Stress has been shown to exacerbate cell death and cognitive deficits after ischemic injury in rodents, however, little is known of the effects of stress on motor recovery. The objective of this present thesis is to examine the effects of chronic stress on skilled motor recovery after devascularization lesion in rats. It was found that pre-lesion stress induced the most behavioural impairments, while post-lesion stress exacerbated infarct volume. The effects of chronic multiple stress on skilled motor recovery after lesion was also examined. Chronic multiple stress did not modulate skilled motor recovery nor did it have any influence on infarct volume. Additionally, stress had effect on edema after devascularization lesion. The present thesis suggests that the time of exposure to chronic stress in respect to the ischemic lesion, in addition to the type of stress, will differentially affect recovery and compensation in rats. / xii, 122 leaves : ill. ; 29 cm.

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published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Humanities / Doctoral / Doctor of Philosophy

published_or_final_version / Nursing Studies / Master / Master of Nursing

published_or_final_version / Nursing Studies / Master / Master of Nursing

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

Ischemic stroke is a leading cause of death and long-term disability in the world. Although many pathological aspects of mechanisms are considered to be involved in the stroke, accumulating evidences implicated that inflammation accounts for its progression and complications. Tumor necrosis factor-alpha (TNF-α) and nitric oxide are considered as key mediators produced by cells like microglia in the pathogenesis of the disease. Therefore, the development of therapies targeting at the suppression of nitric oxide and TNF-α productions may ameliorate the severity of ischemic stroke. Gastrodia and Uncaria Decoction (GUD) is a traditional herbal decoction that is commonly used in the therapy of post-ischemic stroke in China. Although it shows great efficacy in clinical treatment, few studies have been conducted to investigate the mechanisms of action of GUD. Furthermore, GUD contains a complex mixture of constituents and the effects of these compounds are unknown. In this study, individual herbs from GUD were extracted and the bioactive fractions were further separated using liquid-liquid partition, silica gel chromatography and high performance liquid chromatography (HPLC). The inhibitory effect of the extracts on lipopolysaccharide (LPS)-stimulated nitric oxide production in BV-2 microglial cells was utilized as the biological marker for the screening. After several rounds of purification, a purified bioactive compound was isolated. After spectroscopic analysis by nuclear magnetic resonance and gas chromatography-mass spectrometry, the compound was identified as genipin (1R,4aS,5,7aS-tetrahydro-1-hydroxy-7-(hydroxymethyl)-cyclopenta[c]pyran-4-carboxylic acid, methyl ester). Mechanisms of the suppressive action on signaling pathways were investigated in the LPS-activated BV-2 cells. Our results demonstrated that genipin can dose-dependently inhibit LPS-stimulated nitric oxide overproduction. It can also suppress mRNA levels and protein expressions of inducible nitric oxide synthase (iNOS) and TNF-αupon LPS-induction. In addition, the phosphorylations of phosphoinositide-3 kinase (PI3K) and protein kinase B (Akt) were suppressed. In contrast, the phosphorylations of mitogen-activated protein kinases (MAPKs), nuclear translocation of nuclear factor-κB (NF-κB) p65 and degradation of inhibitory κB-α (IκB-α) were not affected by genipin. Finally, genipin protected murine Neuro-2a neuroblast against neurotoxicity stimulated by the conditioned media transferred from LPS-challenged BV-2 cells. In conclusion, the anti-inflammatory effects of genipin are via the modulation of PI3K/Akt signaling pathway. Genipin and its synthetic analogues may have great potential for developing into new drugs in treating ischemic stroke. In addition, genipin can be used as the chemical marker to standardize the extract of Eucommia ulmoides Oliver as anti-inflammatory agents for treating inflammatory conditions associated with ischemic stroke. / published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

