No description available.

No / Starting from the premise that people are essentially narrative beings, I argue that the onset of severe mental illness compromises the narrative enterprise of being able to construct one's Self and one's relationships inmeaningful and coherent ways. This is due to both the curtailment of opportunities for narrative engagement and the dispossession of those whose narratives do not conform to the current conceptualization of narrative and narrativity. In these circumstances, supporting the narrative enterprise is an ethical endeavour that requires that we examine not only which narratives we construct, but also how we construct them. This requires a re-thinking of what might constitute narrative and how we might facilitate or enhance the narrativity of people with severe mental illness. Following this, I suggest four means to support the narrativity of people with severe mental illness: through maintaining narrative continuity, maintaining narrative agency, countering master narratives and attention to small stories.

RNA interference (RNAi) is a post transcriptional gene silencing mechanism that allows potent and specific silencing of cognate mRNA transcripts. Selective silencing can be used to dissect complex polygenic diseases, elucidate the function of known genes and provide a tool for genetic therapy. Its use in the case of dominant inherited disorders including disorders of the central nervous system, depends on its ability to confer single nucleotide discrimination between normal and mutant gene alleles. In this thesis the ability of RNAi effector molecules to provide single nucleotide specificity was examined by targeting two dominant inherited mutations of the acetylcholine receptor that cause slow-channel syndrome. Allele-specific silencing was achieved for one mutation. The other mutation was also silenced but not in an allele specific way despite employing known techniques for increasing single-nucleotide specificity. The model used in this thesis is the congenital myasthenia slow-channel syndrome. This is a dominant inherited disorder of the neuromuscular junction which is both well-characterised and more readily accessible compared to the central nervous system, thus provides a prototype for development of allele-specific RNAi therapeutics. Here we describe a new transgenic animal model of the slow-channel syndrome and show good representation of the human disorder. The need for defining the characteristics that determine the effectiveness and the specificity of RNAi effectors at single-nucleotide level, along with the future uses of the newly described animal model are discussed.

By 2040, the World Health Organization expects neurodegenerative diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease, to surpass cancer as the second most common cause of death worldwide. Currently, only treatments for symptoms of these diseases are available. Thus, research is critical to alleviate this public health burden by elucidating the pathogenic processes and developing novel therapies. While exact mechanisms by which these heterogeneous neuropathological conditions become manifest in patients remain unclear, growing evidence suggests that oxidative stress (OS) makes a significant contribution to neuronal dysfunction and apoptosis in all major neurodegenerative diseases. Recently, the gene oxidation resistance 1 (Oxr1) has emerged as a critical regulator of neuronal survival in response to OS. Oxr1 is expressed throughout the central nervous system, and its highly conserved TLDc domain protects neurons from oxidative damage through an unknown mechanism. This thesis aimed to define mechanisms by which Oxr1 confers neuronal sensitivity to OS, and to determine its role in neurodegenerative diseases. I found that Oxr1 mediates cytoplasmic localization of ALS-associated proteins Fused in Sarcoma (FUS) and transactive response DNA binding protein 43 kDa (TDP-43) through a TLDc domain- and arginine methylation-dependent pathway. Next, I investigated in vivo neuroprotective functions of Oxr1, and demonstrated that neuronal Oxr1 over-expression extends survival and ameliorates behavioural dysfunction and pathology of an ALS mouse model. In particular, neuronal Oxr1 over-expression strikingly delays neuroinflammation during ALS pathogenesis. Finally, I characterised a mouse model that specifically deletes Oxr1 from motor neurons. While loss of Oxr1 in ChAT-positive motor neurons does not cause overt neurodegeneration in the spinal cord, constitutive loss of Oxr1 leads to neuroinflammation in the cerebellum and spinal cord. Taken together, these studies illuminate functions of Oxr1 in the complex antioxidant defence network and present implications for future therapeutic strategies.

