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[PMID]:28450368
[Au] Autor:Ghosh P; Luque-Fernandez MA; Vaidya A; Ma D; Sahoo R; Chorev M; Zera C; McElrath TF; Williams MA; Seely EW; Halperin JA
[Ad] Endereço:Division of Hematology, Brigham and Women's Hospital, Boston, MA.
[Ti] Título:Plasma Glycated CD59, a Novel Biomarker for Detection of Pregnancy-Induced Glucose Intolerance.
[So] Source:Diabetes Care;40(7):981-984, 2017 07.
[Is] ISSN:1935-5548
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Plasma glycated CD59 (pGCD59) is an emerging biomarker in diabetes. We assessed whether pGCD59 could predict the following: the results of the glucose challenge test (GCT) for screening of gestational diabetes mellitus (GDM) (primary analysis); and the diagnosis of GDM and prevalence of large for gestational age (LGA) newborns (secondary analyses). RESEARCH DESIGN AND METHODS: Case-control study of 1,000 plasma samples from women receiving standard prenatal care, 500 women having a normal GCT (control subjects) and 500 women with a failed GCT and a subsequent oral glucose tolerance test (case patients). RESULTS: Compared with control subjects, the median (interquartile range) pGCD59 value was 8.5-fold higher in case patients and 10-fold higher in GDM patients, as follows: control subjects 0.33 (0.19); case patients 2.79 (1.4); GDM patients 3.23 (1.43) ( < 0.001); area under the receiver operating characteristic curve 0.92. LGA prevalence was 4.3% in the lowest quartile and 13.5% in the highest quartile of pGCD59. CONCLUSIONS: One pGCD59 measurement during weeks 24-28 identifies pregnancy-induced glucose intolerance with high sensitivity and specificity and can potentially identify the risk for LGA.
[Mh] Termos MeSH primário: Biomarcadores/sangue
Antígenos CD59/sangue
Diabetes Gestacional/diagnóstico
Intolerância à Glucose/diagnóstico
[Mh] Termos MeSH secundário: Glicemia/metabolismo
Estudos de Casos e Controles
Diabetes Gestacional/sangue
Feminino
Idade Gestacional
Intolerância à Glucose/sangue
Teste de Tolerância a Glucose
Seres Humanos
Lactente
Gravidez
Cuidado Pré-Natal
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Biomarkers); 0 (Blood Glucose); 0 (CD59 Antigens)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.2337/dc16-2598


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[PMID]:27770464
[Au] Autor:Raschke M; Igl BW; Kenny J; Collins J; Dertinger SD; Labash C; Bhalli JA; Tebbe CC; McNeil KM; Sutter A
[Ad] Endereço:Bayer Pharma AG, Muellerstrasse 178, Berlin, 13353, Germany.
[Ti] Título:In Vivo Pig-a gene mutation assay: Guidance for 3Rs-friendly implementation.
[So] Source:Environ Mol Mutagen;57(9):678-686, 2016 12.
