Low back syndrome affects 20% of people, and it is estimated that 30% of patients are unable to return to work after surgery. The monitoring of health care outcomes could improve the delivery of health services. The health performance conceptual framework, derived from the Donabedian model, was used to evaluate the functional outcome, clinical recovery, response to surgery, and physician performance of the surgical management of lumbar spine degeneration. A quantitative study (n=685) was undertaken using an administrative database in a repeated-measures design. The clinical and functional outcome improvements were analyzed using t tests. Surgical complexity on health outcome was examined with ANOVA. Predictors of patient satisfaction was explored using Pearson's correlation and regression analyses. The results demonstrated highly significant improvements in functional (mean change 30%; ODI=16.79 -± SD 19.92) and clinical recovery (mean change 50%; modified-JOA=6.983 -± SD 2.613) with surgery at 3 months; a >50% positive response to surgery; and a > 90% patient satisfaction, sustained over a 2 year period. Complexity of surgery did not impact health performance. Strong correlations between the health performance metrics were detected up to 6-months from surgery. Poor clinical recovery and persistent functional disability were predictive of patient dissatisfaction. The social change implications for health policy are that a constellation of health performance metrics could predict the potential for functional and clinical recovery based on presurgery disability while avoiding medical expenditures for procedures with no health benefit; aid in health quality monitoring, peer comparisons, revision of practice guidelines, and cost benefit analysis by payers.

The hypothesis to be tested states that the pathology of Alzheimer's disease (AD) involves elevated levels of oxidative stress, resulting in elevated levels of cellular oxidative defense mechanisms. If the premise is true, than AD pathologically afflicted cells should have a higher demand for glutathione (GSH) as an innate oxidative defense mechanism hence; greater GSH concentrations, increased GSH resynthesis capabilities, and increased levels of cystathionine gamma-lyase (CNase). Alzheimer diseased and age matched control lymphoblast cells, obtained from OHSU's Oregon Brain Aging Study, were cultured, and GSH biochemistry was subsequently evaluated. GSH was depleted by exposing cells to the GSH depleting agent diethylmaleate (DEM) and the resulting GSH concentrations were measured. GSH resynthesis was measured after depleting GSH with DEM, to a level of approximately half base GSH concentration, then removing the depleting agent, resuspending the cells in fresh medium (DEM-free), and subsequently measuring GSH levels. GSH concentrations were measured by HPLC, and all data was normalized to cellular protein concentration. Cellular CNase specific activity levels were measured by adding cytasthionine, the CNase substrate, and then measuring the amount of cysteine produced by means of the DTNB assay. The AD cell lines showed no increase in base levels of GSH as compared to control cell lines. The AD cell lines showed a statistically significant increase in GSH resynthesis capabilities and cystathionine gamma-lyase specific activity levels. These findings add further weight to the AD oxidative stress hypothesis, which is based on the premise that the causative agent of AD pathogenesis is an increase in the level of cellular free radicals produced.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18850号 / 医博第3961号 / 新制||医||1007(附属図書館) / 31801 / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 吉村 長久, 教授 中畑 龍俊 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19561号 / 医博第4068号 / 新制||医||1013(附属図書館) / 32597 / 京都大学大学院医学研究科医学専攻 / (主査)教授 吉村 長久, 教授 戸口田 淳也, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20810号 / 医博第4310号 / 新制||医||1025(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 清水 章, 教授 萩原 正敏, 教授 松原 和夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21002号 / 医博第4348号 / 新制||医||1027(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 大森 孝一, 教授 山田 亮, 教授 Shohab YOUSSEFIAN / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Indiana University-Purdue University Indianapolis (IUPUI) / Huntington disease (HD) is an autosomal dominant disorder characterized by progressive decline of motor, cognitive, and behavioral function. Saccades (rapid, gaze-shifting eye movements) are affected before a clinical diagnosis of HD is certain (i.e. during the premanifest period of the disease). Fundamental questions remain regarding the neural substrates of abnormal saccades and the course of premanifest disease. This work addressed these questions using magnetic resonance imaging (MRI) and a longitudinal study of premanifest disease progression. Gray matter atrophy is a characteristic of HD that can be reliably detected during the premanifest period, but it is not known how such changes influence saccadic behavior. We evaluated antisaccades (AS) and memory guided saccades (MG) in premanifest and manifest HD, then tested for associations between impaired saccadic measures and gray matter atrophy in brain regions involved in these saccadic tasks. The results suggest that slowed vertical AS responses indicate cortical and subcortical atrophy and may be a noninvasive marker of atrophic changes in the brain. We also investigated the brain changes that underlie AS impairment using an event-related AS design with functional MRI (fMRI). We found that, in premanifest and manifest HD, blood oxygenation level dependent (BOLD) response was abnormally absent in the pre-supplementary motor area and dorsal anterior cingulate cortex following incorrect AS responses. These results are the first to suggest that abnormalities in an error-related response network underlie early disease-related saccadic changes, and they emphasize the important influence of regions outside the striatum and frontal cortex in disease manifestations. Though saccadic abnormalities have been repeatedly observed cross sectionally, they have not yet been studied longitudinally in premanifest HD. We found different patterns of decline; for some measures the rate of decline increased as individuals approached onset, while for others the rate was constant throughout the premanifest period. These results establish the effectiveness of saccadic measures in tracking premanifest disease progression, and argue for their use in clinical trials. Together, these studies establish the utility of saccade measures as a marker of HD neurodegeneration and suggest that they would be a valuable component of batteries evaluating the efficacy of neuroprotective therapies.

Indiana University-Purdue University Indianapolis (IUPUI) / Alzheimer’s disease (AD) is a neurological disorder defined by the presence of plaques comprised mostly of amyloid-β (Aβ), and neurofibrillary tangles consisting of hyperphosphorylated microtubule associated protein tau (MAPT). AD is also characterized by widespread synapse loss and degeneration followed by death of neurons in the brain. Inflammatory processes, such as glial activation, are also implicated. In order to study mechanisms of neurodegeneration and evaluate potential therapeutic agents that could slow or reverse this process, a tissue culture system was developed based on primary embryonic cerebrocortical neurons. This culture system was observed to exhibit time-dependent neurodegeneration, glial proliferation, and synaptic marker loss consistent with AD-affected brains. The regulatory promoter regions of several genes implicated in AD, including the Aβ precursor protein (APP), β-amyloid cleaving enzyme (BACE1), and MAPT, were studied in this culture model. The MAPT gene promoter activity followed the pattern of neuronal maturation and degeneration quite closely, increasing in the initial phase of the tissue culture, then reducing markedly during neurodegeneration while APP and BACE1 gene promoters remained active. Deletion series of these promoters were tested to give an initial indication of the active regions of the gene promoter regions. Furthermore, the effects of exogenous Aβ and overexpression of p25, which are two possible pathogenic mechanisms of gene regulation in AD, were studied. Response to Aβ varied between the promoters and by length of the Aβ fragment used. Overexpression of p25 increased MAPT, but not APP or BACE1, promoter activity. This neurodegeneration model was also used to study the putative neuroprotective action of the NMDA receptor antagonist memantine. Treatment with memantine prevented loss of synaptic markers and preserved neuronal morphology, while having no apparent effect on glial activation. The protective action on synaptic markers was also observed with two other structurally distinct NMDA receptor antagonists, suggesting that the effects of memantine are produced by its action on the NMDA receptor. It is concluded that this tissue culture model will be useful for the study of gene regulation and therapeutic agents for neurodegeneration, and that the efficacy of memantine may result from preservation of synaptic connections in the brain.