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Article ; Online: Response to Comment on "DNA Sensing via TLR-9 Constitutes a Major Innate Immunity Pathway Activated during Erythema Nodosum Leprosum".

Pereira, Geraldo M B / Pessolani, Maria Cristina V / Sarno, Euzenir N

Journal of immunology (Baltimore, Md. : 1950)

2016 Volume 197, Issue 11, Page(s) 4184–4185

Language	English
Publishing date	2016-12-01
Publishing country	United States
Document type	Letter
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1601713
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Article ; Online: Downregulation of PHEX in multibacillary leprosy patients: observational cross-sectional study.

Silva, Sandra R Boiça / Illarramendi, Ximena / Tempone, Antonio J / Silva, Pedro H L / Nery, José A C / Monteiro, Alexandra M V / Pessolani, Maria Cristina V / Boasquevisque, Edson / Sarno, Euzenir N / Pereira, Geraldo M B / Esquenazi, Danuza

Journal of translational medicine

2015 Volume 13, Page(s) 296

Abstract: Background: Peripheral nerve injury and bone lesions, well known leprosy complications, lead to deformities and incapacities. The phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) encodes a homonymous protein (PHEX) ... ...

Abstract	Background: Peripheral nerve injury and bone lesions, well known leprosy complications, lead to deformities and incapacities. The phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) encodes a homonymous protein (PHEX) implicated in bone metabolism. PHEX/PHEX alterations may result in bone and cartilage lesions. PHEX expression is downregulated by intracellular Mycobacterium leprae (M. leprae) in cultures of human Schwann cells and osteoblasts. M. leprae in vivo effect on PHEX/PHEX is not known. Methods: Cross-sectional observational study of 36 leprosy patients (22 lepromatous and 14 borderline-tuberculoid) and 20 healthy volunteers (HV). The following tests were performed: PHEX flow cytometric analysis on blood mononuclear cells, cytokine production in culture supernatant, 25-hydroxyvitamin D (OHvitD) serum levels and (99m)Tc-MDP three-phase bone scintigraphy, radiography of upper and lower extremities and blood and urine biochemistry. Results: Significantly lower PHEX expression levels were observed in lepromatous patients than in the other groups (χ(2) = 16.554, p < 0.001 for lymphocytes and χ(2) = 13.933, p = 0.001 for monocytes). Low levels of 25-(OHvitD) were observed in HV (median = 23.0 ng/mL) and BT patients (median = 27.5 ng/mL) and normal serum levels were found in LL patients (median = 38.6 ng/mL). Inflammatory cytokines, such as TNF, a PHEX transcription repressor, were lower after stimulation with M. leprae in peripheral blood mononuclear cells from lepromatous in comparison to BT patients and HV (χ(2) = 10.820, p < 0.001). Conclusion: Downregulation of PHEX may constitute an important early component of bone loss and joint damage in leprosy. The present results suggest a direct effect produced by M. leprae on the osteoarticular system that may use this mechanism.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Bone and Bones/microbiology ; Cartilage/microbiology ; Cross-Sectional Studies ; Cytokines/metabolism ; Down-Regulation ; Female ; Flow Cytometry ; Healthy Volunteers ; Humans ; Inflammation/metabolism ; Inflammation/microbiology ; Leprosy, Borderline/metabolism ; Leprosy, Multibacillary/metabolism ; Leukocytes, Mononuclear/metabolism ; Male ; Middle Aged ; Osteoblasts/microbiology ; PHEX Phosphate Regulating Neutral Endopeptidase/metabolism ; Schwann Cells/microbiology ; Technetium Tc 99m Medronate ; Young Adult
Chemical Substances	Cytokines ; PHEX Phosphate Regulating Neutral Endopeptidase (EC 3.4.24.-) ; PHEX protein, human (EC 3.4.24.-) ; Technetium Tc 99m Medronate (X89XV46R07)
Language	English
Publishing date	2015-09-11
Publishing country	England
Document type	Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
ISSN	1479-5876
ISSN (online)	1479-5876
DOI	10.1186/s12967-015-0651-5
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Article ; Online: DNA Sensing via TLR-9 Constitutes a Major Innate Immunity Pathway Activated during Erythema Nodosum Leprosum.