[Is] ISSN:1098-2280
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The rodent Pig-a assay is an in vivo method for the detection of gene mutation, where lack of glycosylphosphatidylinositol-anchored proteins on the surface of circulating red blood cells (RBCs) serves as a reporter for Pig-a gene mutation. In the case of rats, the frequency of mutant phenotype RBCs is measured via fluorescent anti-CD59 antibodies and flow cytometry. The Pig-a assay meets the growing expectations for novel approaches in animal experimentation not only focusing on the scientific value of the assay but also on animal welfare aspects (3Rs principles), for example, amenable to integration into pivotal rodent 28-day general toxicology studies. However, as recommended in the Organisation for Economic Co-operation and Development Test Guidelines for genotoxicity testing, laboratories are expected to demonstrate their proficiency. While this has historically involved the extensive use of animals, here we describe an alternative approach based on a series of blood dilutions covering a range of mutant frequencies. The experiments described herein utilized either non-fluorescent anti-CD59 antibodies to provide elevated numbers of mutant-like cells, or a low volume blood sample from a single N-ethyl-N-nitrosourea treated animal. Results from these so-called reconstruction experiments from four independent laboratories showed good overall precision (correlation coefficients: 0.9979-0.9999) and accuracy (estimated slope: 0.71-1.09) of mutant cell scoring, which was further confirmed by Bland-Altman analysis. These data strongly support the use of reconstruction experiments for training purposes and demonstrating laboratory proficiency with very few animals, an ideal situation given the typically conflicting goals of demonstrating laboratory proficiency and reducing the use of animals. Environ. Mol. Mutagen. 57:678-686, 2016. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Alternativas ao Uso de Animais
Etilnitrosoureia/toxicidade
Proteínas de Membrana/genética
Testes de Mutagenicidade/métodos
Mutagênicos/toxicidade
Mutação
[Mh] Termos MeSH secundário: Bem-Estar do Animal
Animais
Antígenos CD59/análise
Eritrócitos/efeitos dos fármacos
Eritrócitos/metabolismo
Citometria de Fluxo
Guias como Assunto
Laboratórios/normas
Masculino
Ratos Endogâmicos
Reticulócitos/efeitos dos fármacos
Reticulócitos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD59 Antigens); 0 (Membrane Proteins); 0 (Mutagens); 0 (phosphatidylinositol glycan-class A protein); P8M1T4190R (Ethylnitrosourea)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171220
[Lr] Data última revisão:
171220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161023
[St] Status:MEDLINE
[do] DOI:10.1002/em.22060


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[PMID]:29173199
[Au] Autor:See VHL; Mas E; Prescott SL; Beilin LJ; Burrows S; Barden AE; Huang RC; Mori TA
[Ad] Endereço:1School of Medicine,Royal Perth Hospital,The University of Western Australia,Perth, WA 6000,Australia.
[Ti] Título:Effects of prenatal n-3 fatty acid supplementation on offspring resolvins at birth and 12 years of age: a double-blind, randomised controlled clinical trial.
[So] Source:Br J Nutr;118(11):971-980, 2017 Dec.
[Is] ISSN:1475-2662
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Resolution of inflammation is an active process involving specialised pro-resolving mediators (SPM) generated from the n-3 fatty acids EPA and DHA. n-3 Fatty acid supplementation during pregnancy may provide an intervention strategy to modify these novel SPM. This study aimed to assess the effect of n-3 fatty acid supplementation in pregnancy on offspring SPM at birth and 12 years of age (12 years). In all, ninety-eight atopic pregnant women were randomised to 3·7 g daily n-3 fatty acids or a control (olive oil), from 20 weeks gestation until delivery. Blood was collected from the offspring at birth and at 12 years. Plasma SPM consisting of 18-hydroxyeicosapentaenoic acid (18-HEPE), E-series resolvins, 17-hydroxydocosahexaenoic acid (17-HDHA), D-series resolvins, 14-hydroxydocosahexaenoic acid (14-HDHA), 10 S,17S-dihydroxydocosahexaenoic acid, maresins and protectin 1, were measured by liquid chromatography-tandem MS. We identified the resolvins RvE1, RvE2, RvE3, RvD1, 17R-RvD1 and RvD2 for the first time in human cord blood. n-3 Fatty acids increased cord blood 18-HEPE (P<0·001) derived from EPA relative to the control group. DHA-derived 17-HDHA at birth was significantly increased in the n-3 fatty acid group relative to the controls (P=0·001), but other SPM were not different between the groups. n-3 Fatty acid supplementation during pregnancy was associated with an increase in SPM precursors in the offspring at birth but the effects were not sustained at 12 years. The presence of these SPM, particularly at birth, may have functions relevant in the newborn that remain to be established, which may be useful for future investigations.
