Thesis (doctoral)--Rijksuniversiteit te Groningen. / Bijlage: [2] folded leaves.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1984. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1981. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 103-126).

A carotid atherosclerotic plaque represents a nidus of inflammation mere centimetres below the blood-brain barrier. This inflammation, along with associated regions of microcalcification, are histopathological features of atheroma at risk of rupture (so-called “vulnerable plaques”) that trigger thromboembolic stroke. While conventional clinical imaging simply measures the degree of vessel stenosis, it is a crude measure that reveals little of the metabolic processes affecting plaque vulnerability. Our research demonstrates the utility of positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) and 18F-sodium fluoride (NaF), measuring inflammation and microcalcification respectively, to identify culprit carotid atheroma in vivo, and establish how these processes influence plaque vulnerability. Furthermore, for stroke care it is the downstream thromboembolic effects upon the brain that are key. While proinflammatory conditions may increase the risk of stroke, the relationship between atheroma inflammation and the peri-infarct inflammatory response following a stroke remains poorly defined. Our work demonstrates how inflammatory activity in symptomatic carotid atheroma, measured using PET, influences both chronic small vessel disease and the evolution of lesion volume in the post-stroke period. Using metabolic imaging we can both identify vulnerable atheroma in vivo and demonstrate how these processes affect infarct evolution. We show that whilst inflammation is a generalised process, microcalcification is a focal process that may represent a point of maximum vulnerability. These results also reveal the complexity of the atheroma-brain interaction that may simultaneously trigger events while also influencing stroke evolution in the early recovery period. This has important implications for understanding pathophysiology of both atherosclerosis and stroke evolution, advancing drug-discovery, and potential clinical applications to minimise the impact from this devastating disease.

A preparation is described utilizing a constant flow, right-heart bypass for perfusion of the isolated main pulmonary arteries at controlled pressures. It is demonstrated that stepwise increments of pressure in the pulmonary arteries are accompanied by increases in systemic vascular resistance and in hind-limb vascular resistance. These changes were demonstrated over the whole range of 5-120 cm H₂O pressure in the pulmonary arteries. In contrast there were no significant changes in renal vascular resistance or heart rate. It is .also shown that changing the temperature of the perfusate in the pulmonary artery from 37°C to 30°C is associated with a decrease in systemic vascular resistance. The effects of raising the pulmonary arterial pressure and of cooling the pulmonary artery were abolished by cervical vagotomy. It is suggested that there is a tonic reflex vasoconstrictor tone generated by activity of receptors lying in or close to the walls of the pulmonary artery. It is further suggested that the differential effects on systemic vascular resistance and renal resistance may distribute cardiac output preferentially to the kidney providing one mechanism by which changes in blood volume may lead to appropriate changes in renal solute excretion. The later hypothesis was put to test by collecting urine from the intact kidneys of animals with isolated pulmonary pouch preparation. A step increase in the pouch pressure evoked a corresponding rise in the urinary volume, osmolar clearance, sodium excretion rate, but not the free water clearance and the potassium excretion rate. The response may be caused by renal hemodynamic changes as a result of the reflex increase in systemic arterial pressure. The rise in sodium excretion rate continued even after the release of the pressure in the pulmonary artery pouch thus the role of a natriuretic hormone in the reflex was suspected. A series of animals with one kidney intact and one kidney isolated and perfused with constant pressure was used in attempt to demonstrate the natriuretic action. These results confirmed the hemodynamic effect on the urinary function of the intact kidney. In the isolated kidney there was no statistically significant increase in sodium excretion rate, therefore the role of a natriuretic agent in the reflex response to distension of the pulmonary artery is still uncertain. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

