OBJECTIVES: The aim of our study was to assess clinical presentation of early-onset schizophrenia spectrum disoders (EO-SSD), the time to first improvement and efficacy associated with selected atypical (AAPs) and typical (TAPs) antipsychotics, as well as two main side effects - weight gain and treatment-emergent extrapyramidal symptoms (EPSs) during the treatment in patients with EO-SSD. METHODS: This was a systematic chart review of all patients receiving routine clinical care in our department, with selected AAPs (risperidone, olanzapine, ziprasidone, quetiapine and clozapine) and TAPs (haloperidol, perphenazine and sulpiride), for schizophrenic psychoses, between 1997 and 2007. During this period, our review identified 173 patients (85 males, 88 females; mean age 15.8±1.6 years); their treatment included 297 treatment trials. Data on premorbid adjustment, prodromal symptoms and psychopathology at admission, as well as comorbidity were evaluated based on the patients' medical records. The time to first improvement could be estimated in 258 treatment trials; of these, 195 (76%) comprised AAPs and 63 (24%) TAPs. The time to first improvement was assessed in agreement with the methodology established for retrospective studies as the number of treatment days prior to the first record of improvement...

Introduction: Family-focused cognitive behavioural therapy (FFCBT) is emphasized as an approach to optimize treatment outcomes for early-onset obsessive-compulsive disorder (OCD). Parental engagement is critical to successful treatment. However, few studies have examined how to promote parental engagement during FFCBT. Additionally, from a parental perspective, there is a limited understanding of factors that influence parental engagement throughout treatment, including the role of nurses. Aims: To determine (i) how parents experience and understand their engagement in FFCBT provided for their child with early-onset OCD in community or outpatient mental health programs, and (ii) how parents describe the role of nurses related to parental engagement during the treatment process. Methods: This study used an interpretive description approach. Semi-structured interviews were completed with parents (n = 17) recruited from community or outpatient children’s mental health programs in the Hamilton Region of Southwestern Ontario. Treatment provider interviews (n = 9) augmented the data collected from parents’ perceptions of their engagement and the role of nurses during FFCBT. Interviews were analyzed using Braun and Clark’s (2006) thematic analysis process. Results: A conceptualized model was constructed to display and communicate the individual, interpersonal, and contextual influences identified by parents and treatment providers. These influences facilitated or inhibited parental engagement during treatment across distinct phases, levels, and stages of engagement. Six distinct nursing roles were identified that promoted parental engagement throughout treatment. / Dissertation / Doctor of Philosophy (PhD) / Without effective treatment, pediatric obsessive-compulsive disorder (OCD) can interfere with childhood development. Early-onset OCD is a unique subtype of the disorder involving pediatric patients with symptoms that present before the age of 10 years. Family-focused cognitive behavioural therapy (FFCBT) emphasizing parental involvement is commonly used to treat pediatric OCD. However, parental engagement during FFCBT, including nurses’ roles, is poorly understood. This study aimed to increase knowledge about parental engagement during FFCBT for children with early-onset OCD receiving treatment in community programs. Data analysis of parent and treatment provider interviews identified various factors and how nurses influenced parental engagement during FFCBT. A model was made to display how these factors helped or hindered parental engagement during treatment and how nurses promoted engagement across three distinct phases. This new knowledge informed recommendations to promote parental engagement for treatment providers, improve service development and delivery, and strengthen nursing education.