[Mh] Termos MeSH primário: Suplementos Nutricionais
Ácidos Graxos Ômega-3/administração & dosagem
Ácidos Graxos Ômega-3/sangue
Fenômenos Fisiológicos da Nutrição Pré-Natal
[Mh] Termos MeSH secundário: Antígenos CD59/sangue
Criança
Pré-Escolar
Ácidos Docosa-Hexaenoicos/sangue
Método Duplo-Cego
Ácido Eicosapentaenoico/análogos & derivados
Ácido Eicosapentaenoico/sangue
Feminino
Seres Humanos
Lactente
Masculino
Azeite de Oliva/administração & dosagem
Gravidez
Cuidado Pré-Natal
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (18(R)-hydroxyeicosapentaenoic acid); 0 (5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid); 0 (CD59 Antigens); 0 (Fatty Acids, Omega-3); 0 (Olive Oil); 25167-62-8 (Docosahexaenoic Acids); 86360-66-9 (14-hydroxydocosahexaenoic acid); 90780-52-2 (17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid); AAN7QOV9EA (Eicosapentaenoic Acid)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171218
[Lr] Data última revisão:
171218
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1017/S0007114517002914


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[PMID]:28943429
[Au] Autor:Cui X; Zhang X; Bu H; Liu N; Li H; Guan X; Yan H; Wang Y; Zhang H; Ding Y; Cheng M
[Ad] Endereço:Clinical Medical School, Weifang Medical University, Weifang, Shandong, 261053, PR China.
[Ti] Título:Shear stress-mediated changes in the expression of complement regulatory protein CD59 on human endothelial progenitor cells by ECM-integrinα ß -F-actin pathway in vitro.
[So] Source:Biochem Biophys Res Commun;494(1-2):416-421, 2017 Dec 09.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Membrane regulatory proteins, such as CD46, CD55, and CD59, prevent excess complement activation and to protect cells from damage. Previous investigations confirmed that shear stress in the physiological range was more favorable for endothelial progenitor cells (EPCs) to repair injured vascular endothelial cells and operates mainly in atheroprotective actions. However, detailed events that contribute to shear stress-induced protection in EPCs, particularly the mechanisms of signal transduction, remain poorly understood. In this study, we observed shear stress-mediated changes in the expression of complement regulatory proteins CD46, CD55, and CD59 on human EPCs and focused on the mechanical transmission mechanism in transformed cells in response to the ECM-F-actin pathway in vitro. Shear stress was observed to promote the expression of complement regulatory protein CD59, but not CD46 or CD55, on EPCs. In addition, the shear stress-induced CD59 expression was confirmed to be associated with the ECM components and was alleviated in EPCs pretreated with GRGDSP, which inhibits ECM components-integrin interaction. Furthermore, shear stress also promotes the rearrangement and polymerization of F-actin. However, shear stress-induced CD59 expression was reduced when the F-actin stress fiber formation process was delayed by Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) or destroyed by cytochalasin D (Cyto D), while Jasplakinolide (JAS) reversed the expression of CD59 through promotion of F-actin polymerization and its stabilizing capacities. Our results indicates that shear stress is an important mediator in EPC expression of CD59 regulated by the ECM-F-actin pathway, which is a key factor in preventing membrane attack complex (MAC) -mediated cell autolysis.
[Mh] Termos MeSH primário: Citoesqueleto de Actina/metabolismo
Actinas/genética
Antígenos CD59/genética
Células Progenitoras Endoteliais/metabolismo
Integrina alfaVbeta3/genética
Mecanotransdução Celular
[Mh] Termos MeSH secundário: Citoesqueleto de Actina/efeitos dos fármacos
Citoesqueleto de Actina/ultraestrutura
Actinas/metabolismo
Antígenos CD55/genética
Antígenos CD55/metabolismo
Antígenos CD59/metabolismo
Complexo de Ataque à Membrana do Sistema Complemento/efeitos dos fármacos
Citocalasina D/farmacologia
Depsipeptídeos/farmacologia
Células Progenitoras Endoteliais/citologia
Células Progenitoras Endoteliais/efeitos dos fármacos
Matriz Extracelular/química
Matriz Extracelular/efeitos dos fármacos
Matriz Extracelular/metabolismo
Sangue Fetal/citologia
Sangue Fetal/efeitos dos fármacos
Sangue Fetal/metabolismo
Regulação da Expressão Gênica
Seres Humanos
Integrina alfaVbeta3/metabolismo
Proteína Cofatora de Membrana/genética
Proteína Cofatora de Membrana/metabolismo
Oligopeptídeos/farmacologia
Cultura Primária de Células
Estresse Mecânico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (CD46 protein, human); 0 (CD55 Antigens); 0 (CD59 Antigens); 0 (Complement Membrane Attack Complex); 0 (Depsipeptides); 0 (Integrin alphaVbeta3); 0 (Membrane Cofactor Protein); 0 (Oligopeptides); 101754-01-2 (CD59 protein, human); 102396-24-7 (jasplakinolide); 22144-77-0 (Cytochalasin D); 91037-75-1 (glycyl-arginyl-glycyl-aspartyl-seryl-proline)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE


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[PMID]:28922377
[Au] Autor:Lepik K; Annilo T; Kukuskina V; Kisand K; Kutalik Z; Peterson P; Peterson H; eQTLGen Consortium
[Ad] Endereço:Institute of Computer Science, University of Tartu, Tartu, Estonia.
