SET translocation is associated with increase in caspase cleaved amyloid precursor protein in CA1 of Alzheimer and Down syndrome patients

Caspase cleaved amyloid precursor protein (APPcc) and SET are increased and mislocalized in the neuronal cytoplasm in Alzheimer Disease (AD) brains. Translocated SET to the cytoplasm can induce tau hyperphosphorylation. To elucidate the putative relationships between mislocalized APPcc and SET, we studied their level and distribution in the hippocampus of 5 controls, 3 Down syndrome and 10 Alzheimer patients. In Down syndrome and Alzheimer patients, APPcc and SET levels were increased in CA1 and the frequency of both localizations in the neuronal cytoplasm was high in CA1, and low in CA4. As the increase of APPcc is already present at early stages of AD, we overexpressed APPcc in CA1 and the dentate gyrus neurons of adult mice with a lentiviral construct. APPcc overexpression in CA1 and not in the dentate gyrus induced endogenous SET translocation and tau hyperphosphorylation. These data suggest that increase in APPcc in CA1 neurons could be an early event leading to the translocation of SET and the progression of AD through tau hyperphosphorylation.     

Epidemiology of achondroplasia: A population‐based study in Europe

Achondroplasia is a rare genetic disorder resulting in short‐limb skeletal dysplasia. We present the largest European population‐based epidemiological study to date using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network. All cases of achondroplasia notified to 28 EUROCAT registries (1991–2015) were included in the study. Prevalence, birth outcomes, prenatal diagnosis, associated anomalies, and the impact of paternal and maternal age on de novo achondroplasia were presented. The study population consisted of 434 achondroplasia cases with a prevalence of 3.72 per 100,000 births (95%CIs: 3.14–4.39). There were 350 live births, 82 terminations of pregnancy after prenatal diagnosis, and two fetal deaths. The prenatal detection rate was significantly higher in recent years (71% in 2011–2015 vs. 36% in 1991–1995). Major associated congenital anomalies were present in 10% of cases. About 20% of cases were familial. After adjusting for maternal age, fathers >34 years had a significantly higher risk of having infants with de novo achondroplasia than younger fathers. Prevalence was stable over time, but regional differences were observed. All pregnancy outcomes were included in the prevalence estimate with 80.6% being live born. The study confirmed the increased risk for older fathers of having infants with de novo achondroplasia.     

Gut Microbial Signatures of Distinct Trimethylamine N-Oxide Response to Raspberry Consumption

The aim of this exploratory study was to evaluate the gut microbial signatures of distinct trimethylamine N-oxide (TMAO) responses following raspberry consumption. Investigations were carried out in 24 subjects at risk of developing metabolic syndrome who received 280 g/day of frozen raspberries for 8 weeks. Blood and stool samples were collected at weeks 0 and 8. Inter-individual variability in plasma TMAO levels was analyzed, 7 subjects were excluded due to noninformative signals and 17 subjects were kept for analysis and further stratified according to their TMAO response. Whole-metagenome shotgun sequencing analysis was used to determine the impact of raspberry consumption on gut microbial composition. Before the intervention, the relative abundance of Actinobacteriota was significantly higher in participants whose TMAO levels increased after the intervention (p = 0.03). The delta TMAO (absolute differences of baseline and week 8 levels) was positively associated with the abundance of gut bacteria such as Bilophila wadsworthia (p = 0.02; r² = 0.37), from the genus Granulicatella (p = 0.03; r² = 0.48) or the Erysipelotrichia class (p = 0.03; r² = 0.45). Changes in the gut microbial ecology induced by raspberry consumption over an 8-week period presumably impacted quaternary amines-utilizing activity and thus plasma TMAO levels.     

Evaluation of a training and communication-network nephrology program for community pharmacists

Objectives To assess the feasibility and impact of implementing ProFiL program to optimize community-pharmacist management of drug-related problems among chronic kidney disease patients followed in a predialysis clinic. The program comprises a training workshop, communication-network program and consultation service. Setting Forty-two community pharmacies, 101 pharmacists, and 90 chronic kidney disease patients attending a predialysis clinic in Laval (Canada). Patients were followed-up for 6 months. Method In a six-month, pilot, open, cluster-randomized controlled trial, community pharmacies were assigned to ProFiL or the usual care. Chronic kidney disease patients of these pharmacies attending a predialysis clinic were recruited. ProFiL pharmacists attended a workshop, received patient information (diagnoses, medications, and laboratory-test results) and had access to a consultation service. Their knowledge and satisfaction were measured before and after the workshop. The mean numbers of pharmacists’ written recommendations to physicians (pharmaceutical opinions) and refusals to dispense a medication were computed. Results Of the ProFiL pharmacists, 84% attended the workshop; their knowledge increased from 52% to 88% (95% CI: 29–40%). Most ProFiL pharmacists rated workshop (95%), communication program (82%) and consultation service (59%) as “excellent” or “very good”; 82% said the program improved the quality of their follow-up. The consultation service received 21 requests. ProFiL and usual care pharmacists issued a mean of 0.50 and 0.02 opinion/patient, respectively, (95% CI of the adjusted difference: 0.28–1.01 opinion/patient). Conclusion The results of this pilot study suggest that ProFiL can be implemented and may help community pharmacists intervene more frequently to manage drug-related problems. However, a larger-scale study with longer follow-up is necessary to evaluate the impact of the program on management of drug-related problems and its clinical relevance. Institution where the study was conducted: Centre ambulatoire, Centre de santé et de services sociaux de Laval. Information about presentation of the work as an abstract or poster: Abstracts of this study have been published in the proceedings of the 3rd Canadian Joint Therapeutics Congress of the Canadian Society for Clinical Pharmacology—Canadian Association for Population Therapeutics—Canadian College of Clinical Pharmacy (Toronto, Canada, May 2006), the Colloque 2006 of the Réseau québécois de recherche sur l’usage des médicaments (Quebec, Canada, June 2006), the 22nd International Conference of the International Society of Pharmacoepidemiology (Lisbon, Portugal, August 2006), and the North American Primary Care Research Group (NAPCRG) annual meeting (Vancouver, Canada, October 2007).     

Role of oxygen derivatives in the cytotoxicity and DNA damage produced by asbestos on rat pleural mesothelial cells in vitro

The role of reactive oxygen metabolites in the toxic effectsof asbestos on pleural mesothelial cells is not well defined.We exposed rat pleural mesothelial cells (RPMC) to chrysotileand crocidolite fibers (0–40 µg/cm²) in the presenceor absence of catalase and superoxide dismutase (SOD). Cellinjury was measured using the colorimetric 3–4 (5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay and DNA damage was evaluated in terms of unscheduledDNA synthesis (UDS). Catalase (100 U/ml) and SOD (250 U/ml)protected RPMC against asbestos-induced cytotoxicity and DNAdamage. However, the inactivated enzymes and bovine serum albuminalso showed some protection, suggesting that the effect of antioxidantenzymes may be partly related to their protein nature. Theseresults suggest that oxygen derivatives are partly involvedin the toxic effects of asbestos on cultures of RPMC. The presenceof extracellular proteins may also decrease asbestos-producedtoxicity by reducing the degree of RPMC–fiber interaction.