The structure and function of Alzheimer's gamma secretase enzyme complex

The production and accumulation of the beta amyloid protein (Aβ) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer’s disease (AD). A multi-subunit enzyme complex, referred to as gamma (γ) secretase, plays a pivotal role in the generation of Aβ from its parent molecule, the amyloid precursor protein (APP). Four core components (presenilin, nicastrin, aph-1, and pen-2) interact in a high-molecular-weight complex to perform intramembrane proteolysis on a number of membrane-bound proteins, including APP and Notch. Inhibitors and modulators of this enzyme have been assessed for their therapeutic benefit in AD. However, although these agents reduce Aβ levels, the majority have been shown to have severe side effects in pre-clinical animal studies, most likely due to the enzymes role in processing other proteins involved in normal cellular function. Current research is directed at understanding this enzyme and, in particular, at elucidating the roles that each of the core proteins plays in its function. In addition, a number of interacting proteins that are not components of γ-secretase also appear to play important roles in modulating enzyme activity. This review will discuss the structural and functional complexity of the γ-secretase enzyme and the effects of inhibiting its activity

Ingestão acidental de moedas por crianças: atuação do Setor de Otorrinolaringologia do Hospital João XXIII Accidental ingestion of coins by children: management of the ENT Department of João XXIII Hospital

Os casos de introdução de corpos estranhos acidentais em crianças são freqüentes nos pronto-atendimentos. O otorrinolaringologista pode atuar nos casos localizados no esôfago. A experiência é fundamental para o sucesso das intervenções. OBJETIVO: Descrever o atendimento de crianças que ingeriram moedas no Setor de Otorrinolaringologia do Hospital João XXIII. FORMA DE ESTUDO: Clínico prospectivo. MATERIAL E MÉTODO: Foram avaliados sete casos de ingestão de moedas (idade, sexo, status na família, tamanho da moeda, conduta/evolução). RESULTADOS: A idade variou de um até nove anos. Dois pacientes eram filhos únicos e cinco eram mais novos. O tamanho da moeda variou de 1,9cm até 2,5cm. Após oito horas de observação, três casos necessitaram de remoção no centro cirúrgico porque a radiografia mostrava a moeda na cricofaringe e em quatro casos houve a descida espontaneamente para o intestino. CONCLUSÃO: O Setor de Otorrinolaringologia tem bons resultados usando laringoscópio de lâmina reta e pinça nos casos alojados na cricofaringe e esofagoscopia rígida para os casos distais. A amostra não permite concluir se o tamanho da moeda e a idade influenciam a descida espontânea para o trato gastrointestinal e se os pacientes filhos únicos ou os mais novos são mais predispostos a este acidente.<br>The ingestion of foreign bodies by children is frequently seen in emergency departments. ENTs can manage those lodged in the esophagus but experience is important for a successful intervention. AIM: Describe seven cases of children that ingested coins, managed at the ENT Department of João XXIII Hospital. STUDY DESIGN: Clinical/prospective. MATERIALS AND METHODS: We describe seven cases (gender, age, family status, coin size and treatment/evolution). RESULTS: Age ranged from one to nine years. Two patients were only children and five were the youngest in their families. Coins sizes ranged from 1.9 to 2.5 cm. After eight hours of observation, three cases were treated in the surgery room because the foreign body was lodged in the cricopharynx. Four cases resolved spontaneously. CONCLUSION: The ENT department has good results removing coins lodged in the upper esophagus using forceps and laryngoscopy; and also using rigid esophagoscopy for the lower esophagus. In this study it was not possible to establish the importance of coin size and patient age in attempting to predict spontaneous resolution, nor if the child being an only child or the youngest in the family may have some predisposition in this kind of accident