Thesis (M. Med. Sc.)--University of Hong Kong, 2005.

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: SHSY, LDH, Ependymin, Alzheimer's. Includes bibliographical references (leaves 34-38 ).

Periodontal disease is a condition in which the gums and bones surrounding the teeth are inflamed. It is a common cause of oral discomfort and tooth loss, but in recent years has been linked to a variety of systemic problems. Among them is cardiovascular disease, which is the top cause of death in the developed world. There is evidence that periodontal pathogens invade the bloodstream from the gingival pockets and contribute to the progression of disease through a variety of different mechanisms. First, they initiate the systemic inflammatory process by invading and activating vascular endothelial cells to upregulate adhesion molecules and chemokines, which then in turn activate macrophages to take up low density lipoprotein and deposit it on the luminal wall. Atherosclerotic plaque is pro-thrombotic, which increases the chances of forming blood clots and ischemic attacks. Periodontal pathogens also can induce the proliferation of antibodies that can cross-react with self-antigens, resulting in an autoimmune disease. The presence of these pathogens also causes oxidative stress through the production of reactive oxygen species, which is highly damaging. Since these pathogens have many ways of contributing to cardiovascular diseases, it has been hypothesized that treating the periodontal problems will help prevent the progression of cardiovascular disease. Several studies show that addressing periodontitis has resulted in decreased levels of inflammatory markers like C-reactive protein, interleukin-6, and fibrinogen, lower incidences of stroke, decreased blood pressure and lipid levels, and a lower left ventricular mass.

INTRODUCTION: Myocardial infarction causes parasympathetic dysfunction in cardiovascular tissue, where central parasympathetic drive decreases but local acetylcholine levels are unchanged. The muscarinic acetylcholine receptor M3 (AChM3R) is shown to have mediating effects in cardiac tissue and vasculature, such as regulation of heart rate and vasodilation of coronary arteries. The objective of this study is to determine the association between AChM3R levels in the heart wall and in the coronary vasculature with self-reported disease states from cadaver donor records. METHODS: Biopsies of the left anterior descending (LAD) artery and the underlying anterior interventricular septum (AIVS) were taken from 14 cadavers. A 5 mm biopsy of the LAD and its underlying AIVS were harvested 2.54-3.81cm from the bifurcation point of the left coronary artery, depending on the tissue integrity of the cadaver specimen. The tissues were immunostained for AChM3R (CHRM3 NB100-58975 at 1:2000) and visualized using a DAB chromogen. Slides were digitally scanned into a virtual image at 20x using the Motic Easyscan (Motic, Inc.). Images were segmented for tunica media and myocardium using Adobe Photoshop CS (Adobe, Inc.). We developed code in Python to calculate the strong positive and positive staining of the tissues. The number of pixels stained was normalized to the tissue area. The donors from which tissue was biopsied were classified into cardiovascular, cerebrovascular, Alzheimer’s disease dementia (AD), or both cerebrovascular and AD disease categories based on self-reported donor declarations. We used SPSS (v27, IBM, Inc.) to run a Pearson correlation to determine the association of staining positivity in the anatomical regions and a MANOVA to determine significant differences in the amount of pixel positivity in the tunica media and myocardium as a function of disease classification. RESULTS: Strong positive and positive staining of the myocardium were not correlated with strong positive in the tunica media. There was a significant positive relationship between strong myocardium staining and positive tunica media staining (r =.727, n=14, p=.003) as well as positive myocardium and positive tunica media staining (r=.674, n=14, p=.008). There was no significant difference between the amount of AChM3R staining and disease classification. CONCLUSIONS: The lack of correlation between strong positive in the myocardium and positive and strong positive in the tunica media suggests that the AChM3R state in the heart wall is independent of changes in the AChM3R of coronary vascular smooth muscle. However, significant correlation between strong positive in the myocardium and positive in the tunica media indicates that changes in AChM3R in the myocardium could be dependent on the presence of a baseline amount of AChM3R in the coronary vascular smooth muscle. Categorization of donor disease states may be too broad to provide statistical significance. Many donors reported co-morbid diseases, which could have affected the influence of cardiovascular disease and dementia on AChM3R modulation. These findings highlight that interventions targeting parasympathetic dysfunction of coronary vasculature may leave the underlying heart wall unaffected. Future studies should consider cardiovascular disease diagnoses to assess AChM3R distribution in the heart wall and coronary vasculature.

Thesis (Ph. D.)--University of Michigan, 1995. / eContent provider-neutral record in process. Description based on print version record.

