Multistep Ion Channel Remodeling and Lethal Arrhythmia Precede Heart Failure in a Mouse Model of Inherited Dilated Cardiomyopathy

Background: Patients with inherited dilated cardiomyopathy (DCM) frequently die with severe heart failure (HF) or die suddenly with arrhythmias, although these symptoms are not always observed at birth. It remains unclear how and when HF and arrhythmogenic changes develop in these DCM mutation carriers. In order to address this issue, properties of the myocardium and underlying gene expressions were studied using a knock-in mouse model of human inherited DCM caused by a deletion mutation DK210 in cardiac troponinT. Methodology/Principal Findings: By 1 month, DCM mice had already enlarged hearts, but showed no symptoms of HF and a much lower mortality than at 2 months or later. At around 2 months, some would die suddenly with no clear symptoms of HF, whereas at 3 months, many of the survivors showed evident symptoms of HF. In isolated left ventricular myocardium (LV) from 2 month-mice, spontaneous activity frequently occurred and action potential duration (APD) was prolonged. Transient outward (Ito) and ultrarapid delayed rectifier K + (IKur) currents were significantly reduced in DCM myocytes. Correspondingly, down-regulation of Kv4.2, Kv1.5 and KChIP2 was evident in mRNA and protein levels. In LVs at 3-months, more frequent spontaneous activity, greater prolongation of APD and further down-regulation in above K + channels were observed. At 1 month, in contrast, infrequent spontaneous activity and down-regulation of Kv4.2, but not Kv1.5 or KChIP2, were observed

The impact of transposable element activity on therapeutically relevant human stem cells

Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use, including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome, and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for the biosafety of stem cells to be used for substitutive and regenerative cell therapiesS.R.H. and P.T.R. are funded by the Government of Spain (MINECO, RYC-2016- 21395 and SAF2015–71589-P [S.R.H.]; PEJ-2014-A-31985 and SAF2015–71589- P [P.T.R.]). GGS is supported by a grant from the Ministry of Health of the Federal Republic of Germany (FKZ2518FSB403)

Flexible dosing of adjunctive zonisamide in the treatment of adult partial-onset seizures: a non-comparative, open-label study (ZEUS)

Objectives - To assess the efficacy and tolerability of zonisamide in a study allowing flexible dosing in a more diverse and less refractory population than assessed in randomized controlled trials. Methods - This 19-week, non-comparative study of adjunctive zonisamide included 281 adults who had at least four partial-onset seizures within 8 weeks on one or two antiepileptic drugs. Alterations to zonisamide doses were allowed after titration, except during two fixed-dose periods (weeks 10-13 and 16-19). Results - At the end of the second fixed-dose period (median dose 300 mg/day), the median reduction in monthly seizure frequency was 33.3-41.1%; >= 50% responder rate was 40.9-44.2%; and seizure freedom rate was 15.0-15.9%, depending on the analysis used. The most common adverse events were fatigue (16.7%) and somnolence (15.3%). Conclusions - Zonisamide demonstrated efficacy in a setting more reflective of clinical practice and was generally well tolerated

A higher mediterranean diet score, including unprocessed red meat, is associated with reduced risk of central nervous system demyelination in a case-control study of australian adults

BACKGROUND:The evidence associating diet and risk of multiple sclerosis (MS) is inconclusive. OBJECTIVES:The aim of this study was to investigate associations between a Mediterranean diet and risk of a first clinical diagnosis of central nervous system demyelination (FCD), a common precursor to MS. METHODS:We used data from the 2003-2006 Ausimmune Study, an Australian multicenter, case-control study examining environmental risk factors for FCD, with participants matched on age, sex, and study region (282 cases, 558 controls; 18-59 y old; 78% female). The alternate Mediterranean diet score (aMED) was calculated based on data from a food-frequency questionnaire. We created a modified version of the aMED (aMED-Red) where ∼1 daily serving (65 g) of unprocessed red meat received 1 point. All other components remained the same as aMED. Conditional logistic regression (254 cases, 451 controls) was used to test associations between aMED and aMED-Red scores and categories and risk of FCD, adjusting for history of infectious mononucleosis, serum 25-hydroxyvitamin D concentrations, smoking, education, total energy intake, and dietary underreporting. RESULTS:There was no statistically significant association between aMED and risk of FCD [per 1-SD increase in aMED score: adjusted odds ratio (aOR): 0.89; 95% CI: 0.75, 1.06; P = 0.181]. There was evidence of a nonlinear relation between aMED-Red and risk of FCD when a quadratic term was used (P = 0.016). Compared with the lowest category of aMED-Red, higher categories were significantly associated with reduced risk of FCD, corresponding to a 37% (aOR: 0.63; 95% CI: 0.41, 0.98; P = 0.039), 52% (aOR: 0.48; 95% CI: 0.28, 0.83; P = 0.009), and 42% (aOR: 0.58; 95% CI: 0.35, 0.96; P = 0.034) reduced risk of FCD in categories 2, 3, and 4, respectively. CONCLUSIONS:A Mediterranean diet, including unprocessed red meat, was associated with reduced risk of FCD in this Australian adult population. The addition of unprocessed red meat to a Mediterranean diet may be beneficial for those at high risk of MS.Lucinda J Black, Kimberley Baker, Anne-Louise Ponsonby, Ingrid van der Mei, Robyn M Lucas, Gavin Pereira, Ausimmune Investigator Grou