Dias, André A / Silva, Camila O / Santos, João Pedro S / Batista-Silva, Leonardo R / Acosta, Chyntia Carolina D / Fontes, Amanda N B / Pinheiro, Roberta O / Lara, Flávio A / Machado, Alice M / Nery, José Augusto C / Sarno, Euzenir N / Pereira, Geraldo M B / Pessolani, Maria Cristina V

Journal of immunology (Baltimore, Md. : 1950)

2016 Volume 197, Issue 5, Page(s) 1905–1913

Abstract: The chronic course of lepromatous leprosy may be interrupted by acute inflammatory episodes known as erythema nodosum leprosum (ENL). Despite its being a major cause of peripheral nerve damage in leprosy patients, the immunopathogenesis of ENL remains ... ...

Abstract	The chronic course of lepromatous leprosy may be interrupted by acute inflammatory episodes known as erythema nodosum leprosum (ENL). Despite its being a major cause of peripheral nerve damage in leprosy patients, the immunopathogenesis of ENL remains ill-defined. Recognized by distinct families of germline-encoded pattern recognition receptors, endogenous and pathogen-derived nucleic acids are highly immunostimulatory molecules that play a major role in the host defense against infections, autoimmunity, and autoinflammation. The aim of this work was to investigate whether DNA sensing via TLR-9 constitutes a major inflammatory pathway during ENL. Flow cytometry and immunohistochemistry analysis showed significantly higher TLR-9 expression in ENL when compared with nonreactional lepromatous patients, both locally in the skin lesions and in circulating mononuclear cells. The levels of endogenous and pathogen-derived TLR-9 ligands in the circulation of ENL patients were also higher. Furthermore, PBMCs isolated from the ENL patients secreted higher levels of TNF, IL-6, and IL-1β in response to a TLR-9 agonist than those of the nonreactional patients and healthy individuals. Finally, E6446, a TLR-9 synthetic antagonist, was able to significantly inhibit the secretion of proinflammatory cytokines by ENL PBMCs in response to Mycobacterium leprae lysate. Our data strongly indicate that DNA sensing via TLR-9 constitutes a major innate immunity pathway involved in the pathogenesis and evolution of ENL. Thus, the use of TLR-9 antagonists emerges as a potential alternative to more effectively treat ENL aiming to prevent the development of nerve injuries and deformities in leprosy.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; DNA/metabolism ; Erythema Nodosum/immunology ; Erythema Nodosum/microbiology ; Female ; Flow Cytometry ; Humans ; Immunity, Innate ; Leprosy, Lepromatous/immunology ; Leprosy, Lepromatous/microbiology ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/microbiology ; Male ; Middle Aged ; Mycobacterium leprae/chemistry ; Mycobacterium leprae/immunology ; Signal Transduction ; Toll-Like Receptor 9/immunology ; Toll-Like Receptor 9/metabolism ; Young Adult
Chemical Substances	TLR9 protein, human ; Toll-Like Receptor 9 ; DNA (9007-49-2)
Language	English
Publishing date	2016-09-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1600042
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Article ; Online: ML1419c peptide immunization induces Mycobacterium leprae-specific HLA-A*0201-restricted CTL in vivo with potential to kill live mycobacteria.

Geluk, Annemieke / van den Eeden, Susan J F / Dijkman, Karin / Wilson, Louis / Kim, Hee Jin / Franken, Kees L M C / Spencer, John S / Pessolani, Maria C V / Pereira, Geraldo M B / Ottenhoff, Tom H M

Journal of immunology (Baltimore, Md. : 1950)

2011 Volume 187, Issue 3, Page(s) 1393–1402

Abstract: MHC class I-restricted CD8(+) T cells play an important role in protective immunity against mycobacteria. Previously, we showed that p113-121, derived from Mycobacterium leprae protein ML1419c, induced significant IFN-γ production by CD8(+) T cells in 90% ...

