http://bura.brunel.ac.uk/handle/2438/206 2013-05-21T16:36:24Z 2013-05-21T16:36:24Z Ezzatizade, Vahid http://bura.brunel.ac.uk/handle/2438/7440 2013-05-20T14:59:14Z 2012-01-01T00:00:00Z

Title: Friedreich ataxia: Investigating the relationships between mismatch repair gene expression, FXN gene expression and GAA repeat instability in human and mouse cells and tissues Authors: Ezzatizade, Vahid Abstract: Friedreich ataxia (FRDA) is the most common inherited ataxia disorder, caused by a GAA repeat expansion mutation within the first intron of the FXN gene. The subsequent deficiency of frataxin protein leads to neurological disability, increased risk of diabetes mellitus, cardiomyopathy and premature death. The exact FRDA disease mechanism is not yet clear, despite some understanding of epigenetic, transcriptional and DNA repair system effects that lead to frataxin reduction. Previous studies have shown that mismatch repair (MMR) genes can affect other trinucleotide repeat disorders by destabilisation of the repeats. Furthermore, it has been proposed that frataxin deficiency might lead to cell malignancy by an as yet undefined mode of action. Therefore, the principle aim of this thesis was to use human and genetically altered mouse cells and tissues to understand the effects of MMR proteins on GAA repeat instability and FXN transcription, and also to identify potential changes in MMR transcription that might cause malignancy in FXN-defective human cells. Firstly, by using FXN and MMR genetically altered mice, MMR proteins were shown to be involved in both intergenerational and somatic GAA repeat instability, although their effects in the two systems were different. Thus, Msh2 or Msh3 were both found to protect against intergenerational transmission of GAA contractions, while loss of Msh2 or Msh3 reduced somatic GAA repeat expansions and increased levels of FXN transcription in brain and cerebellum tissues. Loss of Msh6 induced both intergenerational GAA repeat expansions and contractions, while the frequency of somatic GAA repeat expansions was reduced. Curiously, the level of FXN transcription was also reduced in Msh6-deficient brain and cerebellum tissues. On the other hand, Pms2 was found to protect against both intergenerational and somatic GAA repeat expansions, with loss of Pms2 causing increased GAA repeat expansions and decreased levels of FXN transcription in brain and cerebellum tissues. Finally, loss of Mlh1 led to a reduced frequency of both intergenerational and somatic GAA repeat expansions, but the level of FXN transcription was also reduced in brain and cerebellum tissues. Furthermore, upregulation of MMR mRNA expression was detected in human FRDA fibroblast cells, but downregulation was seen in FRDA cerebellum tissues, suggesting tissue-dependent control of FXN and MMR expression. In summary, these studies indicate that the MMR system can affect GAA repeat expansion instability and FXN transcription through different mechanisms of action. Furthermore, frataxin deficiency can also affect the levels of MMR mRNA expression in a tissue-dependent manner. These findings will assist future investigations aimed at identifying novel FRDA therapies. Description: This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.

2012-01-01T00:00:00Z Zeka, A Jones, BJ Anopa, Y Koulkova, A http://bura.brunel.ac.uk/handle/2438/7439 2013-05-21T09:17:37Z 2011-01-01T00:00:00Z

Title: Exposure variability and behaviour of indoor and outdoor air pollutants in primary schools in the United Kingdom Authors: Zeka, A; Jones, BJ; Anopa, Y; Koulkova, A Abstract: Background and Aims: Current evidence suggests that exposure to common indoor air pollutants is associated with adverse health effects in children. This study was conducted to examine air quality in four primary schools in southern England, in order to establish daily, weekly and seasonal variability of pollutant concentrations within and between the schools, and to understand the behaviour of common indoor and outdoor air pollutants. Methods: Four primary schools were selected for the study, in urban, suburban and rural environments with diverse size and socioeconomic backgrounds. Air quality monitoring was conducted in three rounds (autumn, winter, summer) during the academic year 2009-2010. Each round involved monitoring continuously for one week in four locations of typical children’s exposure: generally three indoors and one outdoors. Measurements were carried out for particulate matter count for size range 0.5-5.0μm (PM0.5-5.0), carbon dioxide (CO2), carbon monoxide (CO), and nitrogen dioxide (NO2). Results: Findings revealed great variability in PM0.5-5.0 concentrations during the week and between rounds of measurements within each school, and between schools. CO concentrations were greatly variable for the suburban and rural schools. Little variability was seen for NO2 concentrations. CO2 levels differed during the day and between days and rounds in each school, and between schools, depending on the daily activity patterns of children and practice of ventilation. Linear regression models predicted indoor levels for PM0.5-5.0, CO and NO2, based on contribution of outdoor concentrations to the same pollutant, ventilation measured by CO2 concentrations and weather variables. Conclusions: Study findings showed variability in pollutant exposure levels between locations, days and seasons in each school, and between all four schools. These differences related to school building design and location, ventilation practices and children’s daily activities. These findings support the need for developing methodology for personal exposure assessment to air pollutants among school children. Description: Copyright @ 2011 ISEE

