The influence of bolus volume and viscosity on the distribution of anterior lingual force during the oral stage of swallowing was investigated using a new force transducer technology. The maximum force amplitudes from five normal adults were measured at anterior, right and left lateral tongue margins during ten volitional swallows of 5-, 10-, and 20-ml volumes of water, applesauce, and pudding. Results indicated significant increases in peak force amplitude as viscosity increased. Volume did not significantly influence maximum lingual force amplitudes. Individual subjects demonstrated consistent patterns of asymmetrical force distribution across the lingual margins tested. The results suggest bolus-specific properties influence the mechanics of oral stage lingual functioning. This finding has important clinical implications in the assessment and treatment of dysphagic individuals. Applications of the force transducer array in future research are addressed.

Two experiments were designed as a preliminary exploration of how stress is used by language-impaired children in the comprehension of spoken language. Response time was measured as subjects decided whether a probe word given immediately after a sentence had been present in the sentence. The results of the first experiment indicated that the probe latency technique was sensitive to the effects of word category (content versus function words) and word position on the response times of children with normal language in the kindergarten, first, third, and sixth grades. In the second experiment, the probe latency task was used to study the effects of stress in relation to word category, word position and sentence meaningfulness in a group of language-impaired children to whom control groups were matched for language ability and chronological age. The response times of the age-matched group were not affected by stress, word category or word position variations. The language-impaired and language matched groups responded to variations in stress and word category, and to sentence meaningfulness in similar ways. Response times to function words were increased significantly by the addition of stress. It was concluded that the absence of sensitivity to stress appears not to be a major causative factor of language impairment.

Secondary amyloidosis was induced in mice with daily consecutive injections of casein or in an accelerated form with the injection of the "Amyloid-Enhancing Factor" (AEF). Innate susceptibility to the disease operated at the level of the production of AEF. AEF activity was purified to one protein component with an apparent molecular weight of 55,100Da. Increased disappearance of the amyloid A (AA) fibril precursor apo-SAA2 did not correlate exactly with amyloid deposition. Multiple splenic macrophage phenotypes and functions were modulated during the two induction protocols. Splenic macrophages from normal or casein-injected mice could not degrade in vitro HDL$ sb3$-SAA2. The catabolism was induced by the exogenous addition of soluble AEF and/or Serum Amyloid P. Finally, AA and amyloid PO proteins were simultaneously deposited in the spleen with respect to time and tissue localization during the two induction protocols. In conclusion, the appearance of AEF in organs during the development of secondary amyloidosis was accompanied by the modulation of the splenic macrophage phenotype and function.