Abstract	MHC class I-restricted CD8(+) T cells play an important role in protective immunity against mycobacteria. Previously, we showed that p113-121, derived from Mycobacterium leprae protein ML1419c, induced significant IFN-γ production by CD8(+) T cells in 90% of paucibacillary leprosy patients and in 80% of multibacillary patients' contacts, demonstrating induction of M. leprae-specific CD8(+) T cell immunity. In this work, we studied the in vivo role and functional profile of ML1419c p113-121-induced T cells in HLA-A0201 transgenic mice. Immunization with 9mer or 30mer covering the p113-121 sequence combined with TLR9 agonist CpG induced HLA-A0201-restricted, M. leprae-specific CD8(+) T cells as visualized by p113-121/HLA-A0201 tetramers. Most CD8(+) T cells produced IFN-γ, but distinct IFN-γ(+)/TNF-α(+) populations were detected simultaneously with significant secretion of CXCL10/IFN-γ-induced protein 10, CXCL9/MIG, and VEGF. Strikingly, peptide immunization also induced high ML1419c-specific IgG levels, strongly suggesting that peptide-specific CD8(+) T cells provide help to B cells in vivo, as CD4(+) T cells were undetectable. An additional important characteristic of p113-121-specific CD8(+) T cells was their capacity for in vivo killing of p113-121-labeled, HLA-A0201(+) splenocytes. The cytotoxic function of p113-121/HLA-A*0201-specific CD8(+) T cells extended into direct killing of splenocytes infected with live Mycobacterium smegmatis expressing ML1419c: both 9mer and 30mer induced CD8(+) T cells that reduced the number of ML1419c-expressing mycobacteria by 95%, whereas no reduction occurred using wild-type M. smegmatis. These data, combined with previous observations in Brazilian cohorts, show that ML1419c p113-121 induces potent CD8(+) T cells that provide protective immunity against M. leprae and B cell help for induction of specific IgG, suggesting its potential use in diagnostics and as a subunit (vaccine) for M. leprae infection.
MeSH term(s)	Amino Acid Sequence ; Animals ; B-Lymphocyte Subsets/immunology ; B-Lymphocyte Subsets/microbiology ; B-Lymphocyte Subsets/pathology ; Bacterial Proteins/administration & dosage ; Bacterial Proteins/immunology ; Bacterial Vaccines/administration & dosage ; Bacterial Vaccines/immunology ; Cells, Cultured ; Cytotoxicity Tests, Immunologic/methods ; Epitopes, T-Lymphocyte/administration & dosage ; Epitopes, T-Lymphocyte/immunology ; HLA-A Antigens/biosynthesis ; HLA-A Antigens/genetics ; HLA-A Antigens/immunology ; HLA-A2 Antigen ; Humans ; Leprosy/immunology ; Leprosy/microbiology ; Leprosy/prevention & control ; Mice ; Mice, Transgenic ; Molecular Sequence Data ; Mycobacterium leprae/immunology ; Mycobacterium leprae/pathogenicity ; Peptide Fragments/administration & dosage ; Peptide Fragments/immunology ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Cytotoxic/microbiology ; T-Lymphocytes, Cytotoxic/pathology ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/microbiology ; T-Lymphocytes, Helper-Inducer/pathology ; Vaccines, Subunit/administration & dosage ; Vaccines, Subunit/immunology
Chemical Substances	Bacterial Proteins ; Bacterial Vaccines ; Epitopes, T-Lymphocyte ; HLA-A Antigens ; HLA-A*02:01 antigen ; HLA-A2 Antigen ; ML1419c protein (113-121), Mycobacterium leprae ; Peptide Fragments ; Vaccines, Subunit
Language	English
Publishing date	2011-06-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1100980
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Article ; Online: Mycobacterium leprae downregulates the expression of PHEX in Schwann cells and osteoblasts.

Silva, Sandra R Boiça / Tempone, Antônio J / Silva, Tatiana P / Costa, Maria Renata S N / Pereira, Geraldo M B / Lara, Flávio A / Pessolani, Maria Cristina V / Esquenazi, Danuza

Memorias do Instituto Oswaldo Cruz

2010 Volume 105, Issue 5, Page(s) 627–632

Abstract: Neuropathy and bone deformities, lifelong sequelae of leprosy that persist after treatment, result in significant impairment to patients and compromise their social rehabilitation. Phosphate-regulating gene with homologies to endopeptidase on the X ... ...

