Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study

Background: Friedreich's ataxia is a progressive degenerative disorder caused by deficiency of the frataxin protein. Expanded GAA repeats within intron 1 of the frataxin (FXN) gene lead to its heterochromatinisation and transcriptional silencing. Preclinical studies have shown that the histone deacetylase inhibitor nicotinamide (vitamin B3) can remodel the pathological heterochromatin and upregulate expression of FXN. We aimed to assess the epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia. Methods: In this exploratory, open-label, dose-escalation study in the UK, male and female patients (aged 18 years or older) with Friedreich's ataxia were given single doses (phase 1) and repeated daily doses of 2–8 g oral nicotinamide for 5 days (phase 2) and 8 weeks (phase 3). Doses were gradually escalated during phases 1 and 2, with individual maximum tolerated doses used in phase 3. The primary outcome was the upregulation of frataxin expression. We also assessed the safety and tolerability of nicotinamide, used chromatin immunoprecipitation to investigate changes in chromatin structure at the FXN gene locus, and assessed the effect of nicotinamide treatment on clinical scales for ataxia. This study is registered with ClinicalTrials.gov, number NCT01589809. Findings: Nicotinamide was generally well tolerated; the main adverse event was nausea, which in most cases was mild, dose-related, and resolved spontaneously or after dose reduction, use of antinausea drugs, or both. Phase 1 showed a dose-response relation for proportional change in frataxin protein concentration from baseline to 8 h post-dose, which increased with increasing dose (p=0·0004). Bayesian analysis predicted that 3·8 g would result in a 1·5-times increase and 7·5 g in a doubling of frataxin protein concentration. Phases 2 and 3 showed that daily dosing at 3·5–6 g resulted in a sustained and significant (p<0·0001) upregulation of frataxin expression, which was accompanied by a reduction in heterochromatin modifications at the FXN locus. Clinical measures showed no significant changes. Interpretation: Nicotinamide was associated with a sustained improvement in frataxin concentrations towards those seen in asymptomatic carriers during 8 weeks of daily dosing. Further investigation of the long-term clinical benefits of nicotinamide and its ability to ameliorate frataxin deficiency in Friedreich's ataxia is warranted

Quality of Life and Physical Function in Older Patients on Dialysis : A Comparison of Assisted Peritoneal Dialysis with Hemodialysis

Copyright © 2016 by the American Society of Nephrology.BACKGROUND AND OBJECTIVES: In-center hemodialysis (HD) is often the default dialysis modality for older patients. Few centers use assisted peritoneal dialysis (PD), which enables treatment at home. This observational study compared quality of life (QoL) and physical function between older patients on assisted PD and HD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients on assisted PD who were >60 years old and on dialysis for >3 months were recruited and matched to patients on HD (needing hospital transport) by age, sex, diabetes, dialysis vintage, ethnicity, and index of deprivation. Frailty was assessed using the Clinical Frailty Scale. QoL assessments included Hospital Anxiety and Depression Scale (HADS), Short Form-12, Palliative Outcomes Symptom Scale (renal), Illness Intrusiveness Rating Scale, and Renal Treatment Satisfaction Questionnaire (RTSQ). Physical function was evaluated by Barthel Score and timed up and go test. RESULTS: In total, 251 patients (129 PD and 122 HD) were recruited. In unadjusted analysis, patients on assisted PD had a higher prevalence of possible depression (HADS>8; PD=38.8%; HD=23.8%; P=0.05) and higher HADS depression score (median: PD=6; HD=5; P=0.05) but higher RTSQ scores (median: PD=55; HD=51; P<0.01). In a generalized linear regression model adjusting for age, sex, comorbidity, dialysis vintage, and frailty, assisted PD continued to be associated with higher RTSQ scores (P=0.04) but not with other QoL measures. CONCLUSIONS: There are no differences in measures of QoL and physical function between older patients on assisted PD and comparable patients on HD, except for treatment satisfaction, which is higher in patients on PD. Assisted PD should be considered as an alternative to HD for older patients, allowing them to make their preferred choices.Peer reviewe

Reduced microrna-150 is associated with poor survival in pulmonary arterial hypertension

Rationale: MicroRNAs (miRNAs or miRs) are implicated in the pathogenesis of various cardiovascular diseases, including pulmonary arterial hypertension (PAH). Objectives: We sought to measure changes in plasma levels of miRNAs in patients with PAH and relate them to the severity of the disease. Methods: A microarray screen was performed on total plasma RNA from eight patients with PAH and eight healthy control subjects. Quantitative polymerase chain reaction confirmed reduced miR-150 concentrations and was then used to measure miR-150 levels in (1) two separate cohorts of patients with PAH, from London (n = 145) and Sheffield (n = 30), respectively; (2) circulating microvesicles and blood cells; and (3) lungs from a monocrotaline rat model. Measurements and Main Results: Fifty-eight miRNAs showed differences in plasma concentration and miR-150 the largest downregulation in PAH. Receiver-operator-characteristic analysis showed both raw and normalized plasma miR-150 levels correlated with 2-year survival (P,0.01) in patientswith PAH. Cox regression analysis confirmed miR-150 levels as a significant predictor of survival. Age, baseline cardiac index, World Health Organization functional class, 6-minute walk distance, disease duration, and red cell distribution width also predicted survival. Entering these covariates in a multivariable model verified plasma miR-150 levels as an independent predictor of survival in PAH (hazard ratio, 0.533; P = 0.010). miR-150 levels alsopredictedsurvival ina second, independent PAH cohort. miR-150 levels were significantly reduced in circulating microvesicles from patients with PAH and the lungs of the monocrotaline rat. Conclusions: Reduced circulating miR-150 levels are associated with poor survival in PAH

Reintroduction of a dioecious aquatic macrophyte (Stratiotes aloides L.) regionally extinct in the wild. Interesting answers from genetics

1. The reintroduction of a plant species regionally extinct in the wild poses a stimulating conservation challenge. If the species is dioecious and the ex situ preserved population is only of one sex, the challenge is even more difficult. To assess whether the female population of Stratiotes aloides originally studied requires a reinforcement to increase its genetic variation, and to determine from which source male individuals should be taken to re-establish a viable population, the genetic structure of nine different accessions of S. aloides across Europe and Asia were analysed – six native populations and the last three Italian populations, preserved ex situ. 2. Amplified fragment length polymorphism (AFLP) fingerprinting of 190 individuals from these populations was performed using six primer combinations and chromosome counts. 3. AFLP markers revealed medium to high values of genetic diversity at the population level, unexpectedly including residual ex situ accessions. Neighbour-joining tree, PCoA and STRUCTURE analyses indicate the presence of three genetic patterns identifiable in the central-western, central and eastern Europe–Asian populations. Chromosome counts revealed the presence of diploid (2n = 24) and tetraploid (2n = 48) populations. 4. Similarity between populations belonging to different hydrographical basins, and differences between neighbouring populations could be explained through long-distance bird-mediated dispersal events. Genetic analysis showed that reinforcement with female individuals from other European populations to increase the genetic diversity of the Italian female population is not necessary. Surprisingly, the geographically closest male population (Bavaria) to the Po basin is not the best option for male reintroduction. Instead, male individuals should be reintroduced from the Rhine basin (Netherlands) and eastern part of the Danube basin (Romania)