Cardiovascular disease is the leading cause of death in patients with underlying chronic kidney disease (CKD). Up to one third of patients presenting with an acute coronary syndrome have CKD stage 3-5. Outcomes following acute myocardial infarction in patients with underlying CKD remain poor. CKD patients are routinely excluded from clinical trials in novel cardioprotective strategies resulting in a paucity of prospective data on which to base guidelines for clinical practice. The aims of this work were to: • Establish and characterise two models of chronic uraemia in rodents: the subtotal nephrectomy model and the adenine diet model. • Determine the effects of underlying chronic uraemia on myocardial ischaemia tolerance. • Examine pharmacological cardioprotective strategies in the context of underlying uraemia using a PARP inhibitor • Investigate the cardioprotective effects of ischaemic conditioning in the context of uraemia. Ischaemic preconditioning and postconditioning protocols were used in both uraemic and non-uraemic animals in a model of acute myocardial infarction. • Preliminary work, using standard molecular biological techniques, was carried out in order to confirm the putative survival pathways responsible for the effect of preconditioning. • Investigate the effect of combining early and late remote ischaemic preconditioning to identify whether summation of these strategies could provide additional tissue protection in a model of acute kidney injury. The results demonstrate that both models develop a uraemic phenotype. Subtotal nephrectomy animals exhibit reduced ischaemia tolerance. PARP inhibition as a pharmacological post conditioning agent was shown to be ineffective at conferring tissue protection, whereas both ischaemic preconditioning and postconditioning were effective cytoprotective strategies in both non-uraemic and uraemic animals. Furthermore, additional benefit was seen when early and late remote preconditioning were summated in a rodent model of acute kidney injury. This work provides a basis for future clinical trials in cardioprotection in the context of underlying CKD.

Apathy is characterised by a lack of motivation towards goal directed behaviour and is a symptom of various neurodegenerative diseases. There are various tools that can be used to assess apathy but a caveat of these is that they usually assess it as a unidimensional concept. Apathy has been recognised to have a multidimensional substructure. The Dimensional Apathy Scale is the only comprehensive measure designed to quantify neurobiologically-based subtypes, called Executive, Emotional and Initiation apathy. The first aim of this study was to explore multidimensional apathy, and its associations with demographic variables, in healthy, community dwelling adults. Secondly, multidimensional apathy was explored in neurodegenerative diseases, specifically Amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD). For each disease group, the validity and reliability of both the self rated and carer rated DAS were also determined. Finally, the association between specific apathy subtype impairments and executive dysfunction was explored in ALS patients. Four hundred healthy community dwelling adults, eighty-three ALS patients (seventy-five carers), thirty-four PD patients (thirty carers) and forty-nine AD patients (eighty-nine carers) were recruited for the questionnaire study. In the healthy community dwelling adults, Executive apathy decreased with age, whereas Emotional increased with age. Gender differences were also shown with higher apathy in males on Emotional apathy. There were also employment differences, in that Executive apathy was higher in unemployed individuals compared to those who were employed. Emotional apathy showed difference in type of employment, where full time employed individuals were significantly more apathetic than those employed part time. These findings were taken into account in selecting the appropriate control samples to match our patient groups. In the patient groups, ALS patients were found to be significantly more impaired on the Initiation subscale when compared to controls. Furthermore, Initiation apathy was found to be the most frequent impairment above abnormality cut-off on the carer rated DAS. PD patients were significantly more impaired on Executive and Initiation apathy when compared to controls. These two subscales were most frequently above abnormality cut-off in the carer rated DAS. Finally, AD patients were significantly more impaired on all subscales when compared to controls and, on the carer rated DAS, global impairment over all subscales was most often reported as above abnormality cut-off. Additionally in AD, there was a significant disparity between carer and patient ratings on Executive and Initiation apathy, indicating patients’ impaired awareness. When comparing patient groups, there was a significant difference between carer rated apathy subtype impairments for each patient group. Validity and reliability of the DAS was found to be robust when compared to standard measures of apathy and depression. In the experimental study, a sample of ALS patients (and their carers) and healthy controls (and their informants) were recruited to complete a battery of neuropsychological tests, the DAS, other apathy and depression measures. ALS patients were impaired on tasks of executive functioning when compared to controls. Furthermore, apathy subtype deficits were associated with executive dysfunction in ALS. In conclusion, apathy is a multidimensional concept that manifests in different subtype profiles dependent on neurodegenerative disease. This has further implications for understanding and assessment of cognitive dysfunction and neuropsychiatric symptoms, such as apathy, in ALS and other neurodegenerative disease patient groups.