Neurodegeneration is a progressive loss of neuron function or structure, including death of neurons, and occurs at many different levels of neuronal circuitry. In this thesis I discuss Parkinson’s Disease (PD), the second most common neurodegenerative disease (NDD). PD is a devastating progressive NDD often with delayed diagnosis due to detection methods that depend on the appearance of visible motor symptoms. By the time cardinal symptoms manifest, 60 to 80 percent or more of the dopamine-producing cells in the substantia nigra are irreversibly lost. Although there is currently no cure, earlier detection would be highly beneficial to manage treatment and track disease progression. However, today’s clinical diagnosis methods are limited to subjective evaluations and observation. Onset, symptoms and progression significantly vary from patient to patient across stages and subtypes that exceed the scope of a standardized diagnosis. The goal of this thesis is to provide the basis of a more general approach to study the brain, investigating early detection method for NDD with focus on PD. It details the preliminary development, testing and validation of tools and methods to objectively quantify and extrapolate motor and non-motor features of PD from behavioral and cognitive output during everyday life. Measures of interest are categorized within three domains: the motor system, cognitive function, and brain activity. This thesis describes the initial development of non-intrusive tools and methods to obtain high-resolution movement and speech data from everyday life and feasibility analysis of facial feature extraction and EEG for future integration. I tested and validated a body sensor system and wavelet analysis to measure complex movements and object interaction in everyday living situations. The sensor system was also tested for differentiating between healthy and impaired movements. Engineering and design criteria of the sensor system were tested for usability during everyday life. Cognitive processing was quantified during everyday living tasks with varying loaded conditions to test methods for measuring cognitive function. Everyday speech was analyzed for motor and non-motor correlations related to the severity of the disease. A neural oscillation detection (NOD) algorithm was tested in pain patients and facial expression was analyzed to measure both motor and non-motor aspects of PD. Results showed that the wearable sensor system can measure complex movements during everyday living tasks and demonstrates sensitivity to detect physiological differences between patients and controls. Preliminary engineering design supports clothing integration and development of a smartphone sensor platform for everyday use. Early results from loaded conditions suggest that attentional processing is most affected by cognitive demands and could be developed as a method to detect cognitive decline. Analysis of speech symptoms demonstrates a need to collect higher resolution spontaneous speech from everyday living to measure speech motor and non-motor speech features such as language content. Facial expression classifiers and the NOD algorithm indicated feasibility for future integration with additional validation in PD patients. Thus this thesis describes the initial development of tools and methods towards a more general approach to detecting PD. Measuring speech and movement during everyday life could provide a link between motor and cognitive domains to characterize the earliest detectable features of PD. The approach represents a departure from the current state of detection methods that use single data entities (e.g.one-off imaging procedures), which cannot be easily integrated with other data streams, are time consuming and economically costly. The long-term vision is to develop a non-invasive system to measure and integrate behavioral and cognitive features enabling early detection and progression tracking of degenerative disease.

Made available in DSpace on 2016-01-26T12:51:47Z (GMT). No. of bitstreams: 1 fernandofilipe_dissert.pdf: 443784 bytes, checksum: bb6328cd8296f1c4b222d0c43cdafda1 (MD5) Previous issue date: 2006-02-13 / Adjacent segment disease is defined as an abnormal process developing in the adjacent level above and/or bellow the arthrodesis of the segment. It is considered a late complication of lumbar spine arthrodesis. It has been very important due to the procedures in the last years. Objective: To evaluate the risk factors associated with the disease at adjacent level as well as its relationship with the natural history of degenerative disease of the lumbar spine. Material and Methods: This was a retrospective study, from January 2000 to December 2002.Thirty-eight patients undergoing arthrodesis in the lumbosacral spine using the pedicle screw fixation participated in the study. Results: These patients had a mean follow-up of 30 months; 10 patients presented adjacent segment disease, 7 disc degeneration, 2 spinal stenosis and one discal spine hernia. The patients´ mean age was 48.5 years; female sex was the majority. Degeneration occurred in 4 patients with stenosis; 4 with spondylolisthesis, and 1 with post disc hernia; all these had been submitted to arthrodesis of lumbosacral spine. The majority was asymptomatic, after being treated by arthrodesis in multiple levels. There was no statistical difference when the above factors were related. Conclusion: Adjacent segment disease is a late complication in the arthrodesis of lumbosacral spine with no relationship of risk factors presented in this study. Therefore, its origin could be related with the natural history of the degenerative disease of lumbar spine. / A doença do nível adjacente é definida como um processo anormal que se desenvolve no nível adjacente, acima e/ou abaixo do segmento artrodesado. Considerada como uma complicação tardia da artrodese da coluna vertebral, tem-se tornado muito importante em decorrência do aumento dos procedimentos nos últimos anos. Objetivo: Avaliar os fatores de risco associados à ocorrência da doença do nível adjacente e sua relação com a história natural da doença degenerativa da coluna vertebral. Material e métodos: Análise retrospectiva de janeiro de 2000 a dezembro de 2002, realizada em 38 pacientes submetidos a artrodese de coluna lombosacra com a utilização de parafuso pedicular. Resultado: Os pacientes analisados apresentavam follow up médio de 30 meses, com a presença de 10 pacientes com doença do nível adjacente; sendo 7 com degeneração discal, 2 com estenose de canal vertebral e 1 com hérnia de disco. A idade média dos pacientes foi 48,5 anos, com predomínio no sexo feminino. A degeneração ocorreu em 4 pacientes com estenose de canal, em 4 pacientes com espondilolistese, em 1 paciente com escoliose e em 1 paciente pós hérnia de disco, os quais tinham sido submetidos a artrodese da coluna lombosacra. A maioria dos pacientes foram submetidos a artrodese em múltiplos níveis e apresentavam-se assintomáticos. Nenhuma diferença estatística foi evidenciada quando relacionados os fatores acima. Conclusão: A doença do nível adjacente é uma complicação tardia existente na artrodese de coluna lombosacra, não relacionada aos fatores de risco apresentados; portanto o seu aparecimento estaria relacionado à história natural da doença degenerativa da coluna lombar.

No description available.

