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Article ; Online: Anti-Tuberculosis Potential of OJT008 against Active and Multi-Drug-Resistant Mycobacterium Tuberculosis: In Silico and In Vitro Inhibition of Methionine Aminopeptidase.

Onyenaka, Collins / Idowu, Kehinde A / Ha, Ngan P / Graviss, Edward A / Olaleye, Omonike A

International journal of molecular sciences

2023 Volume 24, Issue 24

Abstract: Despite the recent progress in the diagnosis of tuberculosis (TB), the chemotherapeutic management of TB continues to be challenging. ...

Abstract	Despite the recent progress in the diagnosis of tuberculosis (TB), the chemotherapeutic management of TB continues to be challenging.
MeSH term(s)	Humans ; Mycobacterium tuberculosis ; Nickel/pharmacology ; Aminopeptidases/genetics ; Aminopeptidases/chemistry ; Tuberculosis/microbiology ; Methionyl Aminopeptidases ; Tuberculosis, Multidrug-Resistant/drug therapy ; Metals/pharmacology ; Cobalt/pharmacology ; Antitubercular Agents/chemistry
Chemical Substances	Nickel (7OV03QG267) ; Aminopeptidases (EC 3.4.11.-) ; Methionyl Aminopeptidases (EC 3.4.11.18) ; Metals ; Cobalt (3G0H8C9362) ; Antitubercular Agents
Language	English
Publishing date	2023-12-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms242417142
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Article ; Online: Differentiating between live and dead Mycobacterium smegmatis using autofluorescence.

Wong, Cynthia / Ha, Ngan P / Pawlowski, Michal E / Graviss, Edward A / Tkaczyk, Tomasz S

Tuberculosis (Edinburgh, Scotland)

2016 Volume 101S, Page(s) S119–S123

Abstract: While there have been research efforts to find faster and more efficient diagnostic techniques for tuberculosis (TB), it is equally important to monitor a patient's response to treatment over time, especially with the increasing prevalence of multi-drug ... ...

Abstract	While there have been research efforts to find faster and more efficient diagnostic techniques for tuberculosis (TB), it is equally important to monitor a patient's response to treatment over time, especially with the increasing prevalence of multi-drug resistant (MDR) and extensively-drug resistant (XDR) TB. Between sputum smear microscopy, culture, and GeneXpert, only culture can verify viability of mycobacteria. However, it may take up to six weeks to grow Mycobacterium tuberculosis (Mtb), during which time the patient may have responded to treatment or the mycobacteria are still viable because the patient has MDR or XDR TB. In both situations, treatment incurs increased patient costs and makes them more susceptible to host-drug effects such as liver damage. Coenzyme Factor 420 (F
MeSH term(s)	Biomarkers/metabolism ; Humans ; Microbial Viability ; Microscopy, Fluorescence ; Mycobacterium Infections, Nontuberculous/diagnosis ; Mycobacterium Infections, Nontuberculous/microbiology ; Mycobacterium smegmatis/enzymology ; Mycobacterium smegmatis/isolation & purification ; Optical Imaging/methods ; Predictive Value of Tests ; Riboflavin/analogs & derivatives ; Riboflavin/metabolism ; Time Factors
Chemical Substances	Biomarkers ; coenzyme F420 (64885-97-8) ; Riboflavin (TLM2976OFR)
Language	English
Publishing date	2016-12
Publishing country	Scotland
Document type	Journal Article
ZDB-ID	2046804-0
ISSN	1873-281X ; 1472-9792
ISSN (online)	1873-281X
ISSN	1472-9792
DOI	10.1016/j.tube.2016.09.010
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Article ; Online: Thioaptamer targeted discoidal microparticles increase self immunity and reduce Mycobacterium tuberculosis burden in mice.

Leonard, Fransisca / Ha, Ngan P / Sule, Preeti / Alexander, Jenolyn F / Volk, David E / Lokesh, Ganesh L R / Liu, Xuewu / Cirillo, Jeffrey D / Gorenstein, David G / Yuan, Jinyun / Chatterjee, Soumya / Graviss, Edward A / Godin, Biana

Journal of controlled release : official journal of the Controlled Release Society

2017 Volume 266, Page(s) 238–247

Abstract: Worldwide, tuberculosis (TB) remains one of the most prevalent infectious diseases causing morbidity and death in >1.5 million patients annually. Mycobacterium tuberculosis (Mtb), the etiologic agent of TB, usually resides in the alveolar macrophages. ... ...

