Introduktion: Synen är det viktigaste mediet genom vilket människan uppfattar omgivningen. Degenerativa processer som försämrar synen kan förbindas till ärftligt betingade eller degenerativa processer och mutationsfaktorer eller multifaktoriella degenerativa näthinnesjukdomar: retinitis pigmentosa, glaukom och åldersrelaterad makula degeneration. Forskarna har försökt förhindra utveckling av näthinnedegenerationen genom användning av stam- eller progenitorceller. Under differentiering och självförnyande processer utsöndrar dessa celler olika endogena tillväxtfaktorer: substanser som är aktiva vid cellens mognads- och reparationsprocesser. Att rädda och skydda celler från apoptos eller återskapa nya fotoreceptorer eller nervceller är forskarnas mål. Under de senaste 10 åren har man provat att ersätta förlorad syn med synproteser (biomimetisk utrustning). Syfte: Syftet med den här studien var att jämföra olika typer av terapier och beskrivna forskningsmetoder över stamcellsterapi vid diverse sjukliga tillstånd i ögat. Resultat: Stam- och progenitorceller kan skydda fotoreceptorer och nervceller från apoptos. De kan ha förmildrande effekt vid olika degenerativa tillstånd i ögat. Det finns fortfarande osäkerhet över möjligheten att transplanterade celler kan bilda tumörliknande strukturer. Det krävs mer forskning för att utesluta detta. I samodling med humana neurala progenitorceller (hNPC) var yttre nukleära lagret (ONL) mellan 10 % och 40 % tjockare, antalet fotoreceptorer som har överlevt signifikant större i båda testade grupper än vid kontrollen. Fotoreceptorers dödlighet har minskat med 30 % till över 50 % . Det är enormt svårt att kunna skapa från stamceller neuronceller som t.ex. Amakrina celler, bipolära celler och ganglionceller. Humana embryonala stamceller (hESC) differentierar bättre än vad musembryonala celler gjorde. Med synproteser som baseras på kvarstående näthinnemöjligheter har man kunnat återskapa en del av synen. Diskussion: Terapin med stamceller kan ha förmildrande effekter vid glaukomatösa förluster av ganglionceller. Närvaro av humana neurala progenitorceller (hNPC) minskar signifikant dödlighet hos fotoreceptorer och neuronceller men möjligheterna att återskapa redan förlorade näthinneceller är begränsade. Det finns fortfarande risk att transplanterade celler bildar tumörliknande strukturer i ögat. Plats och utvecklingsfas där transplantat hamnar spelar stor roll vid lyckad behandling. Det krävs mer forskning innan dessa terapier blir klinisk tillåtna.

The establishment of correct neural circuitry in the nervous system requires the interplay, integration, and coordination of a diverse set of cells and signals during development and in the adult. Two important events are the regulated initiation and growth of dendrites that receive and process synaptic information, and the establishment and maintenance of appropriate neural connectivity. The goals of this study are to identify the molecular mechanisms underlying dendrite growth and initiation, and to understand how neural connectivity is maintained in the adult nervous system. I first identified a novel intracellular signal transduction pathway involving two kinases important in regulating dendrite development. I showed that the ILK-GSK3beta pathway is required for dendrite growth and initiation in both peripheral and central nervous system neurons. I then asked how neural connectivity is maintained in the adult nervous system by examining the role of myelin in the intact nervous system. My results indicate that when myelin contacts aberrantly growing axons, it activates on those axons the p75 neurotrophin receptor (p75NTR), which in turn causes the local degeneration of those axons. I further identified the signal transduction pathway required for axon degeneration consisting of p75NTR and intracellular signaling proteins activated by this receptor, Rho-GDI, Rho, and caspase 6. This data establishes p75NTR as an important regulator of neural connectivity and identifies for the first time a degeneration-inducing signal transduction pathway activated by myelin. It also provides an explanation for why myelin inhibits regeneration of injured central nervous system axons. Taken together, I identified a new signaling pathway important for regulating dendrite initiation and growth, and a novel role for myelin in maintaining neural connectivity. Both of these findings contribute to our knowledge of how such connectivity is established during development and maintained in the adult nervous system.

The establishment of correct neural circuitry in the nervous system requires the interplay, integration, and coordination of a diverse set of cells and signals during development and in the adult. Two important events are the regulated initiation and growth of dendrites that receive and process synaptic information, and the establishment and maintenance of appropriate neural connectivity. The goals of this study are to identify the molecular mechanisms underlying dendrite growth and initiation, and to understand how neural connectivity is maintained in the adult nervous system. I first identified a novel intracellular signal transduction pathway involving two kinases important in regulating dendrite development. I showed that the ILK-GSK3beta pathway is required for dendrite growth and initiation in both peripheral and central nervous system neurons. I then asked how neural connectivity is maintained in the adult nervous system by examining the role of myelin in the intact nervous system. My results indicate that when myelin contacts aberrantly growing axons, it activates on those axons the p75 neurotrophin receptor (p75NTR), which in turn causes the local degeneration of those axons. I further identified the signal transduction pathway required for axon degeneration consisting of p75NTR and intracellular signaling proteins activated by this receptor, Rho-GDI, Rho, and caspase 6. This data establishes p75NTR as an important regulator of neural connectivity and identifies for the first time a degeneration-inducing signal transduction pathway activated by myelin. It also provides an explanation for why myelin inhibits regeneration of injured central nervous system axons. Taken together, I identified a new signaling pathway important for regulating dendrite initiation and growth, and a novel role for myelin in maintaining neural connectivity. Both of these findings contribute to our knowledge of how such connectivity is established during development and maintained in the adult nervous system.