Remediation of phonological awareness (PA) deficits in preschool age children is essential to the prevention of delayed acquisition of reading abilities. The purpose of this research was to develop and assess the efficacy of a program to teach PA to preschool-aged children with delayed PA. Ten preschoolers with articulation disorders participated in 8 training sessions focusing on phonological awareness (PA) and phonemic perception. These children made significant improvements in their PA abilities such that their post-treatment PA test performance was not significantly poorer than that of normally developing children, but was significantly better than that of children with an articulation disorder who did not receive the PA training program. The clinical and theoretical implications of the results are discussed. Future research directions are proposed to confirm these results using an experimental design and to isolate the impact of phonemic perception on PA.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in developed countries. Aggressive research is underway to elucidate putative molecular targets for therapy for both the atrophic and neovascular forms of this disease. Current pharmacotherapy is effective in some patients but not sufficient to halt disease progression or repair damage that has already occurred. Drug intervention and retinal cell replacement represent the two most promising potential treatment avenues. The purpose of this thesis was to investigate the role of a recently identified regulator of neural development, SIRT1, in retinogenesis and to further investigate whether pharmacological inhibition of this protein represents a possible treatment option in neovascular AMD. Via immunohistochemistry and immunocytochemistry we evaluated the expression and subcellular localization of SIRT1 and its innate inhibitor, DBC1, in mouse and human fetal and adult retinas. We further studied SIRT1 in mouse- and human-derived retinal progenitor cells, the former being using in small interfering RNA studies. We found SIRT1 to be widely expressed in developing and adult retinas and to be a regulator of key retinal development genes, namely PAX6, Nestin and CRX. Moreover, we found that photoreceptor precursor cells were among the smallest cells in the heterogeneous population of mouse retinal progenitors. Collectively, these results provide the foundation for manipulating SIRT1 expression in small retinal progenitors as a means of increasing the yield of photoreceptors for transplantation in models of retinal degeneration.We further found SIRT1 to be highly expressed in human-derived choroidal neovascular membranes and sought to pharmacologically inhibit its activity via the drug Nicotinamide. We found Nicotinamide to be a potent regulator of angiogenic and hypoxic signaling in a human retinal pigment epithelial cell line at both the protein level using angiogenesis arrays and at the RNA level using whole genome microarrays. These results point to the SIRT1 inhibitor, Nicotinamide, as a possible agent for treatment of neovascular AMD. Further studies of Nicotinamide are warranted in animal models of AMD. To the best of our knowledge, this is the first time that a detailed analysis of SIRT1 as a regulator of both retinal development and choroidal neovascularization has been reported. / La dégénérescence maculaire liée à l'âge (DMLA) est la principale cause de cécité chez les personnes âgées dans les pays développés. Une recherche dynamique est en cours pour élucider des cibles moléculaires potentiels pour le traitement de la dégénérescence à la fois pour la forme atrophique et la forme néovasculaire de cette maladie. L'actuelle pharmacothérapie est efficace chez certains patients mais pas suffisante pour arrêter la progression de la maladie ou la réparation des dommages qui ont déjà eu lieu. La decouverte de nouveaux medicaments et le remplacement de cellules rétiniennes représentent les deux avenues les plus prometteuses de traitements possibles. Le but de cette thèse est d'étudier le rôle d'un régulateur récemment identifié du développement neuronal, SIRT1, dans le developpement de la retine et de rechercher si l'inhibition pharmacologique de cette protéine représente une option de traitement possible dans la DMLA. Via l'immunohistochimie et l'immunocytochimie, nous avons évalué l'expression et la localisation subcellulaire de SIRT1 et de son inhibiteur inné, DBC1, chez la souris et les humains dans les retines fœtales et adultes. Nous avons également étudié SIRT1 dans les cellules souches de la rétine chez la souris et l'homme. Nous avons trouvé SIRT1 largement exprimé dans la rétine en développement et des adultes et à un régulateur de gènes clés du développement de la rétine, à savoir PAX6, Nestin et CRX. En outre, nous avons constaté que les cellules précurseurs des photorécepteurs ont été parmi les plus petites cellules dans la population hétérogène de cellules progénitrices. Collectivement, ces résultats fournissent la base pour la manipulation de l'expression SIRT1 dans les petits progéniteurs rétiniens comme un moyen d'augmenter le rendement des photorécepteurs à la transplantation dans les modèles de dégénérescence rétinienne. Nous avons en outre constaté que SIRT1 est fortement exprimé dans les membranes néovasculaires humaines et avons cherché à inhiber son activité pharmacologique par le nicotinamide. Nous avons trouvé que Nicotinamide est un puissant régulateur de l'hypoxie et de l'angiogenèse au niveau de la protéine et de l'ARN. Ces résultats indiquent que l'inhibiteur de SIRT1, Nicotinamide est un agent possible pour le traitement de la DMLA néovasculaire. D'autres études de la nicotinamide devraient être poursuivit dans des modèles animaux de la DMLA. Au meilleur de notre connaissance, c'est la première fois qu'une analyse détaillée de SIRT1 l'identifie comme un régulateur du développement tant de la rétine et de la néovascularisation choroïdienne.

Background. Although Detrusor Hyperactivity (DH) with Impaired Contractility (IC) is a common urodynamic finding in elderly subjects, its pathogenesis remains unknown. Human detrusor biopsy studies indicate that subjects with DHIC exhibit ultrastructural evidence of both the dysfunction and degeneration patterns present in isolated DH and IC, respectively. Based on the known cellular effects of estrogen, we proposed a hypothesis that declines in ovarian hormone production could contribute to the pathogenesis of DHIC in elderly women. / Methods. In this thesis project, mature 3--14 month old female F-344 rats were studied 4 months after bilateral ovariectomy (OVx) or sham surgery. Detrusor structure was evaluated at this time point using light and electron microscopy, while classical muscle strip studies were used to measure the impact of OVx on detrusor muscle contractility. In an effort to identify estrogen-regulated proteins in the mammalian detrusor, known candidate proteins were screened using Western blotting, while identification of novel proteins was undertaken through proteomics, with two-dimensional gel protein resolution followed by microsequencing. (Abstract shortened by UMI.)