Abstract	Neuropathy and bone deformities, lifelong sequelae of leprosy that persist after treatment, result in significant impairment to patients and compromise their social rehabilitation. Phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) is a Zn-metalloendopeptidase, which is abundantly expressed in osteoblasts and many other cell types, such as Schwann cells, and has been implicated in phosphate metabolism and X-linked rickets. Here, we demonstrate that Mycobacterium leprae stimulation downregulates PHEX transcription and protein expression in a human schwannoma cell line (ST88-14) and human osteoblast lineage. Modulation of PHEX expression was observed to a lesser extent in cells stimulated with other species of mycobacteria, but was not observed in cultures treated with latex beads or with the facultative intracellular bacterium Salmonella typhimurium. Direct downregulation of PHEX by M. leprae could be involved in the bone resorption observed in leprosy patients. This is the first report to describe PHEX modulation by an infectious agent.
MeSH term(s)	Down-Regulation/genetics ; Flow Cytometry ; Gene Expression Regulation/genetics ; Humans ; Immunohistochemistry ; Leprosy/genetics ; Leprosy/metabolism ; Leprosy/pathology ; Mycobacterium leprae ; Osteoblasts/enzymology ; PHEX Phosphate Regulating Neutral Endopeptidase/genetics ; PHEX Phosphate Regulating Neutral Endopeptidase/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Schwann Cells/enzymology ; Transcription, Genetic/genetics
Chemical Substances	PHEX Phosphate Regulating Neutral Endopeptidase (EC 3.4.24.-)
Language	English
Publishing date	2010-09-08
Publishing country	Brazil
Document type	Journal Article
ZDB-ID	953293-6
ISSN	1678-8060 ; 0074-0276
ISSN (online)	1678-8060
ISSN	0074-0276
DOI	10.1590/s0074-02762010000500005
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Article ; Online: Peptides Derived from Mycobacterium leprae ML1601c Discriminate between Leprosy Patients and Healthy Endemic Controls.

Bobosha, Kidist / van der Ploeg-van Schip, Jolien J / Esquenazi, Danuza A / Guimarães, Marjorie M / Martins, Marcia V / Bekele, Yonas / Fantahun, Yonas / Aseffa, Abraham / Franken, Kees L M C / Gismondi, Ronaldo C / Pessolani, Maria C V / Ottenhoff, Tom H M / Pereira, Geraldo M B / Geluk, Annemieke

Journal of tropical medicine

2012 Volume 2012, Page(s) 132049

Abstract: The stable incidence of new leprosy cases suggests that transmission of infection continues despite worldwide implementation of MDT. Thus, specific tools are needed to diagnose early stage Mycobacterium leprae infection, the likely sources of ... ...

Abstract	The stable incidence of new leprosy cases suggests that transmission of infection continues despite worldwide implementation of MDT. Thus, specific tools are needed to diagnose early stage Mycobacterium leprae infection, the likely sources of transmission. M. leprae antigens that induce T-cell responses in M. leprae exposed and/or infected individuals thus are major targets for new diagnostic tools. Previously, we showed that ML1601c was immunogenic in patients and healthy household contacts (HHC). However, some endemic controls (EC) also recognized this protein. To improve the diagnostic potential, IFN-γ responses to ML1601c peptides were assessed using PBMC from Brazilian leprosy patients and EC. Five ML1601c peptides only induced IFN-γ in patients and HHC. Moreover, 24-hour whole-blood assay (WBA), two ML1601c peptides could assess the level of M. leprae exposure in Ethiopian EC. Beside IFN-γ, also IP-10, IL-6, IL-1β, TNF-α, and MCP-1 were increased in EC from areas with high leprosy prevalence in response to these ML1601c peptides. Thus, ML1601c peptides may be useful for differentiating M. leprae exposed or infected individuals and can also be used to indicate the magnitude of M. leprae transmission even in the context of various HLA alleles as present in these different genetic backgrounds.
Language	English
Publishing date	2012-01-29
Publishing country	Egypt
Document type	Journal Article
ZDB-ID	2546526-0
ISSN	1687-9694 ; 1687-9694
ISSN (online)	1687-9694
ISSN	1687-9694
DOI	10.1155/2012/132049
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Article: The level of PPD-specific IFN-gamma-producing CD4+ T cells in the blood predicts the in vivo response to PPD.

Martins, Marcia Valéria B S / Lima, Mônica Cristina B S / Duppre, Nadia C / Matos, Haroldo J / Spencer, John S / Brennan, Patrick J / Sarno, Euzenir N / Fonseca, Leila / Pereira, Geraldo M B / Pessolani, Maria Cristina V

Tuberculosis (Edinburgh, Scotland)

2007 Volume 87, Issue 3, Page(s) 202–211

Abstract: There are no reliable means for detecting subclinical mycobacterial infections. The recent sequencing of several mycobacterial genomes has now afforded new opportunities for the development of pathogen-specific diagnostic tests, critical in the context ... ...

