Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress

The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the “c9RAN proteins” thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.     

Prevalence and predictors of abnormal arterial function in statin-treated type 2 diabetes mellitus patients

Arterial dysfunction (AD) in type 2 diabetes mellitus (T2DM) predicts cardiovascular events. The objective was to investigate the prevalence and predictors of AD in statin-treated T2DM patients. We measured flow-mediated (FMD) and nitrate-mediated (NMD) brachial artery dilatation in 86 statin-treated T2DM patients. Patients were classified into 2 groups: normal arterial function (FMD ≥3.7% with NMD ≥11.9%) or AD (FMD <3.7% with or without NMD <11.9%). Endothelial dysfunction without smooth muscle cell dysfunction (ED) was defined as FMD less than 3.7% with NMD of at least 11.9%, and endothelial dysfunction with smooth muscle cell dysfunction (ED/SMD) was defined as FMD less than 3.7% with NMD less than 11.9%. Predictors of arterial function were investigated using linear and logistic regression methods. The prevalence of AD was 33.7% (23.2% with ED and 10.5% with ED/SMD). In multivariate linear regression, history of hypertension (P < .01), statin dose (P < .05), and estimated glomerular filtration rate (eGFR) (P = .02) were significant predictors of FMD. Sex (P < .01) and creatinine (P = .03) or eGFR (P = .02) predicted NMD. In multivariate logistic regression, the independent predictors of AD were history of hypertension (odds ratio [OR], 8.79; 95% confidence interval, 2.14-36.12; P < .01), age (OR, 1.08; 1.01-1.17; P = .03), and statin dose (OR, 0.33; 0.12-0.87; P = .02). A history of hypertension (OR, 8.99; 1.87-43.26; P < .01) was the sole independent predictor of ED; eGFR (OR, 0.01; 0.00-0.26; P < .01) independently predicted ED/SMD. Our data suggest that one third of statin-treated diabetic patients have residual AD, mainly due to ED alone. Earlier identification and treatment of hypertension and renal impairment may improve AD and further decrease cardiovascular risk in such patients.     

Identification of new CRF51_01B in Singapore using full genome analysis of three HIV type 1 isolates

A recent HIV-1 molecular epidemiology survey in Singapore identified a novel CRF01_AE/B recombinant form, which accounted for 13 (11.9%) of 109 patient samples. Peripheral blood mononuclear cell DNA from three of these 13 patients was used to generate near full-length sequences to characterize the novel CRF01_AE/B recombinant form. The three isolates had a recombinant structure composed of CRF01_AE and subtype B, and shared identical breakpoints. As the three patients were not epidemiologically linked, this recombinant form has been designated CRF51_01B. Identification of the novel recombinant forms indicates ongoing active HIV-1 transmission in Singapore.     

Major complications related to epidural analgesia in children: a 15-year audit of 3,152 epidurals

Background

Complications associated with epidural analgesia in children have a reported incidence of 40-90 in 10,000 epidurals. We sought to determine the incidence of major complications with the use of continuous epidural analgesia that occurred in our centre over the past 15 years and to describe the nature of these complications.

Methods

The Acute Pain Service database at a tertiary care academic pediatric hospital was reviewed retrospectively over a 15-year period. Data were categorized according to patient age (neonate, infant, child one through eight years, and child > eight years), mode of insertion of the epidural (caudal, transsacral, lumbar, thoracic), complication type, and complication severity.

Results

Over the 15-year period, 3,152 epidurals were performed. The use of caudal-thoracic epidurals in neonates and infants has increased since 2007. Twenty-four major complications were identified (incidence, 7.6 in 1,000 epidurals). The rate of complications in neonates was 4.2% compared with 1.4% in infants, 0.5% in children aged one through eight years, and 0.8% in children over eight years of age. The two most common complications were local skin infection and drug error.

Conclusions

Our incidence of major complications and our finding that complications were more common in neonates and infants are both consistent with previously published data. The two most common types of complications are potentially preventable.