Patients with established coronary artery disease (CAD) remain at elevated risk of major adverse cardiac events (MACE). Specifically, stented coronary artery remains the highest-risk coronary lesion with annualized adverse event rates as high as 8-12% in the following year largely due to in-stent restenosis (ISR) and stent thrombosis. Plasminogen activator inhibitor-1 (PAI-1), an anti-fibrinolytic protein, has previously been associated with CAD with known mechanism of action to regulate the pathophysiological changes associated with in-stent restenosis and stent thrombosis. Moreover, extracellular vesicles (EVs) originating from circulating blood and vascular cells are increasingly being utilized as biomarkers and mediators of vascular disease. We first demonstrate the analytical and biochemical performance of plasma PAI-1 in patients with established CAD. Specifically, PAI-1 performs similarly to established biomarkers including C-reactive protein and NT-proBNP with an analytical (CVa = 4.1%), intra-individual (CVi = 44.0%), and inter-individual (CVg = 118.6%) coefficients of variation. Following this, we demonstrate that plasma PAI-1 is not associated with MACE in one-year follow-up, but reduced levels of PAI-1 remain associated with unplanned revascularization. Subsequently, we sought to evaluate the relationship between PAI-1 and EVs in humans with platelets being a common source of origin. In the largest study of EV to-date in CAD (n=489), we demonstrate the strong predictive ability of PAI-1 platelet-derived EVs (PAI-1+ PEV) with MACE following revascularization. Patients with high circulating levels of PAI-1+ PEV had higher rates of MACE (262.3 vs. 103.0 events per 1,000 person-years; hazard ratio (HR) 2.19; 95% CI, 1.07-4.52; and HR 2.67; 95% CI, 1.22-5.84, discovery and validation cohorts, respectively). Furthermore, we reveal that high PAI-1+ PEV fractions did not enhance thrombogenicity but promoted a pro-inflammatory vascular smooth muscle cell (VSMC) state by enhancing proliferation and migration, through up-regulation of pro-inflammatory genes such as KLF4. Inhibition of the PAI-1-LRP-1 interaction by TM5275 dampened the pro-inflammatory VSMC response, whereas inhibition of the PAI-1-vitronectin interaction by tiplaxtinin had no such effect. Our data reveals the potential of PAI-1+ PEV as a biomarker in the post-revascularization population and postulates the mechanism in an in vitro model of VSMCs. Accordingly, our data demonstrates the potential of PAI-1 PEV as a strong biomarker following revascularization and PAI-1 inhibition by TM5275 is a promising strategy to reduce the pro-inflammatory VSMC state associated with ISR.

No description available.

Vitamin C (ascorbate or Asc) is an essential vitamin for humans. The transport of oxidized ascorbate occurs via Na^+-dependent vitamin C transporters (SVCTI/SVCT2). Ascorbate is a powerful antioxidant that may be beneficial in scavenging the reactive oxygen species associated with cardiovascular diseases. The objectives of this thesis were: to identify the SVCT isoform(s) expressed in pig coronary artery smooth muscle and endothelium, to determine if preloading cultured pig coronary artery smooth muscle cells with ascorbate protects them against oxidative stress, and to overexpress SVCT2 in these cells to see if an increase in ascorbate reserve helps protect the cells even more. Pig coronary artery smooth muscle tissue and cells cultured from the same tissue express SVCT2 and not SVCT1. Cultured pig coronary artery endothelial express SVCT2, however the limited amount of fresh endothelium isolated, restricted us from determining the isoform present in the fresh tissue. Ascorbate preloading (200 (mu)M overnight) did not decrease the damage caused by hydrogen peroxide as measured by oxidation of dichlorodihydrofluorescein diacetate or mitochondrial reductase activity. The mRNA and ^14C-Asc uptake was marginally greater in pig coronary artery smooth muscle cells stably transfected with a linear pcDNA3.1 SVCT2 plasmid than mock transfected controls. The ^14C-Asc uptake was 1.5 times greater than mock transfected cells after 60 min. A new SVCT2 plasmid, that contained SVCT2 coding region only, did not show greater ^14C-Asc accumulation compared to the plasmid that had the entire SVCT2 cDNA in transiently transfected HEK293T cells. This thesis is a beginning towards further study on the molecular and physiological role ascorbate plays in the coronary artery. / Thesis / Master of Science (MS)

Elevated homocysteine (Hcy) concentration has been identified as an independent risk factor for premature CAD. Associations between Hcy concentrations and established cardiovascular risk factors have occasionally, but not consistently, been demonstrated. Plasma fibrinogen and total Hcy concentrations, along with other risk factors, folate and Bvitamin supplements, and medications, were recorded for 40 males (mean age ± SD: 65 ± 9.8 yr) with CAD. Physical activity was assessed using the Modifiable Activity Questionnaire (MAQ), a written questionnaire which appraises leisure and occupational activities by recall for a 12 month period. Univariate analyses revealed those subjects on beta-blocker therapy (n = 12) had lower fibrinogen concentrations than those not on these medications (n = 28) (277.7 ± 16.7 vs. 316.1 ± 10.9 mg/dl , respectively, p = 0.04). A trend existed for those on beta-blockade to also have lower Hcy concentrations (8.3 ± 0.66 vs 9.7 ± 0.43 µmol/L, respectively, p = 0.058). Subjects in the upper tertile of physical activity had significantly lower fibrinogen concentrations than those in the lower tertile (274.7 ± 38 mg/dl vs. 320.2 ± 63, respectively, p = 0.05). Homocysteine concentration was found to be positively associated with age (p = 0.0008). No significant associations were established with multivariate analyses among fibrinogen, Hcy, physical activity, age, BMI, B-vitamin and folate supplements, beta-blocker therapy, total cholesterol, HDL, LDL, triglycerides, and TC/HDL ratio. These results support the hypothesis that hyperhomocysteinemia is an independent risk factor for CAD. Future studies should consider the favorable effects of beta-blockade, which may be a confounding factor, on Hcy and fibrinogen concentrations. Knowledge of associations may contribute toward understanding of the pathogenesis of CAD. / Master of Science

