Thesis (Ph. D.)--University OF MICHIGAN.

DISSERTATION (PH.D.)--THE UNIVERSITY OF MICHIGAN

<p> In 2017, 5.5 million Americans were estimated to have Alzheimer&rsquo;s dementia, and it is expected to affect 13.8 million American&rsquo;s by 2050 (Alzheimer&rsquo;s Association, 2017, p. 24). The estimated lifetime risk of Alzheimer&rsquo;s disease at age 45 is 1 in 5 for women, and 1 in 10 for men (Alzheimer&rsquo;s Association, 2017, p. 23). Dementia is one of the costliest medical conditions; related costs are projected to increase from $259 billion annually in 2017 to more than $1.1 trillion in 2050 (in 2017 dollars; Alzheimer&rsquo;s Association, 2017, p. 60). No current pharmacological treatment has the capacity to stop, slow, or reverse neurological damage caused by this fatal disease (Alzheimer&rsquo;s Association, 2017). Nonpharmacological therapies might delay or prevent symptom expression. In the current study, research relevant to reserve, mindfulness meditation, and Alzheimer&rsquo;s disease is examined. Conferring the most up-to-date research by gathering and integrating interdisciplinary data helps to clarify the direction of future research that ultimately could influence the discovery of a successful prevention or treatment for this debilitating disease. An integrated literature review was conducted by searching multiple databases on ProQuest, for articles containing specific key words (Alzheimer, dementia, mindfulness, meditation, &amp; reserve). Reserve is the brains capacity to compensate for pathology, and the literature appears to indicate that mindfulness meditation may play a strong role in the prevention of Alzheimer&rsquo;s disease and in the delay of symptom expression by utilizing underlying neural mechanisms which increase reserve. These underlying mechanisms include increased attention, reduced cortisol production, reduced oxidation, increased emotional regulation, increased brain volume, and improved sleep.</p><p>

This myocardial response to work overload is associated with a complex reprogramming of the expression of cardiac "fetal genes" such as beta-myosin heavy chain (MHC), atrial natriuretic factor (ANF), and brain natriuretic peptide (BNP). The up-regulation of ANF and BNP is viewed as an event related to the antigrowth properties of those peptides. Little is known about factors that underlie this up-regulation in vivo. In the present work, the contribution of chronic hemodynamic overload on ANF and BNP gene expression was determined in No-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, induced hypertension which may develop with or without hypertrophy. The hypothesis states that chronic hemodynamic overload without attendant hypertrophy would not upregulate ANF and BNP gene expression. The studies were carried out in the context provided by other markers of cardiac hypertrophy including beta-MHC, collagen III as well as the parameters associated with cardiac hypertrophy such as LV renin expression, plasma renin activity (PRA) and angiotensin converting enzyme (ACE) activity, given the coincidental activation of this renin-angiotensin system (RAS) and the development of hypertrophy. (Abstract shortened by UMI.)

One hundred and two patients with cases of intermittent claudication (IC) from the vascular surgery clinics of the Ottawa General and Ottawa Civic Hospitals along with 99 control patients from different outpatient clinics of these Hospitals were recruited. For each subject information about the background, medical history, and lifestyle were collected by a face to face interview, using a questionnaire. A number of blood tests, and clinical examinations were also done to complete the information about the exposure, outcome, and the potential risk factors. Serum copper status was obtained through atomic absorption spectrophotometry and PAOD status was assessed by means of Doppler ultrasound. The variable smoking group was shown to be an effect modifier in this data and therefore, the odds ratios for different strata of smoking group were calculated. The association of serum copper and PAOD was statistically significant in ex-smokers with an odds ratio of 2.38 (95% CI: 1.10, 5.15) for a five unit increase of serum copper. In conclusion, smoking and systolic blood pressure were strongly associated with PAOD. The association of serum copper and PAOD, after adjusting for the variable smoking group, systolic blood pressure, and all other study confounders, was reduced to a non-significant level. However, after considering the variable smoking group as an effect modifier, a statistically significant association between serum copper and PAOD was demonstrated in ex-smokers. (Abstract shortened by UMI.)

