Assuntos
Alérgenos/imunologia , Hipersensibilidade Alimentar/imunologia , Alimentos/efeitos adversos , Educação em Saúde/métodos , Promoção da Saúde/métodos , Adolescente , Criança , Currículo , Feminino , Humanos , Conhecimento , Masculino , Avaliação de Programas e Projetos de Saúde/métodos , Instituições Acadêmicas , Gravação de Videoteipe/métodosRESUMO
PURPOSE: X-linked hyper IgM syndrome (XHIGM) is a combined immunodeficiency caused by mutations in the CD40 ligand (CD40L) gene that typically results in decreased or absent CD40L expression on activated T cells, leading to defective class switching and somatic hypermutation. We describe an infant who presented with respiratory failure due to pulmonary alveolar proteinosis (PAP) with a novel damaging missense mutation in the CD40L gene. METHODS: Whole exome sequencing (WES) was used to identify a mutation in the CD40L gene. CD40L expression and function were determined by flow cytometry. RESULTS: A 5-month-old previously-healthy male presented with respiratory failure and diffuse pulmonary ground glass opacities on CT scan of the chest. Laboratory evaluation revealed an undetectable IgG, normal IgA, and elevated IgM. A bronchoalveolar lavage demonstrated pulmonary alveolar proteinosis. WES demonstrated a c.608G > C mutation in the CD40L gene resulting in p.R203T. Flow cytometry demonstrated normal CD40L expression on activated T cells but absent binding of CD40-Ig to CD40L on activated patient T cells. CONCLUSIONS: The clinical manifestations of XHIGM in our patient had several unique features, including the presentation with PAP, normal serum IgA, and expression of non-functional CD40L on activated T cells. To our knowledge, this is the first published case of PAP in a patient with XHIGM.
Assuntos
Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/diagnóstico , Fenótipo , Proteinose Alveolar Pulmonar/diagnóstico , Biomarcadores , Ligante de CD40/genética , Diagnóstico Diferencial , Humanos , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/genética , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/imunologia , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/terapia , Lactente , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Mutação , Radiografia Torácica , Tomografia Computadorizada por Raios X , Sequenciamento do ExomaRESUMO
Cocaine addiction is an enduring, relapsing, behavioural disorder in which stressors reinstate cocaine-seeking even after prolonged abstinence. Evidence suggests that the 'anxiety-like' behaviour and stress associated with protracted withdrawal may be mediated by increased corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA), a part of the limbic circuitry engaged in the coding and transmission of stimulus-reward associations. In the present study we describe a long-lasting potentiation of glutamatergic transmission induced at lateral amygdala (LA)-to-CeA synapses by rat/human CRF. After 2 weeks of withdrawal from repeated intermittent exposure to cocaine, CRF-induced long-term potentiation (LTP) was greatly enhanced compared to the respective saline control group while, after short-term withdrawal (24 h), there was no significant difference between the two treatment groups, indicating alterations in CRF systems during protracted withdrawal from chronic cocaine. After prolonged withdrawal, CRF-induced LTP was dependent on activation of CRF2, CaV2.3 (R-type) calcium channels and intracellular signalling through protein kinase C in both saline- and cocaine-treated groups. The enhanced CRF-induced LTP after 2 weeks of withdrawal was mediated through augmented CRF1 receptor function, associated with an increased signalling through protein kinase A, and required N-methyl-D-aspartate (NMDA) receptors. Accordingly, single-cell recordings revealed a significantly increased NMDA/AMPA ratio after prolonged withdrawal from the cocaine treatment. These results support a role for CRF1 receptor antagonists as plausible treatment options during withdrawal from chronic cocaine and suggest Ca(V)2.3 blockers as potential candidates for pharmaceutical modulation of CRF systems.