Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes.

Mutations that cause familial Alzheimer's disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid ß-peptide (Aß). Nevertheless, whether Aß is the primary disease driver remains controversial. We report here that FAD mutations disrupt initial proteolytic events in the multistep processing of APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals that a substrate mimetic traps γ-secretase during the transition state, and this structure aligns with activated enzyme-substrate complex captured by molecular dynamics simulations. In silico simulations and in cellulo fluorescence microscopy support stabilization of enzyme-substrate complexes by FAD mutations. Neuronal expression of C99 and/or presenilin-1 in Caenorhabditis elegans leads to synaptic loss only with FAD-mutant transgenes. Designed mutations that stabilize the enzyme-substrate complex and block Aß production likewise led to synaptic loss. Collectively, these findings implicate the stalled process-not the products-of γ-secretase cleavage of substrates in FAD pathogenesis.

Spontaneous pyohaemothorax in a teenager with von Willebrand disease: a case report and review of literature.

An 18-year-old man with a history of type 3 von Willebrand disease (VWD) presented with a spontaneous pyohaemothorax. Type 3 VWD may present with both mucocutaneous and deep-seated bleeds, such as visceral haemorrhages, intracranial bleeds and haemarthrosis. There have been very few cases described in children of spontaneous pyohaemothorax. Management of this patient was challenging due to risks of bleeding following surgical drainage, requiring constant replacement with von Willebrand factor concentrate, while monitoring factor VIII levels to balance the risks of thrombosis.

Sepsis and thyroid storm in a patient with methimazole-induced agranulocytosis.

Paediatric hyperthyroidism cases are mostly caused by Grave's disease. Thyroid storm is a life-threatening condition seen rarely, in severe thyrotoxicosis, occurring in about 1%-2% of patients with hyperthyroidism. Antithyroid medications and beta-blockers are typically the first-line management of thyroid storm. We report a challenging case of a 15-year-old girl who presented with thyroid storm in the setting of septic shock and methimazole-induced agranulocytosis. Since the first-line agents were contraindicated, plasmapheresis was used to control the thyroid storm and as a bridging therapy to the definitive therapy of early thyroidectomy. This is the first paediatric case report that outlines the use of plasmapheresis in the management of complicated thyrotoxicosis in a setting of septic shock.

The Non-Coding RNA Journal Club: Highlights on Recent Papers-7.

We are delighted to share with you our seventh Journal Club and highlight some of the most interesting papers published recently [...].

Smoking cessation outcomes of referral to a specialist hospital outpatient clinic.

BACKGROUND AND OBJECTIVES: Hospital visits are an opportunity to engage smokers in tobacco treatment. However, little is known about engagement in follow-up referrals. The purpose of this study is to report the rates of program engagement and smoking cessation outcomes of patients referred to a specialist outpatient tobacco treatment program after a hospital visit or other referral. METHODS: A retrospective chart review was used to examine the outcomes of 486 participants referred to a hospital-based smoking cessation clinic provided by tobacco treatment specialists. Referral sources, demographics and smoking, medical, psychiatric, and substance use history were obtained. The main outcomes of interest were engagement in the program and 7-day point-prevalence of smoking abstinence. RESULTS: Sixty-eight percent of participants who were referred to the program were considered "engaged," of which 70% were from hospitals, 4% from community programs, 11% were from general practitioners, and 16% were self-referrals. Thirty-percent (98/331) of engagers were abstinent by time of chart review (30% from the hospital, 8% from community programs, 19% from general practitioners, and 39% of self-referrals). Having quit for 1 month or longer at the past quit attempt, greater confidence in quitting smoking, lower expired carbon monoxide levels at baseline, and greater duration in the program were significant predictors of successful smoking cessation. DISCUSSION AND CONCLUSION: Providing tobacco treatment follow-up and referral for smokers after a hospital visit is important to enhance smoking cessation efforts. SCIENTIFIC SIGNIFICANCE: Referral to evidence-based tobacco treatment after hospital visits is effective. Models of tobacco treatment based on sources of referral should further be explored.

Systematic comparison of bacterial feeding strains for increased yield of Caenorhabditis elegans males by RNA interference-induced non-disjunction.

Rare Caenorhabditis elegans males arise when sex chromosome non-disjunction occurs during meiosis in self-fertilizing hermaphrodites. Non-disjunction is a relatively rare event, and males are typically observed at a frequency of less than one in five hundred wild-type animals. Males are required for genetic crosses and phenotypic analysis, yet current methods to generate large numbers of males can be cumbersome. Here, we identify RNAi reagents (dsRNA-expressing bacteria) with improved effectiveness for eliciting males. Specifically, we used RNAi to systematically reduce the expression of over two hundred genes with meiotic chromosome segregation functions, and we identified a set of RNAi reagents that robustly and reproducibly elicited male progeny.