore the potential in vitro synergy between linezolid (lzd) and six other anti-tb drugs in mycobacterium tuberculosis strains, especially multidrug-resistant tuberculosis (mdr-tb) strains. among the different combinations, the lzd-clarithromycin (cla) combination showed the best synergism, which was observed in 85% (34/40) of 40 isolates. in addition, one (2.5%) and twenty-one (52.5%) of 40 isolates showed synergism for the lzd-levofloxcin (lev) and lzd-mox ...201526395151
cough aerosol cultures of mycobacterium tuberculosis: insights on tst / igra discordance and transmission dynamics.the diagnosis of latent tuberculosis (tb) infection (ltbi) is complicated by the absence of a gold standard. discordance between tuberculin skin tests (tst) and interferon gamma release assays (igra) occurs in 10-20% of individuals, but the underlying mechanisms are poorly understood.201526394149
the etiology of lower respiratory tract infections in people with diabetes.patients with diabetes mellitus (dm) are likely to develop many types of infections, which affect the transport of glucose into tissues. diabetes increases the susceptibility to different kinds of respiratory infections, is often identified as an independent risk factor for developing lower respiratory tract infections. pulmonary infections caused by mycobacterium tuberculosis, staphylococcus aureus, gram-negative bacteria and fungi may occur with an increased frequency, whereas infections due t ...201526379004
middle lobe syndrome: an extraordinary presentation of endobronchial tuberculosis.tuberculous infection of the tracheobronchial tree, termed as endobronchial tuberculosis (ebtb), is more common in young adults and females. this clinical entity is poorly understood and the diagnosis is frequently delayed as sputum smears are often negative for acid fast bacilli and the chest radiograph can be normal, resulting in diagnostic confusion. bronchoscopy continues to play a key role in its diagnosis. though atelectasis is not uncommon in these patients, ebtb presenting as a middle lo ...201526379001
synthesis, antibacterial and antitubercular activities of some 5h-thiazolo[3,2-a]pyrimidin-5-ones and sulfonic acid derivatives.a series of 5h-thiazolo[3,2-a]pyrimidin-5-ones were synthesized by the cyclization reactions of s-alkylated derivatives in concentrated h₂so₄. upon treatment of s-alkylated derivatives at different temperatures, intramolecular cyclization to 7-(substituted phenylamino)-5h-thiazolo[3,2-a]pyrimidin-5-ones or sulfonation of cyclized products to sulfonic acid derivatives occurred. the structures of the target compounds were confirmed by ir, ¹h-nmr, (13)c-nmr and hrms studies. the compounds were eval ...201526378507
improved detection by next-generation sequencing of pyrazinamide resistance in mycobacterium tuberculosis isolates.the technical limitations of common tests used for detecting pyrazinamide (pza) resistance in mycobacterium tuberculosis isolates pose challenges for comprehensive and accurate descriptions of drug resistance in patients with multidrug-resistant tuberculosis (mdr-tb). in this study, a 606-bp fragment (comprising the pnca coding region plus the promoter) was sequenced using ion torrent next-generation sequencing (ngs) to detect associated pza resistance mutations in 88 recultured mdr-tb isolates ...201526378284
metabolic modeling predicts metabolite changes in mycobacterium tuberculosis.mycobacterium tuberculosis (mtb) is the causal agent of the disease tuberculosis (tb). metabolic adaptations are thought to be critical to the survival of mtb during pathogenesis. computational tools that can be used to study mtb metabolism in silico and prioritize resource-intensive experimental work could significantly accelerate research.201526377923
the utility of xpert mtb/rif performed on bronchial washings obtained in patients with suspected pulmonary tuberculosis in a high prevalence setting.xpert mtb/rif has been shown to have a superior sensitivity to microscopy for acid fast bacilli (afb) in sputum and has been recommended as a standard first line investigation for pulmonary tuberculosis (ptb). bronchoscopy is a valuable tool in diagnosing ptb in sputum negative patients. there is limited data on the utility of xpert mtb/rif performed on bronchial lavage specimens. our aim was to evaluate the diagnostic efficiency of xpert mtb/rif performed on bronchial washings in sputum scarce/ ...201526377395
lupus vulgaris mimicking hemangioma diagnosed 42 years after onset: a case report.lupus vulgaris is the most common form of cutaneous tuberculosis. it may easily be overlooked if a proper differential diagnosis is omitted.201526376746