Les variations du nombre de copies (i.e., VNC, perte ou gain de matériel génétique de plus de 1 kilobase) figurent parmi les facteurs biologiques les plus associés aux troubles neurodéveloppementaux (TNDs), tels que les troubles du spectre autistique (TSAs) ou la psychose précoce. Les variants génétiques classés comme pathogéniques sont identifiés chez environ 20% des enfants avec des symptômes de TSA référés en génétique clinique. Actuellement, seules les VNCs les plus récurrentes (i.e., plusieurs individus non apparentés ont le même variant) ont été associées avec les TSAs et leurs tailles d’effets ont pu être décrites avec précision grâce à des études d'associations (i.e., cas-contrôles). Cependant, la plupart des VNCs identifiées dans les cliniques neurodéveloppementales et génétiques sont ultra-rares. À ma connaissance, aucune méthode n’a été développée afin d’estimer et de prédire de façon précise la contribution de tels variants aux phénotypes cliniques. De ce fait, l’impact de ces variants ultra-rares sur les risques d'avoir des TNDs, comme les TSAs ou la psychose précoce, reste incertain. Une étude récente de mon groupe de recherche a démontré que les tailles d'effet des délétions et duplications à travers le génome sur les capacités cognitives pouvaient être prédites statistiquement avec 78% de précision en utilisant des mesures d'intolérance à la perte de fonction. Le but de cette thèse est de développer des modèles similaires pour définir les tailles d'effet des VNCs à travers le génome sur les risques de TSA et de psychose précoce, ainsi que sur quelques traits cognitifs et comportementaux affectés dans ces troubles. J’ai analysé tous les VNCs ≥ 50 kilobases identifiées via les données de puces de génotypage et de séquençage sur génome entier chez 137 enfants et adolescents avec une psychose précoce (Boston Children’s hospital), 5,540 probands avec des TSAs (Simons Simplex Collection et MSSNG), et 17,471 personnes de la population générale (Lothian birth cohort, Generation Scotland, IMAGEN et Saguenay Youth Study). Les gènes codants totalement compris dans les VNCs ont été annotés avec neufs variables quantitatives, incluant le score d’intolérance à la perte de fonction et d’autres scores fonctionnels et génétiques. Des modèles statistiques incluant ces scores ont été testés afin de sélectionner celui qui explique le mieux l’effet des VNCs à travers le génome sur le risque de TSA et le quotient intellectuel (QI). Le meilleur modèle a été utilisé par la suite pour investiguer les tailles d’effets des VNCs sur d’autres traits cognitifs et comportementaux liés aux TSAs, ainsi que sur le risque de psychose précoce. Le score d’intolérance à la perte de fonction expliquait le mieux les effets des VNCs sur le risque de TSA et la cognition générale. Les modèles incluant ces scores ont démontré que les délétions et les duplications augmentaient les risques de psychose précoce et de TSA, même après ajustement pour le QI. Il n’y avait aucune différence de tailles d’effets des VNCs entre la psychose précoce et le TSA. La fréquence de loci associé précédemment avec des TNDs et des troubles neuropsychiatriques était également similaire entre dans les TSA et la psychose précoce, et le modèle estimait précisément la taille d'effet de la plupart de ces loci sur le risque de TSA en comparaison aux observation empiriques publiées précédemment. Les CNVs à travers le génome mesurés par le score d’intolérance à la perte de fonction diminuaient de façon similaire le QI dans les populations TSA et générale. Les effets des duplications étaient systématiquement plus faibles que les effets des délétions pour chacun de ces phénotypes, ce qui suggère un effet plus pathogénique des délétions. Les délétions et les duplications affectaient différentiellement la communication sociale, les comportements, et la mémoire phonologique, tandis qu'elles affectaient similairement les capacités motrices dans les populations TSA. L'enrichissement similaire des VNCs à travers le génome dans la psychose précoce et le TSA suggère un effet pléiotropique des VNCs dans ces différentes symptomatologies. Le dépistage routinier pour les VNCs doit être accessible dans les soins cliniques standards des jeunes avec une psychose précoce, comme il est recommandé pour les TSAs. Une telle pratique contribue à établir une médecine personnalisée et peut apporter des bénéfices médicaux comme la détection de comorbidités, la prédiction de la progression de la maladie, et faciliter la communication avec les parents à propos de la nature biologique du trouble. Les modèles appliqués dans ce projet, entraînés sur des VNCs incluant plus de 4,500 gènes, suggèrent des propriétés hautement polygéniques du dosage génique dans les TNDs. J’ai estimé que chaque VNC de 1 mégabase, incluant au moins un gène scorant pour