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: imaging; phosphorescence; eye; retina. Includes bibliographical references (p. 50-55).

Thesis (Ph. D., Neuroscience)--University of Idaho, October 2009. / Major professor: Deborah L. Stenkamp. Includes bibliographical references. Also available online (PDF file) by subscription or by purchasing the individual file.

Age-related macular degeneration (AMD) causes vision impairment which is not recoverable under existing treatment options. It has been a major leading cause of blindness in the aged population. To ameliorate the self-care ability for AMD patients, educational interventions to mediate negative impacts of the disease on quality of life have become a research interest. Current practice in the proposed Hong Kong setting, Elderly Health Centre A and Elderly Health Centre B, depends on nurses giving general advice which is lack of scientific support and non-specific to AMD. Purpose of this dissertation is to translate the best evidence to practice for improving the care of older adults with AMD in the proposed setting. Evidences showed that self-management education programmes were effective in improving emotional distress and self-efficacy. Electronic searches located 9 relevant RCTs of high level and methodologically strong evidences. Data was extracted into tables of evidence. Data summary and synthesis was presented. Assessment on the implementation potential indicated that the SEP was worth to try in the local setting. Twelve recommendations for the practice guidelines of SEP were presented and a communication process to facilitate the change in a top-down approach was introduced. A pilot study plan in Centre A followed by a main study in Centre A and Centre B was presented. A total of 98 elderly patients with AMD will be recruited as 10 SEP groups. Approximately 1.8 years will be used to finish the main study. Outcomes will be measured at the 6th week follow-up. ‘Emotional distress’ will be measured as primary outcome and ‘self-efficacy’ will be measured as secondary outcome. ‘Client satisfaction’, ‘staff satisfaction’ and the ‘utilization rate of the innovation’ will also be assessed in evaluation. A two-tailed paired (one-sample) t-test will be adopted for analysis, with a 95% confidence interval. The basis for effectiveness for the outcome measurements and basis for adoption of the clinical guidelines were stated. Adoption of the developed guidelines in the local setting will optimistically improve the substantial clinical outcomes for AMD patients, mediating the negative impacts of vision impairment or vision loss on their quality of life. / published_or_final_version / Nursing Studies / Master / Master of Nursing

Development of non-invasive imaging biomarkers sensitive to microstructural organization is crucial for deepening our understanding of mechanisms underlying neurodegenerative processes such as aging and further improving early diagnosis and monitoring of neurodegenerative disease such as Alzheimer’s disease (AD) and amnestic mild cognitive impairment (MCI). The diffusional kurtosis imaging (DKI) is an extension of conventional diffusion tensor imaging. It is hypothesized that DKI will provide complementary information to conventional diffusivity metrics in a new dimension that will more comprehensively capture microstructural changes in anisotropic white matter tracts and particularly in relatively isotropic tissues such as gray matter during neurodegenerative processing of aging, MCI and AD and probably improve the early diagnosis of the diseases. Firstly, DKI method and a white-matter model that provided metrics of explicit neurobiological interpretations were applied on healthy participants. In white matter tracts, age-related degenerations appeared to be broadly driven by axonal loss. Demyelination may also be a major driving mechanism, although confined to the anterior brain. In terms of deep gray matter, higher mean kurtosis (MK) and fractional anisotropy (FA) in the globus pallidus, substantia nigra, and red nucleus reflected higher microstructural complexity and directionality compared with the putamen, caudate nucleus, and thalamus. In particular, unique age-related positive correlations for FA, MK, and radial kurtosis (KR) in the putamen opposite to those in other regions were observed. Secondly, to verify the speculation that iron deposition could be one probable underlying mechanism driving changes in microstructure, another advance MRI technique of quantitative susceptibility mapping (QSM) was also used in healthy participants. Significant age-related increases of iron were observed in the putamen, red nucleus, substantia nigra, and caudate nucleus. Putamen exhibited the highest rate of iron accumulation with aging, which was nearly twice of the rates in substantia nigra and caudate nucleus. Significant positive correlations between susceptibility value and diffusion measurements were observed for FA and MK in the putamen as well as FA in the red nucleus. Thirdly, whether DKI metrics could serve as imaging biomarkers to indicate the severity of cognitive deficiency for AD and MCI was investigated. In AD, significantly increased diffusivity and decreased kurtosis parameters were observed in both white and gray matter of the parietal and occipital lobes as compared to MCI. Significantly decreased FA was also observed in the white matter of these lobes in AD. With the exception of FA and KR, all the other five DKI metrics exhibited significant correlations with mini-mental state examination score in both white and gray matter. Lastly, DKI metrics were compared against volumetry for diagnosis of AD and MCI. In AD vs. aMCI, although no significant difference of either FA or MD was observed in white matter tracts, it is encouraging to note that MK captured loss of microstructural complexity in the superior longitudinal fasciculus and internal capsule. MK in the putamen showed the highest power that outperformed volume of the hippocampus for discriminating AD from normal. Besides, FA in the putamen showed the second highest power for discriminating aMCI from normal. / published_or_final_version / Diagnostic Radiology / Doctoral / Doctor of Philosophy

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