Abstract	Worldwide, tuberculosis (TB) remains one of the most prevalent infectious diseases causing morbidity and death in >1.5 million patients annually. Mycobacterium tuberculosis (Mtb), the etiologic agent of TB, usually resides in the alveolar macrophages. Current tuberculosis treatment methods require more than six months, and low compliance often leads to therapeutic failure and multidrug resistant strain development. Critical to improving TB-therapy is shortening treatment duration and increasing therapeutic efficacy. In this study, we sought to determine if lung hemodynamics and pathological changes in Mtb infected cells can be used for the selective targeting of microparticles to infected tissue(s). Thioaptamers (TA) with CD44 (CD44TA) targeting moiety were conjugated to discoidal silicon mesoporous microparticles (SMP) to enhance accumulation of these agents/carriers in the infected macrophages in the lungs. In vitro, CD44TA-SMP accumulated in macrophages infected with mycobacteria efficiently killing the infected cells and decreasing survival of mycobacteria. In vivo, increased accumulations of CD44TA-SMP were recorded in the lung of M. tuberculosis infected mice as compared to controls. TA-targeted carriers significantly diminished bacterial load in the lungs and caused recruitment of T lymphocytes. Proposed mechanism of action of the designed vector accounts for a combination of increased uptake of particles that leads to infected macrophage death, as well as, activation of cellular immunity by the TA, causing increased T-cell accumulation in the treated lungs. Based on our data with CD44TA-SMP, we anticipate that this drug carrier can open new avenues in TB management.
MeSH term(s)	Animals ; Aptamers, Nucleotide/administration & dosage ; Cells, Cultured ; Drug Carriers/administration & dosage ; Female ; Humans ; Hyaluronan Receptors/genetics ; Hyaluronan Receptors/metabolism ; Lung/immunology ; Lung/metabolism ; Macrophages/metabolism ; Mice, Inbred BALB C ; Mycobacterium tuberculosis ; Silicon/administration & dosage ; T-Lymphocytes/immunology ; Tuberculosis/drug therapy ; Tuberculosis/immunology ; Tuberculosis/metabolism
Chemical Substances	Aptamers, Nucleotide ; Drug Carriers ; Hyaluronan Receptors ; Silicon (Z4152N8IUI)
Language	English
Publishing date	2017-11-28
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2017.09.038
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Article ; Online: Evaluation of large genotypic Mycobacterium tuberculosis clusters: contributions from remote and recent transmission.

Teeter, Larry D / Ha, Ngan P / Ma, Xin / Wenger, Jane / Cronin, Wendy A / Musser, James M / Graviss, Edward A

Tuberculosis (Edinburgh, Scotland)

2013 Volume 93 Suppl, Page(s) S38–46

Abstract: Tuberculosis genotypic clustering is used as a proxy for recent transmission. The association between clustering and recent transmission becomes problematic when the genotyping method lacks specificity in defining a cluster, as well as for clusters with ... ...

Abstract	Tuberculosis genotypic clustering is used as a proxy for recent transmission. The association between clustering and recent transmission becomes problematic when the genotyping method lacks specificity in defining a cluster, as well as for clusters with extensive jurisdictional histories and/or common genotypes. We investigated the four largest spoligotype/12 loci MIRU-VNTR-defined clusters in Harris County, Texas from 2006-2012 to determine their historical contribution to tuberculosis morbidity, estimate the contributions from recent and remote transmission, and determine the impact of secondary genotyping on cluster definition. The clusters contained 189, 64, 51 and 38 cases. Each cluster was linked to cluster(s) previously identified by Houston Tuberculosis Initiative; 3 since 1995 and the fourth in 2002. Among cases for which timing of Mycobacterium tuberculosis transmission relative to tuberculosis disease could be ascertained, nearly equal proportions were associated with recent and remote transmission. The extent to which genotyping with an additional 12 MIRU-VNTR loci modified the cluster definition varied from little or no impact for the two smaller clusters to moderate impact for the larger clusters. Tuberculosis control measures to reduce morbidity associated with large clusters must involve strategies to identify and treat individuals who recently acquired infection, as well as persons infected for years.
MeSH term(s)	Age Factors ; Bacterial Typing Techniques/methods ; DNA, Bacterial ; Evolution, Molecular ; Female ; Genotype ; Humans ; Male ; Molecular Epidemiology ; Mycobacterium tuberculosis/isolation & purification ; Social Class ; Texas ; Tuberculosis/epidemiology ; Tuberculosis/prevention & control ; Tuberculosis/transmission ; United States
Chemical Substances	DNA, Bacterial
Language	English
Publishing date	2013-12
Publishing country	Scotland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2046804-0
ISSN	1873-281X ; 1472-9792
ISSN (online)	1873-281X
ISSN	1472-9792
DOI	10.1016/S1472-9792(13)70009-X
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Article ; Online: Characterization of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone as a novel inhibitor of methionine aminopeptidases from Mycobacterium tuberculosis.