tuberculous lymphadenitis in ethiopia predominantly caused by strains belonging to the delhi/cas lineage and newly identified ethiopian clades of the mycobacterium tuberculosis complex.recently, newly defined clades of mycobacterium tuberculosis complex (mtbc) strains, namely ethiopia 1-3 and ethiopia h37rv-like strains, and other clades associated with pulmonary tb (ptb) were identified in ethiopia. in this study, we investigated whether these new strain types exhibit an increased ability to cause tb lymphadenitis (tbln) and raised the question, if particular mtbc strains derived from tbln patients in northern ethiopia are genetically adapted to their local hosts and/or to th ...201526376441
clinical predictors of culture-confirmed pulmonary tuberculosis in children in a high tuberculosis and hiv prevalence area.the burden of childhood tuberculosis (tb) remains significant especially in areas of high hiv prevalence. clinical diagnosis predominates, despite advances in molecular and microbiological diagnostics. the aim of this study is to identify clinical features associated with culture-confirmed pulmonary tb (ptb) in children.201526376315
latent mycobacterium tuberculosis infection. 201526376153
latent mycobacterium tuberculosis infection. 201526376152
latent mycobacterium tuberculosis infection. 201526376151
latent mycobacterium tuberculosis infection. 201526376150
latent mycobacterium tuberculosis infection. 201526376149
synthetic and immunological studies of mycobacterial lipoarabinomannan oligosaccharides and their protein conjugates.lipoarabinomannan (lam) is one of the major constituents of the mycobacterium tuberculosis cell wall and an attractive molecular scaffold for antituberculosis drug and vaccine development. in this paper, a convergent strategy was developed for the synthesis of lam oligosaccharides with an α-1,2-linked dimannopyranose cap at the nonreducing end. the strategy was highlighted by efficient coupling of separately prepared nonreducing end and reducing end oligosaccharides. glycosylations were mainly a ...201526375482
raman spectroscopic monitoring of the growth of pigmented and non-pigmented mycobacteria.raman microspectroscopy has increased in popularity in the field of microbiology because it allows a spectral fingerprinting of bacterial pathogens at an unrivaled speed, which is important for the early treatment of infectious diseases such as tuberculosis. an indispensable prerequisite for the success of this method is a profound knowledge, how the spectral profiles depend on the age of the bacteria. we therefore followed the growth of two rapidly growing mycobacterium tuberculosis relatives, ...201526391403
nr1d1 ameliorates mycobacterium tuberculosis clearance through regulation of autophagy.nr1d1 (nuclear receptor subfamily 1, group d, member 1), an adopted orphan nuclear receptor, is widely known to orchestrate the expression of genes involved in various biological processes such as adipogenesis, skeletal muscle differentiation, and lipid and glucose metabolism. emerging evidence suggests that various members of the nuclear receptor superfamily perform a decisive role in the modulation of autophagy. recently, nr1d1 has been implicated in augmenting the antimycobacterial properties ...201526390081
anti-tubercular drug development: computational strategies to identify potential compounds.inha is an attractive target to combat tuberculosis (tb), which is targeted by many pro-drugs (isoniazid, etc.) and drugs such as triclosan. however, triclosan is less useful as an antitubercular drug due to its low bioavailability and therefore, in order to overcome this difficulty, many derivatives of triclosan were prepared. here, we have combined various computational techniques to virtually screen out four potential triclosan derivatives. molecular docking methods have been employed to scre ...201526386453
mycobacterium tuberculosis: ecology and evolution of a human bacterium.some species of the mycobacterium tuberculosis complex (mtbc), particularly mycobacterium tuberculosis, which causes human tuberculosis (tb), are the first cause of death linked to a single pathogen worldwide. in the last decades, evolutionary studies have much improved our knowledge on mtbc history and have highlighted its long co-evolution with humans. its ability to remain latent in humans, the extraordinary proportion of asymptomatic carriers (one-third of the entire human population), the d ...201526385049
epigenetics and proteomics join transcriptomics in the quest for tuberculosis biomarkers.an estimated one-third of the world's population is currently latently infected with mycobacterium tuberculosis. latent m. tuberculosis infection (ltbi) progresses into active tuberculosis (tb) disease in ~5 to 10% of infected individuals. diagnostic and prognostic biomarkers to monitor disease progression are urgently needed to ensure better care for tb patients and to decrease the spread of tb. biomarker development is primarily based on transcriptomics. our understanding of biology combined w ...201526374119