l’intolérance à la perte de fonction, augmente le risque de TSA. La combinaison de ces résultats ouvre de nouvelles perspectives dans la compréhension des effets des VNCs à travers le génome sur les TNDs et les traits associés (e.g., QI ou symptômes comportementaux). Ces modèles ont été implémentés dans un outil en ligne qui a pour but d'aider les cliniciens à estimer les tailles d’effet des VNCs identifiés en clinique et à interpréter leur contribution au phénotype du patient. / Copy number variants (CNVs; i.e., loss or gain of genetic material of over 1 kilobase) are robustly associated with neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and early-onset psychosis (EOP). Genetic variants classified as pathogenic are identified in approximately 20% of children with ASD symptoms referred to genetic clinics. To date, only the most recurrent CNVs (i.e., similar variants across multiple unrelated individuals) were associated with ASD and their effect-sizes were characterized through association studies (i.e., case-controls). However, most of the CNVs routinely identified in neurodevelopmental and genetic clinics are ultra-rare. To my knowledge, no method was developed to accurately estimate and predict the contribution of such variants to clinical phenotypes. Therefore, the impact of these ultra-rare variants on risk for NDDs, such as ASD and EOP, remains undocumented. A recent study from my research group has shown that the effect-size of genome-wide deletions and duplications on cognitive ability can be statistically predicted with an 78% accuracy using measures of loss-of-function (LoF) intolerance. The aim of this thesis was to develop similar models to define the effect-size of genome-wide CNVs on ASD and EOP risk, as well as on several cognitive and behavioral traits altered in these disorders. I analyzed all CNVs ≥ 50 kilobases called from genotyping arrays and whole genome sequencing data from 137 children and adolescents with EOP (Boston Children’s hospital), 5,540 probands with ASD (Simons Simplex Collection and MSSNG), and 17,471 individuals from unselected populations (Lothian birth cohort, Generation Scotland, IMAGEN and Saguenay Youth Study). Coding genes fully encompassed by CNVs were annotated with nine quantitative variables, including the LoF intolerance score and other functional and genetic scores. Statistical models including these scores were tested to select the one that best explained the effects of genome-wide CNVs on ASD risk and IQ. The best model was subsequently used to investigate the effect-size of genome-wide CNVs on cognitive and behavioral domains related to ASD, as well as on EOP risk. The LoF intolerance score best explained the effect-sizes of genome-wide CNVs on ASD-risk and general cognition. Models including such scores demonstrated that deletions or duplications increased risks for EOP and for ASD, even after adjusting for IQ. There was no difference in effect-sizes between EOP and ASD. The frequency of loci previously associated with NDDs or neuropsychiatric disorders was also similar between EOP and ASD, and the model accurately estimated the effect-size of most of these loci on the risk for ASD comparing to previously published empirical observations. Genome-wide CNVs measured by LoF intolerance score also similarly decreased IQ in both ASD and unselected populations. The effect of duplications was smaller than the effect of deletion for all phenotypes investigated, suggesting a higher pathogenicity of deletions. Deletions and duplications were found to differentially affect social communication, behavior, and phonological memory, whereas both equally affected motor skills in the ASD population. The identical enrichment of genome-wide CNVs in EOP and ASD suggests a pleiotropic effect of CNVs in these different symptomatology. Routine screening for CNVs should be made available in the standard clinical care for EOP youth, as is recommended in ASD. Such practice contributes to the establishment of personalized medicine and may bring medical benefits as detecting medical comorbidities, prediction of the disease progression, and facilitating the communication with parents about the biological nature of the disorder. The models applied in this project, trained on CNVs encompassing more than 4,500 genes, suggest highly polygenic properties of gene dosage in NDDs. I estimated that any 1 megabase CNV, encompassing at least one gene scoring for intolerance to LoF, would increase ASD risk. Overall, these results open new avenues for understanding the effect of genome-wide CNVs on NDD risk and related traits (e.g., IQ or behavioral symptoms). These models were implemented in an online tool which aims to help clinicians estimate the effect-size of CNVs identified in the clinic and interpret their contribution to the patient’s phenotype.