Abstract	There are no reliable means for detecting subclinical mycobacterial infections. The recent sequencing of several mycobacterial genomes has now afforded new opportunities for the development of pathogen-specific diagnostic tests, critical in the context of leprosy and tuberculosis control. In the present study, we applied a multi-parametric flow cytometric analysis that allowed the investigation of T-cell functions in order to define immunological markers that measure previous exposure to mycobacteria. We compared the in vivo response to PPD, the gold standard skin test reagent for measuring previous exposure to Mycobacterium tuberculosis, with in vitro parameters of leukocyte activation in five PPD positive and five PPD negative healthy volunteers. PPD-stimulated peripheral leukocytes expressing CD4, CD69, cutaneous lymphocyte-associated antigen (CLA) and intracellular IFN-gamma were enumerated in whole blood and compared with the size of in vivo PPD-induced induration and IFN-gamma production levels as measured by ELISA in supernatants of PPD-stimulated peripheral blood mononuclear cells. The reactivity to the tuberculin skin test (TST) was associated with markedly increased frequencies of PPD-responsive activated (CD69+) and IFN-gamma-producing CD4+T cells. Detection of PPD-specific IFN-gamma producing leukocytes was restricted to CD4+T cells and a subset of these cells was shown to express the skin homing molecule CLA. Multiple linear regression modeling of responses to PPD showed the highest association between skin test indurations and frequencies of PPD-responsive IFN-gamma-producing CD4+CD69+ T cells. Our data show that the in vitro enumeration of antigen-specific IFN-gamma-producing CD4+ T cells can provide an alternative to the in vivo tuberculin test for the detection of latent Mycobacterium tuberculosis infection. Moreover, the measurement of these immunological parameters can be useful for the screening of new specific antigens defined by the genome sequence allowing selection of the best candidates for new diagnostics (including new skin tests), and vaccines for leprosy and tuberculosis.
MeSH term(s)	Adult ; Antigens, CD/immunology ; Antigens, Differentiation, T-Lymphocyte/immunology ; CD4 Lymphocyte Count ; CD4-Positive T-Lymphocytes/immunology ; Female ; Humans ; Interferon-gamma/metabolism ; Lectins, C-Type ; Lymphocyte Activation ; Male ; Tuberculin ; Tuberculin Test
Chemical Substances	Antigens, CD ; Antigens, Differentiation, T-Lymphocyte ; CD69 antigen ; Lectins, C-Type ; Tuberculin ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2007-05
Publishing country	Scotland
Document type	Comparative Study ; Journal Article
ZDB-ID	2046804-0
ISSN	1873-281X ; 1472-9792
ISSN (online)	1873-281X
ISSN	1472-9792
DOI	10.1016/j.tube.2006.07.006
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Article: Early mitochondrial dysfunction, superoxide anion production, and DNA degradation are associated with non-apoptotic death of human airway epithelial cells induced by Pseudomonas aeruginosa exotoxin A.

Plotkowski, Maria-Cristina / Póvoa, Helvécio C C / Zahm, Jean-Marie / Lizard, Gérard / Pereira, Geraldo M B / Tournier, Jean-Marie / Puchelle, Edith

American journal of respiratory cell and molecular biology

2001 Volume 26, Issue 5, Page(s) 617–626

Abstract: It has been shown that bacterial exoproducts may induce airway epithelium injury. During the epithelial repair process, the respiratory epithelial cells no more establish tight junctional intercellular complexes and may be particularly susceptible to ... ...