rp105 engages phosphatidylinositol 3-kinase p110δ to facilitate the trafficking and secretion of cytokines in macrophages during mycobacterial infection.cytokines are key regulators of adequate immune responses to infection with mycobacterium tuberculosis. we demonstrate that the p110δ catalytic subunit of pi3k acts as a downstream effector of the tlr family member rp105 (cd180) in promoting mycobacteria-induced cytokine production by macrophages. our data show that the significantly reduced release of tnf and il-6 by rp105(-/-) macrophages during mycobacterial infection was not accompanied by diminished mrna or protein expression. mycobacteria ...201526371254
genotypic analysis of genes associated with independent resistance and cross-resistance to isoniazid and ethionamide in mycobacterium tuberculosis clinical isolates.ethionamide (eth) is an antibiotic used for the treatment of multidrug-resistant (mdr) tuberculosis (tb) (mdr-tb), and its use may be limited with the emergence of resistance in the mycobacterium tuberculosis population. eth resistance in m. tuberculosis is phenomenon independent or cross related when accompanied with isoniazid (inh) resistance. in most cases, resistance to inh and eth is explained by mutations in the inha promoter and in the following genes: katg, etha, ethr, msha, ndh, and inh ...201526369965
uncoupling environmental ph and intrabacterial acidification from pyrazinamide susceptibility in mycobacterium tuberculosis.pyrazinamide (pza) is a first-line antitubercular drug for which the mode of action remains unresolved. mycobacterium tuberculosis lacks measurable susceptibility to pza under standard laboratory growth conditions. however, susceptibility to this drug can be induced by cultivation of the bacilli in an acidified growth medium. previous reports suggested that the active form of pza, pyrazinoic acid (poa), operates as a proton ionophore that confers cytoplasmic acidification when m. tuberculosis is ...201526369957
gtra protein rv3789 is required for arabinosylation of arabinogalactan in mycobacterium tuberculosis.mycobacterium tuberculosis possesses a thick and highly hydrophobic cell wall principally composed of a mycolyl-arabinogalactan-peptidoglycan complex, which is critical for survival and virulence. dpre1 is a well-characterized component of decaprenyl-phospho-ribose epimerase, which produces decaprenyl-phospho-arabinose (dpa) for the biosynthesis of mycobacterial arabinans. upstream of dpre1 lies rv3789, which encodes a short transmembrane protein of the gtra family, whose members are often invol ...201526369580
[a case of tuberculous myeloradiculitis with abdominal lymphadenitis presenting with symptoms of radiculomyelopathy].a 30-year old man was admitted with right hip pain and gait disturbances. neurological findings revealed muscular weakness in the lower limbs, hyporeflexia, dysesthesia in the sacral region, and bowel and bladder disturbances. cerebrospinal fluid (csf) examination indicated a white blood cell count of 371/μl (lymphocyte:polymorphonuclear leukocyte = 97:3), protein levels of 463 mg/dl and sugar of 20 mg/dl. although csf culture was negative, tuberculous infection was presumed. magnetic resonance ...201526369375
the efficacy of the bcg vaccine against newly emerging clinical strains of mycobacterium tuberculosis.to date, most new vaccines against mycobacterium tuberculosis, including new recombinant versions of the current bcg vaccine, have usually been screened against the laboratory strains h37rv or erdman. in this study we took advantage of our recent work in characterizing an increasingly large panel of newly emerging clinical isolates [from the united states or from the western cape region of south africa], to determine to what extent vaccines would protect against these [mostly high virulence] str ...201526368806
mycobacterium tuberculosis is a natural ornithine aminotransferase (rocd) mutant and depends on rv2323c for growth on arginine.mycobacterium tuberculosis (mtb) possesses a genetic repertoire for metabolic pathways, which are specific and fit to its intracellular life style. under in vitro conditions, mtb is known to use arginine as a nitrogen source, but the metabolic pathways for arginine utilization have not been identified. here we show that, in the presence of arginine, mtb upregulates a gene cluster which includes an ornithine aminotransferase (rocd) and rv2323c, a gene of unknown function. isotopologue analysis by ...201526368558
effect of antiretroviral therapy on hiv-mediated impairment of the neutrophil antimycobacterial response.experimental and epidemiological evidence suggests that neutrophils are important in the host response to tuberculosis. hiv infection, which increases the risk of tuberculosis, adversely affects neutrophil function.201526368270