John, Sarah F / Aniemeke, Emmanuel / Ha, Ngan P / Chong, Curtis R / Gu, Peihua / Zhou, Jiangbing / Zhang, Ying / Graviss, Edward A / Liu, Jun O / Olaleye, Omonike A

Tuberculosis (Edinburgh, Scotland)

2016 Volume 101S, Page(s) S73–S77

Abstract: Mycobacterium tuberculosis (Mtb) and the Human Immunodeficiency Virus (HIV) pose a major public health threat. The 2015 World Health Organization (WHO) report estimates that one in three HIV deaths is due to Mtb, the causative agent of Tuberculosis (TB). ...

Abstract	Mycobacterium tuberculosis (Mtb) and the Human Immunodeficiency Virus (HIV) pose a major public health threat. The 2015 World Health Organization (WHO) report estimates that one in three HIV deaths is due to Mtb, the causative agent of Tuberculosis (TB). The lethal synergy between these two pathogens leads to a decline in the immune function of infected individuals as well as a rise in morbidity and mortality rates. The deadly interaction between TB and HIV, along with the heightened emergence of drug resistance, drug-drug interactions, reduced drug efficacy and increased drug toxicity, has made the therapeutic management of co-infected individuals a major challenge. Hence, the development of new drug targets and/or new drug leads are imperative for the effective therapeutic management of co-infected patients. Here, we report the characterization of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone (311), a known inhibitor of HIV-1 replication and transcription as a new inhibitor of methionine aminopeptidases (MetAPs) from Mycobacterium tuberculosis: MtMetAP1a and MtMetAP1c. MetAP is a metalloprotease that removes the N-terminal methionine during protein synthesis. The essential role of MetAP in microbes makes it a promising chemotherapeutic target. We demonstrated that 311 is a potent and selective inhibitor of MtMetAP1a and MtMetAP1c. Furthermore, we found that 311 is active against replicating and aged non-growing Mtb at low micromolar concentrations. These results suggest that 311 is a promising lead for the development of novel class of therapeutic agents with dual inhibition of TB and HIV for the treatment of TB-HIV co-infection.
MeSH term(s)	Aminopeptidases/antagonists & inhibitors ; Aminopeptidases/metabolism ; Anti-HIV Agents/pharmacology ; Antitubercular Agents/pharmacology ; Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/metabolism ; Coinfection ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; HIV Infections/drug therapy ; HIV Infections/virology ; High-Throughput Screening Assays ; Humans ; Isoniazid/pharmacology ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/enzymology ; Mycobacterium tuberculosis/growth & development ; Tuberculosis/drug therapy ; Tuberculosis/microbiology
Chemical Substances	2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone ; Anti-HIV Agents ; Antitubercular Agents ; Bacterial Proteins ; Enzyme Inhibitors ; Aminopeptidases (EC 3.4.11.-) ; Isoniazid (V83O1VOZ8L)
Language	English
Publishing date	2016-12
Publishing country	Scotland
Document type	Journal Article
ZDB-ID	2046804-0
ISSN	1873-281X ; 1472-9792
ISSN (online)	1873-281X
ISSN	1472-9792
DOI	10.1016/j.tube.2016.09.025
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Article ; Online: Test variability of the QuantiFERON-TB gold in-tube assay in clinical practice.