Abstract	It has been shown that bacterial exoproducts may induce airway epithelium injury. During the epithelial repair process, the respiratory epithelial cells no more establish tight junctional intercellular complexes and may be particularly susceptible to bacterial virulence factors. In this study, we analyzed the effect of Pseudomonas aeruginosa exotoxin A (ETA) at different periods of time and concentrations on 16 HBE 14o(-) human bronchial epithelial cells in culture conditions inducing a phenotype of repairing cells. ETA treatment for 24 and 48 h led to the killing of 40.0 +/- 5.7% and 79.0 +/- 1.4% of the cells, respectively, as determined by the dimethylthiazole 2,5 diphenyl tetrazolium bromide assay. At 1,000 ng/ml, ETA led to the killing of 25.2 +/- 6.6, 59.4 +/- 5.9, and 82.3 +/- 3.7% of the cells, after treatment periods of 7, 24, and 48 h, respectively. Cell death could not be inhibited by z-VAD-fmk, a broad spectrum caspase inhibitor. By transmission electron microscopy, ultrastructural characteristics described in apoptosis were not detected in ETA-treated cells. Instead, the mitochondria of cells treated for 24 and 48 h with ETA at 100 and 1,000 ng/ml were highly condensed. Human nasal polyp epithelial cells in primary culture exposed to ETA at 1,000 ng/ml did not exhibit characteristic features of apoptotic cells either. Cytofluorometric analysis of ETA-treated 16 HBE 14o(-) cells labeled with DiOC(6)(3) and hydroethidine showed a time- and dose-dependent reduction of the mitochondrial transmembrane potential, detected 7 h after ETA treatment, and an increase in superoxide production, detected at 24 h, respectively. By a photometric assay, DNA degradation was also detected 7 h after cell treatment with ETA at 100 and 1,000 ng/ml. Taken together, our results show that ETA-induced death of epithelial respiratory cells was preceded by early mitochondrial dysfunction and superoxide anion production, but was not followed by the classically described apoptotic pathways.
MeSH term(s)	ADP Ribose Transferases/toxicity ; Apoptosis/drug effects ; Bacterial Toxins ; Bronchi ; Caspase Inhibitors ; Cell Death/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; DNA/metabolism ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Epithelial Cells/ultrastructure ; Exotoxins/toxicity ; Humans ; Intracellular Membranes/drug effects ; Membrane Potentials/drug effects ; Mitochondria/drug effects ; Mitochondria/metabolism ; Mitochondria/ultrastructure ; Nasal Polyps/drug therapy ; Nasal Polyps/metabolism ; Nasal Polyps/pathology ; Necrosis ; Respiratory Mucosa/drug effects ; Respiratory Mucosa/metabolism ; Respiratory Mucosa/ultrastructure ; Superoxides/metabolism ; Virulence Factors ; Pseudomonas aeruginosa Exotoxin A
Chemical Substances	Bacterial Toxins ; Caspase Inhibitors ; Enzyme Inhibitors ; Exotoxins ; Virulence Factors ; Superoxides (11062-77-4) ; DNA (9007-49-2) ; ADP Ribose Transferases (EC 2.4.2.-)
Language	English
Publishing date	2001-11-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/ajrcmb.26.5.4489
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Article ; Online: Pathogen-specific epitopes as epidemiological tools for defining the magnitude of Mycobacterium leprae transmission in areas endemic for leprosy.

Martins, Marcia V S B / Guimarães, Marjorie M da S / Spencer, John S / Hacker, Mariana A V B / Costa, Luciana S / Carvalho, Fernanda M / Geluk, Annemieke / van der Ploeg-van Schip, Jolien J / Pontes, Maria A A / Gonçalves, Heitor S / de Morais, Janvier P / Bandeira, Tereza J P G / Pessolani, Maria C V / Brennan, Patrick J / Pereira, Geraldo M B

PLoS neglected tropical diseases

2012 Volume 6, Issue 4, Page(s) e1616

Abstract: During recent years, comparative genomic analysis has allowed the identification of Mycobacterium leprae-specific genes with potential application for the diagnosis of leprosy. In a previous study, 58 synthetic peptides derived from these sequences were ... ...

Abstract	During recent years, comparative genomic analysis has allowed the identification of Mycobacterium leprae-specific genes with potential application for the diagnosis of leprosy. In a previous study, 58 synthetic peptides derived from these sequences were tested for their ability to induce production of IFN-γ in PBMC from endemic controls (EC) with unknown exposure to M. leprae, household contacts of leprosy patients and patients, indicating the potential of these synthetic peptides for the diagnosis of sub- or preclinical forms of leprosy. In the present study, the patterns of IFN-γ release of the individuals exposed or non-exposed to M. leprae were compared using an Artificial Neural Network algorithm, and the most promising M. leprae peptides for the identification of exposed people were selected. This subset of M. leprae-specific peptides allowed the differentiation of groups of individuals from sites hyperendemic for leprosy versus those from areas with lower level detection rates. A progressive reduction in the IFN-γ levels in response to the peptides was seen when contacts of multibacillary (MB) patients were compared to other less exposed groups, suggesting a down modulation of IFN-γ production with an increase in bacillary load or exposure to M. leprae. The data generated indicate that an IFN-γ assay based on these peptides applied individually or as a pool can be used as a new tool for predicting the magnitude of M. leprae transmission in a given population.
MeSH term(s)	Adult ; Aged ; Antigens, Bacterial/immunology ; Epitopes/immunology ; Female ; Humans ; Interferon-gamma Release Tests/methods ; Leprosy/diagnosis ; Leprosy/transmission ; Male ; Middle Aged ; Mycobacterium leprae/immunology ; Neural Networks, Computer
Chemical Substances	Antigens, Bacterial ; Epitopes
Language	English
Publishing date	2012-04-24
Publishing country	United States
Document type	Evaluation Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2727
ISSN (online)	1935-2735
ISSN	1935-2727
DOI	10.1371/journal.pntd.0001616
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mycobacterium leprae virulence-associated peptides are indicators of exposure to M. leprae in Brazil, Ethiopia and Nepal.