Background: Previous studies that have examined functional status in relation to vascular events have focused on the short term after events and have measured functional status a limited number of times. The trajectories of functional status before and after vascular events are not well characterized, and the factors influencing these trajectories are not well known. Methods: A comprehensive, structured, narrative review was performed on the topic of trajectories of disability and cognition surrounding vascular events. Then using 2 large population-based epidemiologic cohorts, the Northern Manhattan Study (NOMAS) and the Cardiovascular Health Study (CHS), trajectories of functional status were examined. In Analysis A, in NOMAS, the effect of inflammatory biomarkers (interleukin-6 [IL6], tumor necrosis factor receptor-1 [TNFR1], C-reactive protein [CRP], and lipoprotein-associated phospholipase-A2 [LpPLA2]) on the intercept and slope of functional status was determined over a median of 13 years, measured with yearly assessments by the Barthel index. In Analysis B, in NOMAS, a similar modeling strategy was used to examine whether subclinical ischemic disease on brain MRIs, measured by subclinical brain infarct (SBI) and white matter hyperintensity volume (WMHV), was associated with functional trajectories. In Analysis C, in CHS, participants had yearly assessments of disability with a combined activities of daily living (ADL) and instrumental ADL scale. The slope of change in disability was compared before and after vascular events (stroke and myocardial infarction [MI]). Results: In Analysis A, CRP (-0.41 BI points per 1 SD increase, 95% CI -0.82 to 0.002) and LpPLA2 (-0.40, 95% CI -0.75 to -0.04) were associated with baseline BI but not change over time. TNFR1 was associated with baseline BI (-0.93, 95% CI -1.59 to -0.26) and change over time (-0.36 BI points per year, 95% CI -0.69 to -0.03). In Analysis B, functional change was -0.85 BI points per year (95%CI -1.01 to -0.69); among those with SBI there were -0.88 additional points annually (-1.44 to -0.32). In WMHV models, annual functional change was -1.04 points (-1.2 to -0.88), with -0.74 additional points annually per SD WMHV increase (-0.99 to -0.49). In Analysis C, stroke (0.88, 95% CI 0.57-1.20, p<0.0001) was associated with a greater acute increase in disability than MI (0.20, 0.06-0.35, p=0.006). The annual increase in disability before stroke (0.06 points per year, 0.002-0.12, p=0.04) more than tripled after stroke (0.15 additional points per year, 0.004-0.30, p=0.04). The annual increase in disability before MI (0.04 points per year, 0.004-0.08, p=0.03) did not change significantly after MI (0.02 additional points per year, -0.07-0.11, p=0.7). Conclusions: In these large population-based studies with repeated measures of functional status and disability over long-term follow-up, several trajectories were found. In Analysis A, TNFR1 predicted worse overall functional status as well as accelerated decline over time. In Analysis B, both SBI and WMHV were associated with accelerated decline. In Analysis C, there was a steeper decline in function after stroke but not MI. These findings help to elucidate the course and potential etiologies of long-term functional decline related to vascular events, and they suggest directions for future research in this area.

Purpose: In the United States, stroke is the leading cause of disability. The majority of survivors sustain permanent physical and/or cognitive impairments. Stroke survivors with impairments experience depression, loss of functional independence, and poor quality of life (QOL). Stroke disparities exist among different racial and ethnic groups of the US population. Latinos experience a first time stroke at a younger age compared to non-Latino Whites. As a result, Latinos live with impairments for a greater number of years. The vast majority of stroke survivors return to live in their communities. Reintegrating into home and social activities is key to survivors’ perceived QOL. This dissertation project sought to understand from an ecological framework the post-stroke community reintegration experiences of Latino older adults in an urban New York City neighborhood. The study also sought to examine the viewpoints of health and social service providers, whose opinions, actions, and programs can support stroke survivors’ reintegration into community. Methods: Qualitative in-depth interviews were conducted with 30 Latino stroke survivors 50 years of age and older who had experienced a disabling stroke within 36 months. In addition, 20 health and social service providers based in a large medical center, and multiple senior centers in the northern Manhattan section of New York City were interviewed. The stroke survivor data was analyzed using a phenomenological approach. A thematic analysis approach was used to analyze the data from the health and social service informants. Data analysis identified physical, psychological, social, and environmental factors pertinent to stroke survivors’ community integration experiences. These identified factors were categorized into macro-, exo-, meso-, and micro-levels to capture the psycho, social, and environmental ecology in which community reintegration takes place for Latino stroke survivors. Results: Qualitative accounts of survivors revealed several microsystem factors, including a struggle to maintain a positive self-concept and to engage in activities associated with valued identities and roles, while simultaneously suffering chronic pain, fatigue, and functional limitations. Changes in their affect lead survivors to socially isolate themselves. In addition, they relied more on women than men for social support, a salient mesosystem factor. Survivors encountered significant exosystem level barriers in the environment that limited their ability to travel and access activities. For some, these barriers inadvertently left survivors homebound. Survivors also encountered a societal culture, a macrosystem factor, which stigmatized them due to their impairments. Interviews with health and social service professionals revealed various factors that influenced community reintegration of people with stroke. At the macrosystem level, funding for programs and healthcare financing dictated services and eligibility criteria. In the exosystem, a segmented medical model of care postponed the conversation on community integration. Professional practices, organizational level constraints and culture were mesosystem level factors that influenced community reintegration. The confluence of these factors created an ecological system that influenced stroke survivors’ opportunities to socially engage in their home and community life. Conclusion: An ecological approach provides a useful framework to understand the complexity and potential interplay of factors that contribute to community integration post-stroke for Latino older adults in an urban area.