Background: Human Leucocyte Antigens (HLA) represent the genetic loci most strongly linked to Multiple Sclerosis (MS). Apart from HLA-DR and HLA–DQ, HLA-DP alleles have been previously studied regarding their role in MS pathogenesis, but to a much lesser extent. Our objective was to investigate the risk/resistance influence of HLA-DPB1 alleles in Hellenic patients with early- and adult-onset MS (EOMS/AOMS), and possible associations with the HLA-DRB1*15:01 risk allele. Methods: One hundred MS-patients (28 EOMS, 72 AOMS) fulfilling the McDonald-2010 criteria were enrolled. HLA genotyping was performed with standard low-resolution Sequence-Specific Oligonucleotide techniques. Demographics, clinical and laboratory data were statistically processed using well-defined parametric and nonparametric methods and the SPSSv22.0 software. Results: No significant HLA-DPB1 differences were found between EOMS and AOMS patients for 23 distinct HLA-DPB1 and 12 HLA-DRB1 alleles. The HLA-DPB1*03 allele frequency was found to be significantly increased, and the HLA-DPB1*02 allele frequency significantly decreased, in AOMS patients compared to controls. The HLA-DPB1*04 allele was to be found significantly decreased in AOMS and EOMS patients compared to controls. Conclusions: Our study supports the previously reported risk susceptibility role of the HLA-DPB1*03 allele in AOMS among Caucasians. Additionally, we report for the first time a protective role of the HLA-DPB1*04 allele among Hellenic patients with both EOMS and AOMS.

Kognitiv sjukdom är ett globalt hälsoproblem och antalet insjuknade personer kommer medtiden att öka i takt med den åldrande befolkningen. De upplevelser som anhöriga till personermed tidigt debuterande kognitiv sjukdom under 65 år har kan skilja sig från de upplevelsersom anhöriga till personer med debut över 65 års ålder har. Det behövs därför en ökadkunskap inom hälso- och sjukvården samt socialtjänsten om anhörigas behov av stöd ochinformation för att främja hälsa och välbefinnande. Syftet med denna litteraturöversikt var att beskriva anhörigas upplevelse av att leva med ennärstående som diagnostiserats med tidig debuterande kognitiv sjukdom. Metoden somanvändes för att besvara syftet var en strukturerad kvalitativ litteraturöversikt med systematiskmetodologi baserat på kvalitativa artiklar, vilka söktes i två databaser.Resultatet är baserat på 15 artiklar som analyserats genom integrerad analys vilka utmynnadei två huvudkategorier; Upplevelsen av förändrad livssituation och livsvillkor och Vikten avomgivningens stöd. Resultatet diskuterades mot Doris Carnevali omvårdnadsmodell som teoretiskutgångspunkt. Resultatet visar på svårigheterna med att erhålla en diagnos för kognitivsjukdom i ung ålder samt bristen på den kunskap och stöd som de anhöriga behöver för atthantera de livsförändringar som uppstår. Slutsatsen var att anhöriga till personer med kognitiv sjukdom med tidig debut under 65 årsålder mötte flera känslomässiga, praktiska och ekonomiska utmaningar som kunde ha ennegativ inverkan på hälsan. Stödet till anhöriga behöver förbättras inom hälso- och sjukvårdenoch ute i samhället för att minska stigmatiseringen och öka välbefinnandet. Genomsjuksköterskans specialistkompetens inom vård vid kognitiv sjukdom kan individanpassatstöd, kunskap och information ges till anhöriga och närstående, för att underlätta och förbättraderas livssituation och välbefinnande. / Dementia represents a global health challenge, and its incidence is expected to rise with the aging population. The experiences of individuals with early-onset dementia under the age of 65 may differ from those of individuals with onset after the age of 65. Therefore, there is a pressing need for increased awareness within healthcare and social services regarding the caregivers' needs for support and information to promote health and well-being. The aim of this literature review was to elucidate caregivers' experiences of living with a relative diagnosed with early-onset dementia. The method employed to address this aim was a structured qualitative literature review using systematic methodology based on qualitative articles sourced from two databases. The results are derived from the analysis of 15 articles, employing an integrated analysis approach that resulted in two main categories: Experience of altered life situation and conditions and Importance of environmental Support. These findings