[Ti] Título:C-reactive protein upregulates the whole blood expression of CD59 - an integrative analysis.
[So] Source:PLoS Comput Biol;13(9):e1005766, 2017 09.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Elevated C-reactive protein (CRP) concentrations in the blood are associated with acute and chronic infections and inflammation. Nevertheless, the functional role of increased CRP in multiple bacterial and viral infections as well as in chronic inflammatory diseases remains unclear. Here, we studied the relationship between CRP and gene expression levels in the blood in 491 individuals from the Estonian Biobank cohort, to elucidate the role of CRP in these inflammatory mechanisms. As a result, we identified a set of 1,614 genes associated with changes in CRP levels with a high proportion of interferon-stimulated genes. Further, we performed likelihood-based causality model selection and Mendelian randomization analysis to discover causal links between CRP and the expression of CRP-associated genes. Strikingly, our computational analysis and cell culture stimulation assays revealed increased CRP levels to drive the expression of complement regulatory protein CD59, suggesting CRP to have a critical role in protecting blood cells from the adverse effects of the immune defence system. Our results show the benefit of integrative analysis approaches in hypothesis-free uncovering of causal relationships between traits.
[Mh] Termos MeSH primário: Proteína C-Reativa/metabolismo
Antígenos CD59/metabolismo
[Mh] Termos MeSH secundário: Adulto
Antígenos CD59/sangue
Estudos de Coortes
Estônia
Seres Humanos
Inflamação/metabolismo
Regulação para Cima/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD59 Antigens); 101754-01-2 (CD59 protein, human); 9007-41-4 (C-Reactive Protein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005766


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[PMID]:28815695
[Au] Autor:Sahoo R; Ghosh P; Chorev M; Halperin JA
[Ad] Endereço:Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
[Ti] Título:A distinctive histidine residue is essential for in vivo glycation-inactivation of human CD59 transgenically expressed in mice erythrocytes: Implications for human diabetes complications.
[So] Source:Am J Hematol;92(11):1198-1203, 2017 Nov.
[Is] ISSN:1096-8652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Clinical and experimental evidences support a link between the complement system and the pathogenesis of diabetes complications. CD59, an extracellular cell membrane-anchored protein, inhibits formation of the membrane attack complex (MAC), the main effector of complement-mediated tissue damage. This complement regulatory activity of human CD59 (hCD59) is inhibited by hyperglycemia-induced É›-amino glycation of Lys . Biochemical and structural analyses of glycated proteins with known three-dimensional structure revealed that glycation of É›-amino lysyl residues occurs predominantly at "glycation motives" that include lysyl/lysyl pairs or proximity of a histidyl residue, in which the imidazolyl moiety is ≈ 5Å from the É›-amino group. hCD59 contains a distinctive Lys /His putative glycation motif within its active site. In a model of transgenic diabetic mice expressing in erythrocytes either the wild type or a H44Q mutant form of hCD59, we demonstrate in vivo that the His is required for Lys glycation and consequent functional inactivation of hCD59, as evidenced using a mouse erythrocytes hemolytic assay. Since (1) the His residue is not present in CD59 from other animal species and (2) humans are particularly prone to develop complications of diabetes, our results indicate that the Lys /His glycation motif in human CD59 may confer humans a higher risk of developing vascular disease in response to hyperglycemia.
[Mh] Termos MeSH primário: Antígenos CD59/genética
Antígenos CD59/metabolismo
Eritrócitos/metabolismo
Regulação da Expressão Gênica
Histidina/metabolismo
[Mh] Termos MeSH secundário: Animais
Glicemia
Complicações do Diabetes/genética
Complicações do Diabetes/metabolismo
Diabetes Mellitus Experimental
Membrana Eritrocítica/metabolismo
Glicosilação
Hemólise
Seres Humanos
Lisina/metabolismo
Camundongos
Camundongos Transgênicos
Mutação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (CD59 Antigens); 101754-01-2 (CD59 protein, human); 4QD397987E (Histidine); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1002/ajh.24886


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[PMID]:28714084
[Au] Autor:Ji Z; LeBaron MJ
[Ad] Endereço:Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan, 48674.
[Ti] Título:Applying the erythrocyte Pig-a assay concept to rat epididymal sperm for germ cell mutagenicity evaluation.
[So] Source:Environ Mol Mutagen;58(7):485-493, 2017 Aug.
[Is] ISSN:1098-2280
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Pig-a assay, a recently developed in vivo somatic gene mutation assay, is based on the identification of mutant erythrocytes that have an altered repertoire of glycosylphosphatidylinositol (GPI)-anchored cell surface markers. We hypothesized that the erythrocyte Pig-a assay concept could be applied to rat cauda epididymal spermatozoa (sperm) for germ cell mutagenicity evaluation. We used GPI-anchored CD59 as the Pig-a mutation marker and examined the frequency of CD59-negative sperm using flow cytometry. A reconstruction experiment that spiked un-labeled sperm (mutant-mimic) into labeled sperm at specific ratios yielded good agreement between the detected and expected frequencies of mutant-mimic sperm, demonstrating the analytical ability for CD59-negative sperm detection. Furthermore, this methodology was assessed in F344/DuCrl rats administered N-ethyl-N-nitrosourea (ENU), a prototypical mutagen, or clofibrate, a lipid-lowering drug. Rats treated with 1, 10, or 20 mg/kg body weight/day (mkd) ENU via daily oral garage for five consecutive days showed a dose-dependent increase in the frequency of CD59-negative sperm on study day 63 (i.e., 58 days after the last ENU dose). This ENU dosing regimen also increased the frequency of CD59-negative erythrocytes. In rats treated with 300 mkd clofibrate via daily oral garage for consecutive 28 days, no treatment-related changes were detected in the frequency of CD59-negative sperm on study day 85 (i.e., 57 days after the last dose) or in the frequency of CD59-negative erythrocytes on study day 29. In conclusion, these data suggest that the epidiymal sperm Pig-a assay in rats is a promising method for evaluating germ cell mutagenicity. Environ. Mol. Mutagen. 58:485-493, 2017. © 2017 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Epididimo
Proteínas de Membrana/genética
Testes de Mutagenicidade/métodos
Mutagênicos/toxicidade
Espermatozoides/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Antígenos CD59/genética
Clofibrato/toxicidade
Eritrócitos/efeitos dos fármacos
Eritrócitos/metabolismo
Eritrócitos/patologia
Etilnitrosoureia/toxicidade
Citometria de Fluxo
Glicosilfosfatidilinositóis/biossíntese
Masculino
Ratos Endogâmicos F344
Espermatozoides/metabolismo
Espermatozoides/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD59 Antigens); 0 (Glycosylphosphatidylinositols); 0 (Membrane Proteins); 0 (Mutagens); 0 (phosphatidylinositol glycan-class A protein); HPN91K7FU3 (Clofibrate); P8M1T4190R (Ethylnitrosourea)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1002/em.22109


  8 / 1471 MEDLINE  
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[PMID]:28622911
[Au] Autor:Tabib A; Karbian N; Mevorach D
[Ad] Endereço:Rheumatology Research Center and Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
[Ti] Título:Demyelination, strokes, and eculizumab: Lessons from the congenital CD59 gene mutations.
[So] Source:Mol Immunol;89:69-72, 2017 Sep.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Neurological symptoms of patients with p.Cys89Tyr mutation in the CD59 gene include recurrent peripheral neuropathy resembling Guillain-Barré syndrome, characterized by sensory-motor demyelinating neuropathy with secondary axonal damage and moderate enhancement of the nerve roots on spine MRI, together with recurrent strokes and retinal involvement. Three additional mutations in CD59, leading to loss of function, have been described, and overall, 12/12 (100%) of patients with any mutation presented with neurological symptoms; 11/12 (92%) patients presented with recurrent peripheral neuropathy, 6/12 (50%) with recurrent strokes, and 1/12 (8%) with retinal involvement. We review the possible thrombophilic profile associated with the mutations. In these patients, excessive intravascular hemolysis saturates scavenger mechanisms resulting in free hemoglobin in plasma that irreversibly reacts with nitric oxide to form nitrate and methemoglobin, leading to arterial thrombosis. CD59 loss of function is also one of the major thrombophilic mechanisms in patients with paroxysmal nocturnal hemoglobinuria. We then describe the relationship with demyelination. The lack of CD59 allows uncontrolled complement amplification following low-level spontaneous-, viral-, or post viral-induced complement activation, resulting in severe demyelination in the peripheral nervous system. It is interesting, and certainly encouraging, that after 3 years, following 4 patients with Cys89Tyr mutations who are treated with eculizumab, no strokes occurred and non-permanent neurological insults underwent resolution without any new neurological exacerbations.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/uso terapêutico
Antígenos CD59/genética
Doenças Desmielinizantes/tratamento farmacológico
Mutação
Acidente Vascular Cerebral/tratamento farmacológico
[Mh] Termos MeSH secundário: Ativação do Complemento/efeitos dos fármacos
Inativadores do Complemento/uso terapêutico
Doenças Desmielinizantes/genética
Seres Humanos
Acidente Vascular Cerebral/genética
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (CD59 Antigens); 0 (Complement Inactivating Agents); 101754-01-2 (CD59 protein, human); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170618
[St] Status:MEDLINE


  9 / 1471 MEDLINE  
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[PMID]:28533125
[Au] Autor:Hoffman WH; Artlett CM; Boodhoo D; Gilliland MGF; Ortiz L; Mulder D; Tjan DHT; Martin A; Tatomir A; Rus H
[Ad] Endereço:Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States. Electronic address: whoffman@augusta.edu.
[Ti] Título:Markers of immune-mediated inflammation in the brains of young adults and adolescents with type 1 diabetes and fatal diabetic ketoacidosis. Is there a difference?
[So] Source:Exp Mol Pathol;102(3):505-514, 2017 Jun.
[Is] ISSN:1096-0945
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Due to the limited data on diabetic ketoacidosis and brain edema (DKA/BE) in children/adolescents and the lack of recent data on adults with type 1 diabetes (T1D), we addressed the question of whether neuroinflammation was present in the fatal DKA of adults. We performed immunohistochemistry (IHC) studies on the brains of two young adults with T1D and fatal DKA and compared them with two teenagers with poorly controlled diabetes and fatal DKA. C5b-9, the membrane attack complex (MAC) had significantly greater deposits in the grey and white matter of the teenagers than the young adults (p=0.03). CD59, a MAC assembly inhibitory protein was absent, possibly suppressed by the hyperglycemia in the teenagers but was expressed in the young adults despite comparable average levels of hyperglycemia. The receptor for advanced glycation end products (RAGE) had an average expression in the young adults significantly greater than in the teenagers (p=0.02). The autophagy marker Light Chain 3 (LC3) A/B was the predominant form of programmed cell death (PCD) in the teenage brains. The young adults had high expressions of both LC3A/B and TUNEL, an apoptotic cell marker for DNA fragmentation. BE was present in the newly diagnosed young adult with hyperglycemic hyperosmolar DKA and also in the two teenagers. Our data indicate that significant differences in neuroinflammatory components, initiated by the dysregulation of DKA and interrelated metabolic and immunologic milieu, are likely present in the brains of fatal DKA of teenagers when compared with young adults.