2011-01-01T00:00:00Z Stallings-Smith, S Zeka, A Goodman, P Kabir, Z Clancy, L http://bura.brunel.ac.uk/handle/2438/7432 2013-05-21T13:05:29Z 2013-01-01T00:00:00Z

Title: Reductions in cardiovascular, cerebrovascular, and respiratory mortality following the national Irish smoking ban: Interrupted time-series analysis Authors: Stallings-Smith, S; Zeka, A; Goodman, P; Kabir, Z; Clancy, L Abstract: Background: Previous studies have shown decreases in cardiovascular mortality following the implementation of comprehensive smoking bans. It is not known whether cerebrovascular or respiratory mortality decreases post-ban. On March 29, 2004, the Republic of Ireland became the first country in the world to implement a national workplace smoking ban. The aim of this study was to assess the effect of this policy on all-cause and cause-specific, non-trauma mortality. Methods: A time-series epidemiologic assessment was conducted, utilizing Poisson regression to examine weekly age and gender-standardized rates for 215,878 non-trauma deaths in the Irish population, ages ≥35 years. The study period was from January 1, 2000, to December 31, 2007, with a post-ban follow-up of 3.75 years. All models were adjusted for time trend, season, influenza, and smoking prevalence. Results: Following ban implementation, an immediate 13% decrease in all-cause mortality (RR: 0.87; 95% CI: 0.76-0.99), a 26% reduction in ischemic heart disease (IHD) (RR: 0.74; 95% CI: 0.63-0.88), a 32% reduction in stroke (RR: 0.68; 95% CI: 0.54-0.85), and a 38% reduction in chronic obstructive pulmonary disease (COPD) (RR: 0.62; 95% CI: 0.46-0.83) mortality was observed. Post-ban reductions in IHD, stroke, and COPD mortalities were seen in ages ≥65 years, but not in ages 35-64 years. COPD mortality reductions were found only in females (RR: 0.47; 95% CI: 0.32-0.70). Post-ban annual trend reductions were not detected for any smoking-related causes of death. Unadjusted estimates indicate that 3,726 (95% CI: 2,305-4,629) smoking-related deaths were likely prevented post-ban. Mortality decreases were primarily due to reductions in passive smoking. Conclusions: The national Irish smoking ban was associated with immediate reductions in early mortality. Importantly, post-ban risk differences did not change with a longer follow-up period. This study corroborates previous evidence for cardiovascular causes, and is the first to demonstrate reductions in cerebrovascular and respiratory causes. Description: Copyright @ 2013 Stallings-Smith et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

2013-01-01T00:00:00Z Ashworth-Beaumont, Jim http://bura.brunel.ac.uk/handle/2438/7376 2013-04-25T09:41:14Z 2012-01-01T00:00:00Z

Title: The effect of anodal transcranial direct current stimulation on spatial motor skill learning in healthy and spinal cord injured humans Authors: Ashworth-Beaumont, Jim Abstract: Anodal transcranial direct current stimulation (tDCS) is an intervention which is thought to enhance motor learning in healthy and stroke-injured states, when applied adjunctively during skill learning. We set out to investigate whether anodal tDCS might enhance functional rehabilitation from incomplete tetraplegic SCI. To address current limitations in the measurement of task-dependent skill, a novel integrated skill training and measurement task, the Motor Skill Rehabilitation Task (MSRT) was designed and developed. Measures of performance from this task delivered the functional measure of spatial motor skill learning, Task Productivity Rate (TPR). TPR was analysed and validated as a univariate dependent outcome, which is of potential importance to the future development of clinical measures measuring goal-directed motor skills. The MSRT was included alongside conventional behavioural measures in a repeated-measures RCT pilot study, the first to investigate the effect of anodal tDCS on rehabilitation of motor skill from chronic spinal cord injury. Adjunctive application of anodal tDCS had a statistically significant benefit upon retention of skill in the incomplete spinal cord injured population, but only when the independent factor of sensory acuity was included in the analysis. Differences between the development of task-dependent skill and generic dexterity over time suggested that spatial skill development was subject to an interaction of short-term and lasting effects. A larger study in healthy persons further investigated these phenomena, also applying Transcranial Magnetic Stimulation (TMS)–evoked measurements to investigate intervention-dependent effects upon the excitability of projections between the primary motor cortex and muscles involved in the prehension task. The findings revealed that active tDCS did not enhance skill learning at 7 days beyond the training period, but did significantly alter the development of motor skill following a period of learning and subsequent skill consolidation which was associated with underlying perturbation of motor control strategy. Significant and divergent patterns of cortical plasticity were evoked in projections to muscles necessary for reaching and grasping. The main findings of this thesis do not support anodal tDCS as an effective adjunctive means of enhancing spatial motor skill in rehabilitation from incomplete tetraplegic SCI. If applied in patient populations, the clinical benefits of anodal tDCS may be contingent both on the nature of the sensorimotor deficit affecting upper limb function and the spatial demands of the behavioural task. The findings of this project serve to inform further research in relation to the effect of anodal tDCS on the brain and behavioural outcomes, the potential for efficacy in target patient groups and the sensitivity of outcome measures to spatial and temporal dimensions of practical motor skills. Description: This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.

2012-01-01T00:00:00Z