Human brain tumours have been investigated using proton and phosphorus nuclear magnetic resonance (NMR). The localization technique, chemical shift imaging has been used to obtain phosphorus spectra of tumours in vivo. High resolution proton spectroscopy has been performed on biopsy samples and extracts of human brain tumours. To obtain the localized phosphorus spectra, one dimensional chemical shift imaging with a surface coil was adapted to a 1.5 T Siemens Magnetom imager. The ratios of areas, PDE/ATP and PME/ATP were found to be higher in glioblastomas and astrocytomas than in normal brain. Pi/ATP and PCr/ATP were also high in astrocytomas. The pH of brain tumours ranged from alkaline to neutral, with meningiomas consistently having alkaline pH. A three dimensional localization sequence was written and tested on the Magnetom and used to obtain phosphorus spectra from the brains of normal volunteers. One dimensional $\sp1$H spectra, COSY spectra and T$\sb2$ data were obtained from ex vivo biopsy samples. A parameter, P, was defined as the ratio of the area between 3.4 and 3.1. ppm over the area between 1.5 ppm and 1.1 ppm. The parameter distinguished glioblastomas from astrocytomas and normal brain. This area parameter, P, also appeared to be indicative of malignant potential or biological aggressiveness. Crosspeaks in the ex vivo proton COSY spectra of brain specimens could be used to classify glioblastomas, astrocytomas, metastases to the brain, meningiomas and normal brain in agreement with histopathological diagnosis. The T$\sb2$ values at 1.3 ppm were fitted to a two exponential equation. The longer component could be used to separate clearly glioblastomas from normal brain, normal brain having a much longer long T$\sb2$ component. Astrocytomas formed a continuum of values between glioblastomas and normal brain, with the grade of the astrocytoma roughly correlating with the value of the long T$\sb2$ component. High resolution $\sp1$H spectroscopy of perchloric acid extracts of biopsy samples was performed. The extracts confirmed that lactate, acetate, creatine and choline derivatives, NAA, glutamate, glutamine, alanine, valine and leucine were present in the samples. Comparisons of extract and ex vivo spectra indicated that the 1.3 ppm peak in the ex vivo spectra is predominantly due to the methylene moiety of lipids.

Multiple Sclerosis (MS) is a chronic, autoimmune disease of the central nervous system. MS is believed to be a Th1 inflammatory disease, speculated to be mediated by CD4+ T lymphocytes. The specific contribution of monokines to disease has not been extensively studied in MS. I thus hypothesize that Th1 regulatory monokine levels are elevated in MS patients, and these increased levels correlate to disease severity. This project deals with the quantitation of regulatory monokine mRNA and protein levels in MS patients and their subsequent comparison to healthy control levels. The influence of cytokine-directed immunotherapy, specifically IFN-beta1a and IL-10, on these monokine levels is also addressed. Highly enriched monocytes were isolated and separately cultured for 24 hours in the presence of RPMI media alone, or supplemented with IFN-beta1a or IL-10. Protein and mRNA levels were determined for various monokines by intracellular staining, ELISA, and Riboquant RNase Protection Assay. Increased monokine levels of IL-1, IL-6, IL-12, and TNF-alpha were found to correlate significantly with increased MS disease severity as compared to healthy control levels. IL-10 and IFN-gamma were also detected in MS patient samples, however these levels did not differ significantly from healthy control levels. IL-10 24-hour exposure was found to significantly reduce all elevated MS patient monokine levels. IFN-beta1a showed minimal effects in reducing elevated MS patient monokine levels, and in certain patients boosted their Th1 and proinflammatory monokine levels. These findings suggest a role for monocytes and monokines in the immunopathogenesis of MS, and also indicate further study into IL-10 as a potential MS therapy may be warranted.

Synovial hyperplasia is a hallmark of rheumatoid arthritis (RA). This pathological change may be due to an increase in cell proliferation and/or a decrease in cell death (apoptosis). However, the rates at which these opposing mechanisms occur in the arthritic and control synovium, remain a subject of debate. Our objective was to address this debate using recently developed polyclonal antibodies to thymidylate synthase (TS, another potential cell proliferation marker), and activated caspase 3 and cleaved polyADPribose polymerase (PARP p85), two markers of apoptosis. PCNA and Ki-67, two well characterized proliferation markers were also used in this study. Germinal centers of human tonsil tissue were used as positive controls for proliferation and apoptosis. Another equally important factor in RA is the role of reactive nitrogen and oxygen species (RNOS) such as nitric oxide (NO) and superoxide (O 2-) in inflammation mediated protein damage. Such damage is evidenced by the immunohistochemical detection of nitrotyrosine in a variety of animal models and human inflammatory disorders. Therefore, I studied arthritic joint tissue for the presence of protein nitrotyrosine using immunohistochemical and immunoblotting techniques. (Abstract shortened by UMI.)

Abstract not available.

No description available.