by Ho Wai-chun. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references. / Abstract also in Chinese. / Title / Dedication / Abstract --- p.i / Table of Contents --- p.iv / Glossary of abbreviation used in the thesis --- p.vi / List of figures --- p.viii / List of tables --- p.xvii / Acknowledgement --- p.xix / Statement of Originality --- p.xx / Chapter Chapter 1 ...... --- Introduction --- p.14 / Chapter Chapter 2...... --- Basic Principle / Chapter 2.1 --- The liver - a vital organ --- p.2-1 / Chapter 2.2 --- Blood supply to the liver --- p.2-7 / Chapter 2.3 --- Normal arterial anatomy of the coeliac axis --- p.2-11 / Chapter 2.4 --- Common anomalies of the coeliac axis --- p.2-17 / Chapter 2.5 --- Previous classification of coeliac anomaies --- p.2-24 / Chapter 2.6 --- Knowledge of arterial anomaly in relation to surgery --- p.2-31 / Chapter 2.7 --- Trans-catheter treatment of hepatocellular carcinoma --- p.2-33 / Chapter 2.8 --- Prevalence of hepatocellular carcinoma in H.K Chinese --- p.2-42 / Chapter 2.9 --- Management of hepatocellular carcinoma in Hong Kong --- p.2-43 / Chapter Chapter 3...... --- Definitions --- p.3-1 / Chapter Chapter 4...... --- Objectives of the study --- p.4-1 / Chapter Chapter 5...... --- "Materials, methods and subjects" / Chapter 5.1 --- Materials --- p.5-1 / Chapter 5.2 --- Methods --- p.5-3 / Chapter 5.3 --- Subjects --- p.5-10 / Chapter Chapter 6...... --- Results / Chapter 6.1 --- Coeliac axis --- p.6-5 / Chapter 6.2 --- Common hepatic artery --- p.6-9 / Chapter 6.3 --- Proper hepatic artery --- p.6-11 / Chapter 6.4 --- Right hepatic artery --- p.6-12 / Chapter 6.5 --- Middle hepatic artery --- p.6-20 / Chapter 6.6 --- Left hepatic artery --- p.6-28 / Chapter 6.7 --- Gastroduodenal artery --- p.6-33 / Chapter 6.8 --- Right gastric artery --- p.6-37 / Chapter 6.9 --- Left gastric artery --- p.5-45 / Chapter 6.10 --- Splenic artery --- p.6-49 / Chapter 6.11 --- Summary of results --- p.6-51 / Chapter Chapter 7...... --- Discussion / Chapter 7.1 --- Introduction --- p.74 / Chapter 7.2 --- Selective Internal Radiation --- p.7-3 / Chapter 7.3 --- Coeliac axis --- p.7-10 / Chapter 7.4 --- Common hepatic & proper hepatic artery --- p.7-7 / Chapter 7.5 --- Right hepatic artery --- p.7-14 / Chapter 7.6 --- Middle hepatic artery --- p.7-18 / Chapter 7.7 --- Left hepatic artery --- p.7-25 / Chapter 7.8 --- Gastroduodenal artery --- p.7-30 / Chapter 7.9 --- Right gastric artery --- p.7-35 / Chapter 7.10 --- Left gastric artery --- p.7-43 / Chapter 7.11 --- Splenic artery --- p.7-45 / Chapter 7.12 --- Comparison with the golden classics --- p.7-47 / Chapter 7.13 --- Comparison of subjects with HCC & without HCC --- p.7-50 / Chapter 7.14 --- Comparison of the male group and the female group --- p.7-51 / Chapter Chapter 8...... --- Conclusions / References --- p.B-1 / Bibliography --- p.B-1 / Appendix I Schematic diagram of histological anatomy of the liver --- p.A-l / Appendix II Embryology --- p.A-2 / "Appendix III Percentages of occurrence of the different types of coeliac axis, by Michels' study" --- p.A-3 / "Appendix IV Percentages of occurrence of the different types of the hepatic arterial blood supply, by Michels' study" --- p.A-4 / Appendix V No. of deaths from malignant liver cancer in Hong Kong froml984 to1993 --- p.A-5 / Appendix VI Flow chart for HCC management in PWH of Hong Kong --- p.A-6 / Appendix VII Comparison with Michels' study --- p.A-7 / Appendix VIII Comparison of the group with HCC and the group without HCC --- p.A-8 / Appendix IX Comparison of the male and female group --- p.A-9