Metcalfe, John Z / Cattamanchi, Adithya / McCulloch, Charles E / Lew, Justin D / Ha, Ngan P / Graviss, Edward A

American journal of respiratory and critical care medicine

2012 Volume 187, Issue 2, Page(s) 206–211

Abstract: Rationale: Although IFN-γ release assays (IGRAs) are widely used to screen for Mycobacterium tuberculosis infection in high-income countries, published data on repeatability are limited.: Objectives: To determine IGRA repeatability.: Methods: The ... ...

Abstract	Rationale: Although IFN-γ release assays (IGRAs) are widely used to screen for Mycobacterium tuberculosis infection in high-income countries, published data on repeatability are limited. Objectives: To determine IGRA repeatability. Methods: The study population included consecutive patients referred to The Methodist Hospital (Houston, TX) between August 1, 2010 and July 31, 2011 for latent tuberculosis (TB) infection screening with an IGRA (QuantiFERON-TB Gold In-Tube; Cellestis, Carnegie, Australia). We performed multiple IGRA tests using leftover stimulated plasma according to a prospectively formulated quality control protocol. We analyzed agreement in interpretation of test results classified according to manufacturer-recommended criteria and repeatability of quantitative TB response. Measurements and main results: During the study period, 1,086 test results were obtained from 543 subjects. Per the manufacturer's cut-point, the result of the second test was discordant from that of the first in 28 (8%) of 366 patients with valid test results, including 13 with an initial negative result and 15 with an initial positive result. Although agreement between repeat test results was high (κ = 0.84; 95% confidence interval, 0.79-0.90), the normal expected range of within-subject variability in TB response on retesting included differences of ± 0.60 IU/ml for all individuals (coefficient of variation, 14%), and ± 0.24 IU/ml (coefficient of variation, 27%) for individuals whose initial TB response was between 0.25 and 0.80 IU/ml. Conclusions: There is substantial variability in TB response when IGRAs are repeated using the same patient sample. IGRA results should be interpreted cautiously when TB response is near interpretation cut-points.
MeSH term(s)	Adult ; Female ; Humans ; Immunoassay/methods ; Immunoassay/standards ; Interferon-gamma/immunology ; Latent Tuberculosis/diagnosis ; Male ; Reagent Kits, Diagnostic ; Reproducibility of Results
Chemical Substances	Reagent Kits, Diagnostic ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2012-10-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.201203-0430OC
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Article ; Online: Polymorphic allele of human IRGM1 is associated with susceptibility to tuberculosis in African Americans.

King, Katherine Y / Lew, Justin D / Ha, Ngan P / Lin, Jeffery S / Ma, Xin / Graviss, Edward A / Goodell, Margaret A

PloS one

2011 Volume 6, Issue 1, Page(s) e16317

Abstract: An ancestral polymorphic allele of the human autophagy-related gene IRGM1 is associated with altered gene expression and a genetic risk for Crohn's Disease (CD). We used the single nucleotide polymorphism rs10065172C/T as a marker of this polymorphic ... ...

Abstract	An ancestral polymorphic allele of the human autophagy-related gene IRGM1 is associated with altered gene expression and a genetic risk for Crohn's Disease (CD). We used the single nucleotide polymorphism rs10065172C/T as a marker of this polymorphic allele and genotyped 370 African American and 177 Caucasian tuberculosis (TB) cases and 180 African American and 110 Caucasian controls. Among African Americans, the TB cases were more likely to carry the CD-related T allele of rs10065172 (odds ratio of 1.54; 95% confidence interval, 1.17-2.02; P<0.01) compared to controls. Our finding suggests that this CD-related IRGM1 polymorphic allele is also associated with human susceptibility to TB disease among African Americans.
MeSH term(s)	African Americans/genetics ; Alleles ; Crohn Disease/genetics ; European Continental Ancestry Group/genetics ; GTP-Binding Proteins/genetics ; GTP-Binding Proteins/physiology ; Genetic Markers ; Genetic Predisposition to Disease/ethnology ; Genetic Predisposition to Disease/genetics ; Humans ; Polymorphism, Single Nucleotide ; Tuberculosis/ethnology ; Tuberculosis/genetics
Chemical Substances	Genetic Markers ; GTP-Binding Proteins (EC 3.6.1.-) ; IRGM protein, human (EC 3.6.1.-)
Language	English
Publishing date	2011-01-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0016317
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Article ; Online: Molecular epidemiology of Mycobacterium tuberculosis among South African gold miners.