Stroke is one of the leading causes of mortality and disability worldwide. The majority of stroke patients are elderly. Advanced age, hypertension, diabetes mellitus, atrial fibrillation, smoking and heavy alcohol drinking are the major risk factors. Treatment of modifiable risk factors is an important strategy for primary and secondary stroke prevention. The primary aim of this thesis was to examine stroke risk factor profile, risk factor management and clinical outcomes, as well as their association with ethnicity (defined as English-speaking background ? ESB, and non-English-speaking background - NESB) in a group of elderly patients from a multiethnic background. Stroke risk factor profile and outcomes of stroke were similar between English and non-English-speaking background patients. However, a higher prevalence of diabetes mellitus in the NESB patient group was observed in the study (41% vs. 10% in the ESB patient group) (Chapter 2). In addition, predictive factors and predictive models for stroke outcomes were developed. Advanced age, visual field loss and stroke type were the main predictors for mortality and functional dependency at 12 months post-stroke (Chapter 3). Delirium occurred in one quarter of the elderly patient post-stroke and was also associated with a worse clinical outcome (Chapter 4). Risk factor management may be suboptimal in elderly patients. For example, anticoagulant therapy for stroke prevention in patients with atrial fibrillation was underused, particularly in NESB patients (Chapter 2). The reasons for under-usage of anticoagulant therapy were investigated in a general practitioner survey (Chapter 6). Results showed that NESB, older age, cognitive impairment (especially living alone) were significant potential barriers for anticoagulant prescription by general practitioners. Stroke units have been proven to be a better care model for stroke patients, with shortened hospital length of stay and improved clinical outcomes. Clinical audits from Bankstown Combined (Co-located) Acute and Rehabilitation Stroke Unit and later the newly established Blacktown Combined Co-located Stroke Unit have demonstrated these benefits (Chapter 5). However, further studies need to be performed in order to determine whether a combined co-located stroke unit care model is superior to other stroke unit care models, and if so, the reasons behind this.

Source: Masters Abstracts International, Volume: 47-06, page: 3527. Adviser: Charles E. Begley. Includes bibliographical references.

Two studies of voluntary movement in Parkinson's disease were carried out. In the first study, both parkinsonians and age-matched controls performed unconstrained prehensile movements in which subjects produced reaching and grasping (hand opening/closing) movements under varying conditions of movement amplitude, speed and object size. The act of prehension requires the intersegmental coordination of limb transport and grasp trajectories. Although parkinsonians were slower overall than controls, patients and controls similarly adjusted the spatial and temporal characteristics of their limb movement and grasp in response to changes in task demands. All groups showed increases in the speed of limb transport, the speed of hand opening and began hand opening proportionately earlier at faster movement speeds. All groups similarly increased hand opening velocity and initiated grasp earlier for smaller amplitude movements. Likewise, grasp was initiated earlier when reaching for wider objects. However, in contrast to controls, the onset time of hand opening during limb transport was delayed in these patients and was found to be more closely coupled with the timing of limb transport than in the controls. Moreover, patients showed greater curvature in their motion paths at the wrist during limb transport suggesting that the timing of joint motion (shoulder and elbow) may be different in these patients as well. Underlying differences between the groups in the temporal sequencing of movement are discussed. / In a second study, parkinson and control subjects performed continuous tracking movements in pursuit of sinusoidal and constant-speed target trajectories varying in frequency and amplitude. This task provided explicit temporal and spatial accuracy constraints by requiring subjects to reproduce the precise trajectory (i.e., velocity profile) of target movement. The results show that patients, similar to controls, were capable of modifying peak movement velocity while varying their times to reversal (i.e., movement durations) in response to changes in the movement time requirements of target motion. Indeed, both patients and controls were shown to alter the timing of movement deceleration in order to maintain their movement durations within the temporal limits of target movement. In contrast to controls, patients show progressive reduction in endpoint accuracy (undershooting the target) and, hence, reduced movement amplitudes, over the course of the trial. However, when endpoint accuracy requirements were reduced, by providing mechanical constraints on movement amplitude, patients were able to increase movement amplitudes while satisfying the temporal requirements of the task. These results are interpreted in terms of tradeoffs in performance between competing spatial and temporal demands of pursuit tracking. The significance of movement accuracy constraints on motor function in parkinsonian performance is discussed.