were discussed in the context of Doris Carnevali's nursing model as a theoretical framework. The results highlight the challenges associated with obtaining a diagnosis of dementia at a young age, as well as the lack of knowledge and support needed by caregivers to manage the life changes that ensue. In conclusion, caregivers of individuals with early-onset dementia under the age of 65 encountered numerous emotional, practical, and economic challenges that could adversely affect their health. Support for caregivers needs to be improved within healthcare and society to reduce stigma and enhance well-being. Through the nurse's specialist competence in care for dementia, individually tailored support, knowledge and information can be given to relatives and close friends to facilitate and improve their living situation and well-being

Background: Neonatal sepsis is one of the most important causes of elevated morbidity and mortality rates in neonatal intensive care units worldwide. While the clinical manifestations of neonatal sepsis tend to be nonspecific, its rapid development and life-threatening potential call for reliable markers for early detection. Methods: We conducted a retrospective single-center study including all neonates suspected of having developed neonatal sepsis from 2013 to 2016. Perinatal and clinical characteristics as well as microbiological and laboratory findings were evaluated. Neonatal sepsis was defined as either culture-proven sepsis (positive blood culture) or clinical sepsis (at least one symptom and elevated C-reactive protein (CRP) concentrations within 72 h with negative blood culture). We further differentiated between early-onset (EOS) and late-onset (LOS) sepsis. Results: Microbiological colonization screening by throat and rectal swabs frequently did not detect the organism that subsequently caused the sepsis. Depending on the age of the newborn with sepsis (EOS or LOS), associations between different anamnestic and clinical factors (prenatal or postnatal ones) were found. In particular, the central–peripheral temperature difference showed a strong association with LOS. Laboratory results useful for the early detection of neonatal sepsis included interleukin-6 (IL-6) and CRP concentrations. Conclusions: Elevated IL-6 >100 ng/L was a strong marker for neonatal sepsis. When choosing the antibiotics for treatment, data from microbiological colonization screening should be considered but not solely relied on. Some indicators of infection also depended on postnatal age.

La sepsis neonatal precoz actualmente es una importante causa de morbilidad y mortalidad en el período neonatal, y su rápido diagnóstico puede ayudar a instaurar un tratamiento antibiótico eficaz. El objetivo de este trabajo es estudiar la relación de diferentes marcadores de sepsis, tanto bioquímicos como hematológicos, en muestras de sangre de cordón procedentes de neonatos; que previamente fueron clasificados en grupos de estudio en función de la presencia o ausencia de factores de riesgo (infeccioso, prematuridad, otras causas, o sepsis neonatal precoz confirmada). Los marcadores bioquímicos de sepsis (PCR, PCT e IL-6) y hematológicos en sangre de cordón no han resultado de utilidad en el diagnóstico de sepsis neonatal precoz, y los datos clínicos continúan siendo los más determinantes. Las nuevas técnicas de biología molecular en sangre de cordón fueron indicativas de la presencia de sospecha de infección en aquellos neonatos con uno o varios factores de riesgo infeccioso. / Early-onset neonatal sepsis is currently a major cause of morbidity and mortality in the neonatal period, and its rapid diagnosis can help to establish an effective antibiotic treatment. The objective of this work is to study the relationship of different markers of sepsis, both biochemical and haematological, in cord blood samples taken from infants; that were previously classified in groups according to the presence or absence of risk factors (infectious, prematurity, other causes, or confirmed early neonatal sepsis). Biochemical markers sepsis (CRP, PCT and IL-6) and haematological in cord blood have not proved useful in the diagnosis of early neonatal sepsis, and clinical data continue to be the most decisive. New techniques of molecular biology in cord blood were indicative of the presence of suspected infection in those neonates with one or several factors of risk of infection.