Mathema, Barun / Lewis, James J / Connors, Jeremy / Chihota, Violet N / Shashkina, Elena / van der Meulen, Minty / Graviss, Edward A / Ha, Ngan P / Kreiswirth, Barry N / Grant, Alison D / Fielding, Katherine L / Dorman, Susan E / Churchyard, Gavin J

Annals of the American Thoracic Society

2014 Volume 12, Issue 1, Page(s) 12–20

Abstract: Rationale: HIV-associated tuberculosis remains a major health problem among the gold-mining workforce in South Africa. We postulate that high levels of recent transmission, indicated by strain clustering, are fueling the tuberculosis epidemic among gold ...

Abstract	Rationale: HIV-associated tuberculosis remains a major health problem among the gold-mining workforce in South Africa. We postulate that high levels of recent transmission, indicated by strain clustering, are fueling the tuberculosis epidemic among gold miners. Objectives: To combine molecular and epidemiologic data to describe Mycobacterium tuberculosis genetic diversity, estimate levels of transmission, and examine risk factors for clustering. Methods: We conducted a cross-sectional study of culture-positive M. tuberculosis isolates in 15 gold mine shafts across three provinces in South Africa. All isolates were subject IS6110-based restriction fragment length polymorphisms, and we performed spoligotyping analysis and combined it with basic demographic and clinical information. Measurements and main results: Of the 1,602 M. tuberculosis patient isolates, 1,240 (78%) had genotyping data available for analysis. A highly diverse bacillary population was identified, comprising a total of 730 discrete genotypes. Four genotypic families (Latin American Mediterranean spoligotype family; W-Beijing; AH or X; and T1-T4) accounted for over 50% of all strains. Overall, 45% (560/1,240) of strains were genotypically clustered. The minimum estimate for recent transmission (n - 1 method) was 32% (range, 27-34%). There were no individual-level risk factors for clustering, apart from borderline evidence for being non-South African and having self-reported HIV infection. Conclusions: The high M. tuberculosis genetic diversity and lack of risk factors for clustering are indicative of a universal risk for disease among gold miners and likely mixing with nonmining populations. Our results underscore the urgent need to intensify interventions to interrupt transmission across the entire gold-mining workforce in South Africa.
MeSH term(s)	Adult ; Cross-Sectional Studies ; DNA, Bacterial/genetics ; Female ; Genotype ; Gold ; Humans ; Incidence ; Male ; Mining ; Molecular Epidemiology/methods ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/isolation & purification ; Polymorphism, Restriction Fragment Length ; South Africa/epidemiology ; Tuberculosis/epidemiology ; Tuberculosis/microbiology
Chemical Substances	DNA, Bacterial ; Gold (7440-57-5)
Language	English
Publishing date	2014-11-24
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2717461-X
ISSN	2325-6621 ; 1943-5665 ; 2325-6621
ISSN (online)	2325-6621 ; 1943-5665
ISSN	2325-6621
DOI	10.1513/AnnalsATS.201404-150OC
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Article ; Online: Tuberculosis screening by tuberculosis skin test or QuantiFERON-TB Gold In-Tube Assay among an immigrant population with a high prevalence of tuberculosis and BCG vaccination.

Painter, John A / Graviss, Edward A / Hai, Hoang Hoa / Nhung, Duong Thi Cam / Nga, Tran Thi Thanh / Ha, Ngan P / Wall, Kirsten / Loan, Le Thien Huong / Parker, Matt / Manangan, Lilia / O'Brien, Rick / Maloney, Susan A / Hoekstra, R M / Reves, Randall

PloS one

2013 Volume 8, Issue 12, Page(s) e82727

Abstract: Rationale: Each year 1 million persons acquire permanent U.S. residency visas after tuberculosis (TB) screening. Most applicants undergo a 2-stage screening with tuberculin skin test (TST) followed by CXR only if TST-positive at > 5 mm. Due to cross ... ...