No description available.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumour. Despite advances in GBM treatment, there is a high frequency of local relapse due to the acquisition of drug resistance. Investigation of glioma cell lines will help us to understand the molecular basis of this hard to treat tumour. In this study, the rat C6 glioma cell line was used as a model alongside two drug selected derivatives (C6-etoposide and C6-irinotecan) to investigate the mechanisms of chemo-resistance in glioma by identifying candidate proteins, genes, and key signalling pathways. Proteomic (2D gel electrophoresis) and genomic (gene array) analyses were performed to determine protein and gene expression changes. Integration of this data with cellular pathway analysis resulted in the prediction that cellular migration and the response to oxidative stress would be distinct in the drug selected C6 cell lines. Cell migration was subsequently assessed using wound scratch repair and transwell migration assays, whilst the response to oxidative stress produced by reactive oxygen species was determined fluorimetrically. The C6 cell line exposed to irinotecan (DNA topoisomerase I inhibitor) showed reduced migration, even under the influence of chemoattractant, compared to other cell lines, consistent with alterations in the expression of collagen genes. The C6 cell line exposed to etoposide (DNA topoisomerase II inhibitor) showed greater resistance to oxidative stress which was proposed to be due to alterations in the signalling pathways downstream of the PTEN/PI3Kinase. Future studies, investigating the effect of PI3Kinase pathway inhibitors are considered and it is proposed that further research into this signalling pathway will be able to uncover the molecular basis of distinct chemo-resistance in this important model cell system for aggressive glioma.

<p> The sequelae of brain injury often result in the need for life-long rehabilitation. Yet, patients in the United States often have limited opportunity to participate in a professional rehabilitation environment following their initial injury. This research investigates whether provision of a health literacy presentation on neuroplasticity and translational rehabilitation principles can contribute to increased internal Locus of Control (LoC) in rehabilitation participants. The researcher provided a 15 minute presentation to participants in two community brain injury groups. Results indicate an increase in the understanding of neuroplastic principles in two of three probes and in internal LoC in four of six probes. Clinical implications are discussed.</p>

Advances in Parkinson's disease research are uncovering a complex pathology that extends well beyond basal ganglia and dopamine-related structures, one that impacts sensory processing and sensorimotor integration as much as it does motor planning and execution, with implications for the functional consequences of the disorder. The current research project is motivated by evidence that perceptual, alongside classical motor deficits, may be ascribed to the clinical presentation of the hypokinetic dysarthria of Parkinson's disease. Three studies were conducted to assess the roles of auditory, somatosensory and sensorimotor integration processes involved in speakers' perception of the volume of their own speech. The combination of loudness magnitude estimation and masking of sensory feedback in the first two studies reveals differences in psychophysical loudness functions that suggest that speech loudness perception deficits in Parkinson's disease are the result of problems with the organization and integration of multi-sensory feedback due to inadequate motor planning. A third, electroencephalographic study supports this conclusion with evidence of atypical cortical event-related potentials among parkinsonian participants, indicating defective preparatory and corrective neural processes otherwise undetectable in the psychophysical experiments. Based on the findings from this series of experiments, the self-perception of speech intensity is attributed to motorically specified parameters of vocal effort. The interpretation of associated sensory feedback is determined by those parameters. The perceptual deficit associated with hypokinetic dysarthria is thus proposed to result directly from deficits in generating speech movements, with concomitant effects on the subsequent identification, organization and interpretation of reafferent information. / Les progrès de la recherche sur la maladie de Parkinson dévoilent une pathologie complexe qui s'étend bien au-delà des ganglions de la base et autres structures dopaminergiques, impacte les processus sensoriels et l'intégration sensorimotrice autant que la planification et l'exécution motrice, avec des implications pour les conséquences fonctionnelles de la maladie. Le projet de recherche actuel est motivé par l'observation que certains troubles perceptuels, parallèles aux troubles moteurs classiques, font partie de la présentation clinique de la dysarthrie hypokinétique de la maladie de Parkinson. Trois études ont été entreprises afin d'évaluer les rôles des processus auditifs, somatosensoriels, et d'intégration sensorimotrice impliqués dans l'auto-perception du volume de la voix. Les analyses d'estimation d'ampleur vocalique et de masquage de la rétroaction sensorielle des deux premières études révèlent des différences dans les fonctions psychophysiques du volume. Les résultats suggèrent que les déficits de la perception parkinsonienne sont une conséquence des problèmes d'organisation et d'intégration de la rétroaction multisensorielle reliée au mouvement. La troisième étude, électro-encéphalographique, renforce cette hypothèse en démontrant la présence de potentiels évoqués corticaux atypiques parmi les participants parkinsoniens qui sont associés à des déficiences dans les processus préparatoires et correctifs par ailleurs indétectables avec les expériences psychophysiques. D'après les résultats de cette série d'expériences, l'auto-perception du volume de la voix est attribuée à des paramètres d'effort vocal spécifiés au niveau moteur. L'interprétation de toute rétroaction sensorielle associée se détermine selon ces paramètres. Le déficit perceptuel lié à la dysarthrie hypokinétique peut ainsi être interprété comme l'effet direct de déficiences dans la génération des mouvements de la parole, agissant par la suite sur l'identification, l'organisation et l'interprétation subséquente des informations ré-afférentes.