Neurodegenerative disorders are heterogenous in nature and include a range of ataxias with oculomotor apraxia, which are characterised by a wide variety of neurological and ophthalmological features. This family includes recessive and dominant disorders. A subfamily of autosomal recessive cerebellar ataxias are characterised by defects in the cellular response to DNA damage. These include the well characterised disorders Ataxia-Telangiectasia (A-T) and Ataxia-Telangiectasia Like Disorder (A-TLD) as well as the recently identified diseases Spinocerebellar ataxia with axonal neuropathy Type 1 (SCAN1), Ataxia with Oculomotor Apraxia Type 2 (AOA2), as well as the subject of this thesis, Ataxia with Oculomotor Apraxia Type 1 (AOA1). AOA1 is caused by mutations in the APTX gene, which is located at chromosomal locus 9p13. This gene codes for the 342 amino acid protein Aprataxin. Mutations in APTX cause destabilization of Aprataxin, thus AOA1 is a result of Aprataxin deficiency. Aprataxin has three functional domains, an N-terminal Forkhead Associated (FHA) phosphoprotein interaction domain, a central Histidine Triad (HIT) nucleotide hydrolase domain and a C-terminal C2H2 zinc finger. Aprataxins FHA domain has homology to FHA domain of the DNA repair protein 5’ polynucleotide kinase 3’ phosphatase (PNKP). PNKP interacts with a range of DNA repair proteins via its FHA domain and plays a critical role in processing damaged DNA termini. The presence of this domain with a nucleotide hydrolase domain and a DNA binding motif implicated that Aprataxin may be involved in DNA repair and that AOA1 may be caused by a DNA repair deficit. This was substantiated by the interaction of Aprataxin with proteins involved in the repair of both single and double strand DNA breaks (XRay Cross-Complementing 1, XRCC4 and Poly-ADP Ribose Polymerase-1) and the hypersensitivity of AOA1 patient cell lines to single and double strand break inducing agents. At the commencement of this study little was known about the in vitro and in vivo properties of Aprataxin. Initially this study focused on generation of recombinant Aprataxin proteins to facilitate examination of the in vitro properties of Aprataxin. Using recombinant Aprataxin proteins I found that Aprataxin binds to double stranded DNA. Consistent with a role for Aprataxin as a DNA repair enzyme, this binding is not sequence specific. I also report that the HIT domain of Aprataxin hydrolyses adenosine derivatives and interestingly found that this activity is competitively inhibited by DNA. This provided initial evidence that DNA binds to the HIT domain of Aprataxin. The interaction of DNA with the nucleotide hydrolase domain of Aprataxin provided initial evidence that Aprataxin may be a DNA-processing factor. Following these studies, Aprataxin was found to hydrolyse 5’adenylated DNA, which can be generated by unscheduled ligation at DNA breaks with non-standard termini. I found that cell extracts from AOA1 patients do not have DNA-adenylate hydrolase activity indicating that Aprataxin is the only DNA-adenylate hydrolase in mammalian cells. I further characterised this activity by examining the contribution of the zinc finger and FHA domains to DNA-adenylate hydrolysis by the HIT domain. I found that deletion of the zinc finger ablated the activity of the HIT domain against adenylated DNA, indicating that the zinc finger may be required for the formation of a stable enzyme-substrate complex. Deletion of the FHA domain stimulated DNA-adenylate hydrolysis, which indicated that the activity of the HIT domain may be regulated by the FHA domain. Given that the FHA domain is involved in protein-protein interactions I propose that the activity of Aprataxins HIT domain may be regulated by proteins which interact with its FHA domain. We examined this possibility by measuring the DNA-adenylate hydrolase activity of extracts from cells deficient for the Aprataxin-interacting DNA repair proteins XRCC1 and PARP-1. XRCC1 deficiency did not affect Aprataxin activity but I found that Aprataxin is destabilized in the absence of PARP-1, resulting in a deficiency of DNA-adenylate hydrolase activity in PARP-1 knockout cells. This implies a critical role for PARP-1 in the stabilization of Aprataxin. Conversely I found that PARP-1 is destabilized in the absence of Aprataxin. PARP-1 is a central player in a number of DNA repair mechanisms and this implies that not only do AOA1 cells lack Aprataxin, they may also have defects in PARP-1 dependant cellular functions. Based on this I identified a defect in a PARP-1 dependant DNA repair mechanism in AOA1 cells. Additionally, I identified elevated levels of oxidized DNA in AOA1 cells, which is indicative of a defect in Base Excision Repair (BER). I attribute this to the reduced level of the BER protein Apurinic Endonuclease 1 (APE1) I identified in Aprataxin deficient cells. This study has identified and characterised multiple DNA repair defects in AOA1 cells, indicating that Aprataxin deficiency has far-reaching cellular consequences. Consistent with the literature, I show that Aprataxin is a nuclear protein with nucleoplasmic and nucleolar distribution. Previous studies have shown that Aprataxin interacts with the nucleolar rRNA processing factor nucleolin and that AOA1 cells appear to have a mild defect in rRNA synthesis. Given the nucleolar localization of Aprataxin I examined the protein-protein interactions of Aprataxin and found that Aprataxin interacts with a number of rRNA transcription and processing factors. Based on this and the nucleolar localization of Aprataxin I proposed that Aprataxin may have an alternative role in the nucleolus. I therefore examined the transcriptional activity of Aprataxin deficient cells using nucleotide analogue incorporation. I found that AOA1 cells do not display a defect in basal levels of RNA synthesis, however they display defective transcriptional responses to DNA damage. In summary, this thesis demonstrates that Aprataxin is a DNA repair enzyme responsible for the repair of adenylated DNA termini and that it is required for stabilization of at least two other DNA repair proteins. Thus not only do AOA1 cells have no Aprataxin protein or activity, they have additional deficiencies in PolyADP Ribose Polymerase-1 and Apurinic Endonuclease 1 dependant DNA repair mechanisms. I additionally demonstrate DNA-damage inducible transcriptional defects in AOA1 cells, indicating that Aprataxin deficiency confers a broad range of cellular defects and highlighting the complexity of the cellular response to DNA damage and the multiple defects which result from Aprataxin deficiency. My detailed characterization of the cellular consequences of Aprataxin deficiency provides an important contribution to our understanding of interlinking DNA repair processes.