Abstract	Rationale: Each year 1 million persons acquire permanent U.S. residency visas after tuberculosis (TB) screening. Most applicants undergo a 2-stage screening with tuberculin skin test (TST) followed by CXR only if TST-positive at > 5 mm. Due to cross reaction with bacillus Calmette-Guérin (BCG), TST may yield false positive results in BCG-vaccinated persons. Interferon gamma release assays exclude antigens found in BCG. In Vietnam, like most high TB-prevalence countries, there is universal BCG vaccination at birth. Objectives: 1. Compare the sensitivity of QuantiFERON-TB Gold In-Tube Assay (QFT) and TST for culture-positive pulmonary TB. 2. Compare the age-specific and overall prevalence of positive TST and QFT among applicants with normal and abnormal CXR. Methods: We obtained TST and QFT results on 996 applicants with abnormal CXR, of whom 132 had TB, and 479 with normal CXR. Results: The sensitivity for tuberculosis was 86.4% for QFT; 89.4%, 81.1%, and 52.3% for TST at 5, 10, and 15 mm. The estimated prevalence of positive results at age 15-19 years was 22% and 42% for QFT and TST at 10 mm, respectively. The prevalence increased thereafter by 0.7% year of age for TST and 2.1% for QFT, the latter being more consistent with the increase in TB among applicants. Conclusions: During 2-stage screening, QFT is as sensitive as TST in detecting TB with fewer requiring CXR and being diagnosed with LTBI. These data support the use of QFT over TST in this population.
MeSH term(s)	Adolescent ; Adult ; BCG Vaccine/therapeutic use ; Emigrants and Immigrants ; Female ; Humans ; Male ; Sensitivity and Specificity ; Skin Tests/methods ; Tuberculosis/diagnosis ; Tuberculosis/epidemiology ; Young Adult
Chemical Substances	BCG Vaccine
Language	English
Publishing date	2013-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0082727
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Article: Rapid attenuation of circadian clock gene oscillations in the rat heart following ischemia-reperfusion.

Kung, Theodore A / Egbejimi, Oluwaseun / Cui, Jiajia / Ha, Ngan P / Durgan, David J / Essop, M Faadiel / Bray, Molly S / Shaw, Chad A / Hardin, Paul E / Stanley, William C / Young, Martin E

Journal of molecular and cellular cardiology

2007 Volume 43, Issue 6, Page(s) 744–753

Abstract: The intracellular circadian clock consists of a series of transcriptional modulators that together allow the cell to perceive the time of day. Circadian clocks have been identified within various components of the cardiovascular system (e.g. ... ...

Abstract	The intracellular circadian clock consists of a series of transcriptional modulators that together allow the cell to perceive the time of day. Circadian clocks have been identified within various components of the cardiovascular system (e.g. cardiomyocytes, vascular smooth muscle cells) and possess the potential to regulate numerous aspects of cardiovascular physiology and pathophysiology. The present study tested the hypothesis that ischemia/reperfusion (I/R; 30 min occlusion of the rat left main coronary artery in vivo) alters the circadian clock within the ischemic, versus non-ischemic, region of the heart. Left ventricular anterior (ischemic) and posterior (non-ischemic) regions were isolated from I/R, sham-operated, and naïve rats over a 24-h period, after which mRNAs encoding for both circadian clock components and known clock-controlled genes were quantified. Circadian clock gene oscillations (i.e. peak-to-trough fold differences) were rapidly attenuated in the I/R, versus the non-ischemic, region. Consistent with decreased circadian clock output, we observe a rapid induction of E4BP4 in the ischemic region of the heart at both the mRNA and protein levels. In contrast with I/R, chronic (1 week) hypobaric chamber-induced hypoxia did not attenuate oscillations in circadian clock genes in either the left or right ventricle of the rat heart. In conclusion, these data show that in a rodent model of myocardial I/R, circadian clocks within the ischemic region become rapidly impaired, through a mechanism that appears to be independent of hypoxia.
MeSH term(s)	Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Biological Clocks/genetics ; CLOCK Proteins ; Cell Hypoxia ; Circadian Rhythm/genetics ; Gene Expression Regulation ; Male ; Myocardial Reperfusion Injury/genetics ; Myocardium/metabolism ; Myocardium/pathology ; Rats ; Rats, Wistar ; Trans-Activators/genetics ; Trans-Activators/metabolism
Chemical Substances	Basic Helix-Loop-Helix Transcription Factors ; Trans-Activators ; CLOCK Proteins (EC 2.3.1.48) ; Clock protein, rat (EC 2.3.1.48)
Language	English
Publishing date	2007-09-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2007.08.018
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In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito