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1.
Clin Immunol ; 234: 108910, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34922003

RESUMO

Genetic variants in PIK3CD, PIK3R1 and NFKB1 cause the primary immune deficiencies, activated PI3Kδ syndrome (APDS) 1, APDS2 and NFκB1 haploinsufficiency, respectively. We have identified a family with known or potentially pathogenic variants NFKB1, TNFRSF13B and PIK3R1. The study's aim was to describe their associated immune and cellular phenotypes and compare with individuals with monogenic disease. NFκB1 pathway function was measured by immunoblotting and PI3Kδ pathway activity by phospho-flow cytometry. p105/p50 expression was absent in two individuals but elevated pS6 only in the index case. Transfection of primary T cells demonstrated increased basal pS6 signalling due to mutant PIK3R1, but not mutant NFKB1 or their wildtype forms. We report on the presence of pathogenic variant NFKB1, with likely modifying variants in TNFRSF13B and PIK3R1 in a family. We describe immune features of both NFκB1 haploinsufficiency and APDS2, and the inhibition of excessive PI3K signalling by rapamycin in vitro.


Assuntos
Classe Ia de Fosfatidilinositol 3-Quinase/genética , Haploinsuficiência , Síndromes de Imunodeficiência/genética , Subunidade p50 de NF-kappa B/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Adolescente , Adulto , Feminino , Humanos , Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/imunologia , Masculino , Mutação , Adulto Jovem
2.
Clin Immunol ; 171: 12-17, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27497628

RESUMO

Good syndrome (GS) or thymoma-associated immunodeficiency, is a rare condition that has only been studied in retrospective case series. General consensus was that GS has a worse prognosis than other humoral immunodeficiencies. In this study, physicians of GS patients completed two questionnaires with a two year interval with data on 47 patients, 499 patient years in total. Results on epidemiology, disease characteristics, and outcome are presented. Mean age at diagnosis was 60years and median follow-up from onset of symptoms was 9years. There was a high frequency of respiratory tract infections due to encapsulated bacteria. Median survival was 14years. Survival was reduced compared to age-matched population controls (5-year survival: 82% versus 95%, p=0.008). In this cohort survival was not associated with gender (HR 0.9, 95% CI 0.3-3.0), autoimmune diseases (HR 2.9, 95% CI 0.8-10.1) or immunosuppressive use (HR 0.3, 95% CI: 0.1-1.2).


Assuntos
Síndromes de Imunodeficiência/epidemiologia , Timoma/epidemiologia , Neoplasias do Timo/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/diagnóstico por imagem , Doenças Autoimunes/epidemiologia , Criança , Feminino , Humanos , Síndromes de Imunodeficiência/diagnóstico por imagem , Infecções/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Inquéritos e Questionários , Timoma/diagnóstico por imagem , Neoplasias do Timo/diagnóstico por imagem
4.
J Clin Immunol ; 35(2): 112-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25504528

RESUMO

XMEN disease (X-linked immunodeficiency with Magnesium defect, Epstein-Barr virus infection and Neoplasia) is a novel primary immune deficiency caused by mutations in MAGT1 and characterised by chronic infection with Epstein-Barr virus (EBV), EBV-driven lymphoma, CD4 T-cell lymphopenia, and dysgammaglobulinemia [1]. Functional studies have demonstrated roles for magnesium as a second messenger in T-cell receptor signalling [1], and for NKG2D expression and consequently NK- and CD8 T-cell cytotoxicity [2]. 7 patients have been described in the literature; the oldest died at 45 years and was diagnosed posthumously [1-3]. We present the case of a 58-year-old Caucasian gentleman with a novel mutation in MAGT1 with the aim of adding to the phenotype of this newly described disease by detailing his clinical course over more than 20 years.


Assuntos
Proteínas de Transporte de Cátions/genética , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/etiologia , Mutação , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/complicações , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Encéfalo/patologia , Análise Mutacional de DNA , Fluordesoxiglucose F18 , Humanos , Imunofenotipagem , Linfonodos/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fenótipo , Tomografia por Emissão de Pósitrons , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Tomografia Computadorizada por Raios X , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/diagnóstico
5.
J Am Coll Cardiol ; 41(8): 1251-60, 2003 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-12706917

RESUMO

OBJECTIVES: The goal of this study was to evaluate combinations of eptifibatide with reduced-dose tenecteplase (TNK) in ST-elevation myocardial infarction (STEMI). BACKGROUND: Glycoprotein IIb/IIIa inhibitors enhance thrombolysis. The role of combination therapy in clinical practice remains to be established. METHODS: Patients (n = 438) with STEMI <6 h were enrolled. In dose-finding, 189 patients were randomized to different combinations of double-bolus eptifibatide and reduced-dose TNK. In dose-confirmation, 249 patients were randomized 1:1 to eptifibatide 180 microg/kg bolus, 2 microg/kg/min infusion, and 180 microg/kg bolus 10 min later (180/2/180) plus half-dose TNK (0.27 mg/kg) or standard-dose (0.53 mg/kg) TNK monotherapy. All patients received aspirin and unfractionated heparin (60 U/kg bolus; infusion 7 U/kg/h [combination], 12 U/kg/h [monotherapy]). The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 epicardial flow at 60 min. RESULTS: In dose-finding, TIMI grade 3 flow rates were similar across groups (64% to 68%). Arterial patency was highest for eptifibatide 180/2/180 plus half-dose TNK (96%, p = 0.02 vs. eptifibatide 180/2/90 plus half-dose TNK). In dose-confirmation, this combination, compared with TNK monotherapy, tended to achieve more TIMI 3 flow (59% vs. 49%, p = 0.15), arterial patency (85% vs. 77%, p = 0.17), and ST-segment resolution (median 71% vs. 61%, p = 0.08) but was associated with more major hemorrhage (7.6% vs. 2.5%, p = 0.14) and transfusions (13.4% vs. 4.2%, p = 0.02). Intracranial hemorrhage occurred in 1.0%, 0.6%, and 1.7% of patients treated with any combination, eptifibatide 180/2/180 and half-dose TNK, and TNK monotherapy, respectively. CONCLUSIONS: Double-bolus eptifibatide (180/2/180) plus half-dose TNK tended to improve angiographic flow and ST-segment resolution compared with TNK monotherapy but was associated with more transfusions and non-cerebral bleeding. Further study is needed before this combination can be recommended for general use.


Assuntos
Fibrinolíticos/uso terapêutico , Sistema de Condução Cardíaco/fisiopatologia , Infarto do Miocárdio/tratamento farmacológico , Peptídeos/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ativador de Plasminogênio Tecidual/uso terapêutico , Adulto , Idoso , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Angiografia Coronária , Circulação Coronária/efeitos dos fármacos , Esquema de Medicação , Quimioterapia Combinada , Eptifibatida , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Peptídeos/administração & dosagem , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/efeitos dos fármacos , Tenecteplase , Ativador de Plasminogênio Tecidual/administração & dosagem , Resultado do Tratamento
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