Text in English / Literature notes an increase in the number of children and adolescents diagnosed with bipolar disorder. Several challenges faced by clinicians who diagnose and treat early-onset bipolar disorder have been discussed with particular emphasis being placed on its pharmacological management. The contributions made by psychologists including psychosocial interventions, have been explored in this regard; however, there still exists a paucity of voices in the field of psychology that discuss the experiences surrounding the management of this disorder. Most studies on early-onset bipolar disorder do not distinguish between childhood and adolescent presentations. Adolescence has been recognized herein, as a distinct developmental and transitional phase and thus, it forms the basis of this inquiry. This qualitative study thus explores clinical psychologists’ experiences ofmanaging adolescents diagnosed with bipolar disorder and will be approached from a social constructionist perspective which was selected as a means of exploring the meanings that individuals attribute to their experiences as they engage with others in their environment. A literature review evaluated the current available literature on juvenile bipolar disorder. Clinical psychologists in private practices were interviewed using semi-structured interviews. The participants were selected using purposive sampling. Two pilot studies were used to pre-test the study. One participant took part in pilot study 1 and one in pilot study 2. Thereafter, four semi-structured interviews were held with four participants who took part in the main study. Themes were drawn from the data and were explored using thematic content analysis. An analysis of the themes revealed several shared experiences in clinical psychologists’ management of juvenile bipolar disorder which were similar to what is reflected in the current available literature on early-onset bipolar disorder. / Psychology / M.A. (Clinical Psychology)

Diagnosis of Alzheimer’s disease is encouraged as a first step towards people planning for their future with the condition. Despite the proposed benefits of diagnosis, it is also widely recognised that Alzheimer’s disease can expose people to stigma. Therefore, this thesis explores the relationship between stigma and future outlook, from the perspective of people affected by early and late-onset Alzheimer’s disease. In order to recognise the physicality of the condition and how psychological and social factors influence experiences, a biopsychosocial perspective is employed throughout. People with Alzheimer’s disease (n=15 people with late-onset, 7 people with early-onset) and their supporters (n=22) completed questionnaires about perceived stigma. This was followed by 14 interviews with a subsample of participants, which explored stigma and future outlook in more depth. Perceived stigma reporting across participants was low in the questionnaires; whereas interviews revealed higher levels of stigma with people discussing mixed, unpredictable reactions from a range of sources. Participants expressed awareness of the unpredictable nature of their futures with the condition. The subsequent lack of control was managed through focusing on ‘one day at a time’ and avoiding looking too far ahead. Across reflections on stigma and future outlook there was a deliberate focus on positive experiences for people affected by early and late-onset Alzheimer’s disease. The similar management of experiences across participants minimised possible age-based differences. These findings are supported by socioemotional selectivity theory, which suggests people are motivated to maintain positive emotional states when facing ‘time-limiting’ conditions irrespective of age. The research suggests people’s experiences of stigma and future outlook interact, with stigma-driven assumptions about the future affecting how people manage their daily lives. The avoidance of looking ahead suggests that policy which encourages future planning should consider its utility and explore ways of helping people to manage both exposure to stigma, and planning for the future, whilst focusing on daily living.