Spinal muscular atrophy (SMA) and Charcot-Marie-Tooth disease type 2D (CMT2D)/distal SMA type V (dSMAV) are two incurable neuromuscular disorders that predominantly manifest during childhood and adolescence. Both conditions are caused by mutations in widely and constitutively expressed genes that encode proteins with essential housekeeping functions, yet display specific lower motor neuron pathology. SMA results from recessive inactivating mutations in the survival motor neuron 1 (SMN1) gene, while CMT2D/dSMAV manifests due to dominant point mutations in the glycyl-tRNA synthetase (GlyRS) gene, GARS. Using a number of different model systems, ranging from Caenorhabditis elegans to the mouse, this thesis aimed to identify potential novel therapeutic compounds for SMA, and to increase our understanding of the mechanisms underlying both diseases. I characterised a novel C. elegans allele, which possesses a point mutation in the worm SMN1 orthologue, smn-1, and showed its potential for large-scale screening by highlighting 4-aminopyridine in a screen for compounds able to improve the mutant motility defect. Previously, the gene encoding three isoforms of chondrolectin (Chodl) was shown to be alternatively spliced in the spinal cord of SMA mice before disease onset. I performed functional analyses of the three isoforms in neuronal cells with experimentally reduced Smn levels, and determined that the dysregulation of Chodl likely reflects a combination of compensatory mechanism and contributor to pathology, rather than mis-splicing. Finally, working with two Gars mutant mice and a new Drosophila model, I have implicated semaphorin-plexin pathways and axonal guidance in the GlyRS toxic gain-of-function disease mechanism of CMT2D/dSMAV.

No description available.

La família és una peça clau en el suport del malalt durant el procés de la malaltia. No obstant això, les conseqüències psicològiques que comporta l'impacte de la malaltia i continus cures, sovint repercuteixen en la seva pròpia salut i per tant en la seva qualitat de vida. Objectiu: El present estudi analitza les principals necessitats del cuidador primari, així com les motivacions per a l'adquisició del rol i el manteniment de la cura. S'han identificat les principals estratègies d'afrontament que empren els cuidadors al llarg del procés de la malaltia per fer front a l'impacte de l'estrès, així com l'anàlisi del vincle afectiu que el cuidador manté amb el malalt. Metodologia: A través d'un estudi qualitatiu de tall transversal es van realitzar 35 entrevistes individuals i 10 grups focals. Es va comptar amb la participació de 26 dones i 9 homes amb una mitjana de 34 anys, tots ells cuidadors primaris de nens i nenes amb càncer albergats en un centre d'atenció que ofereix ajuda a malalts infantils de càncer de l'occident de Mèxic. Resultats: El perfil del cuidador primari correspon, principalment a dones, amb un nivell educatiu mitjà, casades i d'un estrat socioeconòmic baix, que exerceixen el seu rol de cuidadores i de mestresses de casa. La motivació de la cura està associada a sentiments amor, deure i altruisme. La majoria dels cuidadors empraven estratègies d'afrontament centrades en l'emoció i mantenien un vincle de tipus segur amb el malalt. / La familia es una pieza clave en el apoyo del enfermo durante el proceso de la enfermedad. Sin embargo, las consecuencias psicológicas que conlleva el impacto de la enfermedad y continuos cuidados, a menudo repercuten en su propia salud y por ende en su calidad de vida. Objetivo: El presente estudio analiza las principales necesidades del cuidador primario, así como las motivaciones para la adquisición del rol y el mantenimiento del cuidado. Se han identificado las principales estrategias de afrontamiento que emplean los cuidadores a lo largo del proceso de la enfermedad para hacer frente al impacto del estrés, así como el análisis del vínculo afectivo que el cuidador mantiene con el enfermo. Metodología: A través de un estudio cualitativo de corte transversal se realizaron 35 entrevistas individuales y 10 grupos focales. Se contó con la participación de 26 mujeres y 9 hombres con una media de 34 años, todos ellos cuidadores primarios de niños y niñas con cáncer albergados en un centro de atención que brinda ayuda a enfermos infantiles de cáncer del occidente de México. Resultados: El perfil del cuidador primario corresponde, principalmente a mujeres, con un nivel educativo medio, casadas y de un estrato socioeconómico bajo, que ejercen su rol de cuidadoras y de amas de casa. La motivación del cuidado está asociada a sentimientos amor, deber y altruismo. La mayoría de los cuidadores empleaban estrategias de afrontamiento centradas en la emoción y mantenían un vínculo de tipo seguro con el enfermo. / The family is essential in supporting the patient during the disease process. However, the psychological consequences that entails the impact of the disease and ongoing care, often affect their own health and quality of life. Objective: This study analyzes the main needs of primary caregiver, and the reasons for the acquisition and maintenance of the role of care. The study has identified the main coping strategies used by caregivers throughout the disease process to face the impact of stress and the attachment between the caregiver and the patient. Methodology: Through a cross-sectional qualitative study was conducted 35 individual interviews and 10 reflective groups. It was attended by 26 women and 9 men with an average of 34 years, all primary caregivers of children housed in a cancer care center that provides assistance to children of cancer patients in western Mexico. Results: The primary caregiver profile corresponds mainly to women, with an average educational level and a low socioeconomic status who carry out their role as caregivers and homemakers. The motivation of care is associated with feelings love, obligation and altruism. Most caregivers used coping strategies focused on emotion and had a positive and safe attachment with the patient.