Bobosha, Kidist / Tang, Sheila Tuyet / van der Ploeg-van Schip, Jolien J / Bekele, Yonas / Martins, Marcia V S B / Lund, Ole / Franken, Kees L M C / Khadge, Saraswoti / Pontes, Maria Araci de Andrade / Gonçalves, Heitor de Sá / Hussien, Jemal / Thapa, Pratibha / Kunwar, Chhatra B / Hagge, Deanna A / Aseffa, Abraham / Pessolani, Maria Cristina Vidal / Pereira, Geraldo M B / Ottenhoff, Tom H M / Geluk, Annemieke

Memorias do Instituto Oswaldo Cruz

2012 Volume 107 Suppl 1, Page(s) 112–123

Abstract: Silent transmission of Mycobacterium leprae, as evidenced by stable leprosy incidence rates in various countries, remains a health challenge despite the implementation of multidrug therapy worldwide. Therefore, the development of tools for the early ... ...

Abstract	Silent transmission of Mycobacterium leprae, as evidenced by stable leprosy incidence rates in various countries, remains a health challenge despite the implementation of multidrug therapy worldwide. Therefore, the development of tools for the early diagnosis of M. leprae infection should be emphasised in leprosy research. As part of the continuing effort to identify antigens that have diagnostic potential, unique M. leprae peptides derived from predicted virulence-associated proteins (group IV.A) were identified using advanced genome pattern programs and bioinformatics. Based on human leukocyte antigen (HLA)-binding motifs, we selected 21 peptides that were predicted to be promiscuous HLA-class I T-cell epitopes and eight peptides that were predicted to be HLA-class II restricted T-cell epitopes for field-testing in Brazil, Ethiopia and Nepal. High levels of interferon (IFN)-γ were induced when peripheral blood mononuclear cells (PBMCs) from tuberculoid/borderline tuberculoid leprosy patients located in Brazil and Ethiopia were stimulated with the ML2055 p35 peptide. PBMCs that were isolated from healthy endemic controls living in areas with high leprosy prevalence (EChigh) in Ethiopia also responded to the ML2055 p35 peptide. The Brazilian EChigh group recognised the ML1358 p20 and ML1358 p24 peptides. None of the peptides were recognised by PBMCs from healthy controls living in non-endemic region. In Nepal, mixtures of these peptides induced the production of IFN-γ by the PBMCs of leprosy patients and EChigh. Therefore, the M. leprae virulence-associated peptides identified in this study may be useful for identifying exposure to M. leprae in population with differing HLA polymorphisms.
MeSH term(s)	Bacterial Proteins/immunology ; Brazil ; Computational Biology ; Cytokines/immunology ; Epitope Mapping ; Epitopes, T-Lymphocyte/immunology ; Ethiopia ; Humans ; Mycobacterium leprae/immunology ; Mycobacterium leprae/isolation & purification ; Mycobacterium leprae/pathogenicity ; Mycobacterium leprae/virology ; Nepal ; Peptide Fragments/immunology ; Recombinant Proteins/immunology ; Virulence/immunology
Chemical Substances	Bacterial Proteins ; Cytokines ; Epitopes, T-Lymphocyte ; Peptide Fragments ; Recombinant Proteins
Language	English
Publishing date	2012-12-24
Publishing country	Brazil
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	953293-6
ISSN	1678-8060 ; 0074-0276
ISSN (online)	1678-8060
ISSN	0074-0276
DOI	10.1590/s0074-02762012000900018
Database	MEDical Literature Analysis and Retrieval System OnLINE

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