mycobacterium tuberculosis upregulates tnf-α expression via tlr2/erk signaling and induces mmp-1 and mmp-9 production in human pleural mesothelial cells.tumor necrosis factor (tnf)-α and matrix metalloproteinases (mmps) are elevated in pleural fluids of tuberculous pleuritis (tbp) where pleural mesothelial cells (pmcs) conduct the first-line defense against mycobacterium tuberculosis (mtb). however, the clinical implication of tnf-α and mmps in tbp and the response of pmcs to mtb infection remain unclear.201526367274
current efforts and future prospects in the development of live mycobacteria as vaccines.the development of more effective vaccines against mycobacterium tuberculosis (mtb) remains a major goal in the effort to reduce the enormous global burden of disease caused by this pathogen. whole-cell vaccines based on live mycobacteria with attenuated virulence represent an appealing approach, providing broad antigen exposure and intrinsic adjuvant properties to prime durable immune responses. however, designing vaccine strains with an optimal balance between attenuation and immunogenicity ha ...201526366616
strategies for efficient numerical implementation of hybrid multi-scale agent-based models to describe biological systems.biologically related processes operate across multiple spatiotemporal scales. for computational modeling methodologies to mimic this biological complexity, individual scale models must be linked in ways that allow for dynamic exchange of information across scales. a powerful methodology is to combine a discrete modeling approach, agent-based models (abms), with continuum models to form hybrid models. hybrid multi-scale abms have been used to simulate emergent responses of biological systems. her ...201526366228
tuberculosis of the oral cavity: an uncommon but still a live issue.this paper aims at characterizing clinical features, occurrence, diagnostic process and treatment of oral tuberculosis (tb), basing on the available literature. oral tb manifestations are uncommon and usually secondary to pulmonary changes. they predominantly appear as ulcers. eruptions are usually single, painful and resistant to conventional treatment. diagnosis always needs to be confirmed histopathologically. anti-tubercular systemic therapy is required in every patient diagnosed with oral t ...201526366156
crystal structure of the mycobacterium tuberculosis transcriptional regulator rv0302.mycobacterium tuberculosis is a pathogenic bacterial species, which is neither gram positive nor gram negative. it has a unique cell wall, making it difficult to kill and conferring resistance to antibiotics that disrupt cell wall biosynthesis. thus, the mycobacterial cell wall is critical to the virulence of these pathogens. recent work shows that the mycobacterial membrane protein large (mmpl) family of transporters contributes to cell wall biosynthesis by exporting fatty acids and lipidic ele ...201526362239
a user-friendly web portal for analyzing conformational changes in structures of mycobacterium tuberculosis.initiation of the tuberculosis structural consortium has resulted in the expansion of the mycobacterium tuberculosis (mtb) protein structural database. currently, 969 experimentally solved structures are available for 354 mtb proteins. this includes multiple crystal structures for a given protein under different functional conditions, such as the presence of different ligands or mutations. in depth analysis of the multiple structures reveal that subtle differences exist in conformations of a giv ...201526361768
a rare association of tuberculous longitudinally extensive transverse myelitis (letm) with brain tuberculoma.longitudinally extensive transverse myelitis is characterized by contiguous inflammatory lesion of spinal cord involving three or more spinal segments. it is a well-recognized but rare presentation of mycobacterium tuberculosis infection.201526361577
pd-1, pd-l1 and pd-l2 gene expression on t-cells and natural killer cells declines in conjunction with a reduction in pd-1 protein during the intensive phase of tuberculosis treatment.the pd-1 axis is a cell intrinsic immunoregulatory pathway that mediates t cell exhaustion in chronic infection particularly in some viral infections. we hypothesized that pd-1, pd-l1 and pd-l2 would be highly expressed in untreated tuberculosis patients compared to controls due to their chronic infection and would decrease with successful tb treatment.201526359860
multicenter clinical evaluation of three commercial reagent kits based on the interferon-gamma release assay for the rapid diagnosis of tuberculosis in china.to evaluate the performance of three interferon-gamma release assay (igra) kits in detecting mycobacterium tuberculosis infection in china.201526358858