[Mh] Termos MeSH primário: Biomarcadores/metabolismo
Diabetes Mellitus Tipo 1/genética
Cetoacidose Diabética/genética
Inflamação Neurogênica/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Autofagia
Encéfalo/fisiopatologia
Edema Encefálico/diagnóstico
Edema Encefálico/etiologia
Edema Encefálico/genética
Antígenos CD59/genética
Antígenos CD59/metabolismo
Fragmentação do DNA
Diabetes Mellitus Tipo 1/complicações
Cetoacidose Diabética/complicações
Regulação da Expressão Gênica
Seres Humanos
Imuno-Histoquímica
Marcação In Situ das Extremidades Cortadas
Mediadores da Inflamação/metabolismo
Proteínas Associadas aos Microtúbulos/genética
Proteínas Associadas aos Microtúbulos/metabolismo
Inflamação Neurogênica/etiologia
Adulto Jovem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (CD59 Antigens); 0 (Inflammation Mediators); 0 (Microtubule-Associated Proteins); 0 (light chain 3, human); 101754-01-2 (CD59 protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170524
[St] Status:MEDLINE


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[PMID]:28516949
[Au] Autor:Hill A; DeZern AE; Kinoshita T; Brodsky RA
[Ad] Endereço:Department of Haematology, St. James' University Hospital, Leeds, UK.
[Ti] Título:Paroxysmal nocturnal haemoglobinuria.
[So] Source:Nat Rev Dis Primers;3:17028, 2017 05 18.
[Is] ISSN:2056-676X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal haematopoietic stem cell (HSC) disease that presents with haemolytic anaemia, thrombosis and smooth muscle dystonias, as well as bone marrow failure in some cases. PNH is caused by somatic mutations in PIGA (which encodes phosphatidylinositol N-acetylglucosaminyltransferase subunit A) in one or more HSC clones. The gene product of PIGA is required for the biosynthesis of glycosylphosphatidylinositol (GPI) anchors; thus, PIGA mutations lead to a deficiency of GPI-anchored proteins, such as complement decay-accelerating factor (also known as CD55) and CD59 glycoprotein (CD59), which are both complement inhibitors. Clinical manifestations of PNH occur when a HSC clone carrying somatic PIGA mutations acquires a growth advantage and differentiates, generating mature blood cells that are deficient of GPI-anchored proteins. The loss of CD55 and CD59 renders PNH erythrocytes susceptible to intravascular haemolysis, which can lead to thrombosis and to much of the morbidity and mortality of PNH. The accumulation of anaphylatoxins (such as C5a) from complement activation might also have a role. The natural history of PNH is highly variable, ranging from quiescent to life-threatening. Therapeutic strategies include terminal complement blockade and bone marrow transplantation. Eculizumab, a monoclonal antibody complement inhibitor, is highly effective and the only licensed therapy for PNH.
[Mh] Termos MeSH primário: Hemoglobinúria Paroxística/patologia
Hemoglobinúria Paroxística/terapia
Proteínas de Membrana/genética
[Mh] Termos MeSH secundário: Anticorpos Monoclonais Humanizados/uso terapêutico
Transplante de Medula Óssea
Antígenos CD55/metabolismo
Antígenos CD59/metabolismo
Proteínas Inativadoras do Complemento/metabolismo
Hemoglobinúria Paroxística/genética
Hemoglobinúria Paroxística/metabolismo
Seres Humanos
Mutação
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (CD55 Antigens); 0 (CD59 Antigens); 0 (Complement Inactivator Proteins); 0 (Membrane Proteins); 0 (phosphatidylinositol glycan-class A protein); 101754-01-2 (CD59 protein, human); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171121
[Lr] Data última revisão:
171121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.1038/nrdp.2017.28



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