challenging mycobacterium tuberculosis dormancy mechanisms and their immunodiagnostic potential.mycobacterium tuberculosis is the etiologic agent of tuberculosis, one of the world's greatest cause of morbidity and mortality due to infectious disease. many evolutionary mechanisms have contributed to its high level of adaptation as a host pathogen. prior to become dormant, a group of about 50 genes related to metabolic changes are transcribed by the dosr regulon, one of the most complex and important systems of host-pathogen interaction. this genetic mechanism allows the mycobacteria to pers ...201526358744
structures of mycobacterium tuberculosis anthranilate phosphoribosyltransferase variants reveal the conformational changes that facilitate delivery of the substrate to the active site.anthranilate phosphoribosyltransferase (anprt) is essential for the biosynthesis of tryptophan in mycobacterium tuberculosis (mtb). this enzyme catalyzes the second committed step in tryptophan biosynthesis, the mg²⁺-dependent reaction between 5'-phosphoribosyl-1'-pyrophosphate (prpp) and anthranilate. the roles of residues predicted to be involved in anthranilate binding have been tested by the analysis of six mtb-anprt variant proteins. kinetic analysis showed that five of six variants were ac ...201526356348
rapid molecular detection of multidrug-resistant tuberculosis by pcr-nucleic acid lateral flow immunoassay.several existing molecular tests for multidrug-resistant tuberculosis (mdr-tb) are limited by complexity and cost, hindering their widespread application. the objective of this proof of concept study was to develop a simple nucleic acid lateral flow (nalf) immunoassay as a potential diagnostic alternative, to complement conventional pcr, for the rapid molecular detection of mdr-tb. the nalf device was designed using antibodies for the indirect detection of labeled pcr amplification products. mul ...201526355296
mediastinal fibrosis of the pulmonary artery secondary to tuberculosis.mediastinal fibrosis is an uncommon disease involving the esophagus, respiratory tract, and great vessels. we report a man who presented with dyspnea on exertion. computed tomography of the chest demonstrated granulomatous disease with dense calcifications leading to severe stenosis of the main pulmonary artery (pa) and narrowing of the superior vena cava. the results of tuberculosis (tb) interferon-γ release assay and tb-polymerase chain reaction were positive for mycobacterium tuberculosis. th ...201526354666
pupylation-dependent and -independent proteasomal degradation in mycobacteria.bacteria make use of compartmentalizing protease complexes, similar in architecture but not homologous to the eukaryotic proteasome, for the selective and processive removal of proteins. mycobacteria as members of the actinobacteria harbor proteasomes in addition to the canonical bacterial degradation complexes. mycobacterial proteasomal degradation, although not essential during normal growth, becomes critical for survival under particular environmental conditions, like, for example, during per ...201526352358
expression of the genes encoding the trk and kdp potassium transport systems of mycobacterium tuberculosis during growth in vitro.two potassium (k(+))-uptake systems, trk and kdp, are operative in mycobacterium tuberculosis (mtb), but the environmental factors triggering their expression have not been determined. the current study has evaluated the expression of these genes in the mtb wild-type and a trk-gene knockout strain at various stages of logarithmic growth in relation to extracellular k(+) concentrations and ph. in both strains, mrna levels of the k(+)-uptake encoding genes were relatively low compared to those of ...201526351637
elevated host lipid metabolism revealed by itraq-based quantitative proteomic analysis of cerebrospinal fluid of tuberculous meningitis patients.tuberculous meningitis (tbm) remains to be one of the most deadly infectious diseases. the pathogen interacts with the host immune system, the process of which is largely unknown. various cellular processes of mycobacterium tuberculosis (mtb) centers around lipid metabolism. to determine the lipid metabolism related proteins, a quantitative proteomic study was performed here to identify differential proteins in the cerebrospinal fluid (csf) obtained from tbm patients (n = 12) and healthy control ...201526348777
α-methyl acyl coa racemase provides mycobacterium tuberculosis catabolic access to cholesterol esters.metabolism of cholesterol by mycobacterium tuberculosis (mtb) contributes to its pathogenesis. we show that chse4-chse5 (rv3504/rv3505) specifically catalyzes dehydrogenation of the (25s)-3-oxo-cholest-4-en-26-oyl-coa diastereomer in cholesterol side chain β-oxidation. thus, a dichotomy between the supply of both 25r and 25s metabolic precursors by upstream cytochrome p450s and the substrate stereospecificity of chse4-chse5 exists. we reconcile the dilemma of 25r metabolite production by demonst ...201526348625
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