From this series of studies, we conclude that microalbuminuria may represent a novel risk factor in SLE, and lupus patients are more susceptible to endothelial dysfunction caused by hyperhomocysteinemia. The use of antimalarial agents is beneficial for lupus patients with active disease on corticosteroid, and antioxidant vitamins are useful in lowering the oxidative stress markers but do not affect the endothelial function. The results highlight the importance of targeting the known modifiable risk factors in order to prevent premature atherosclerosis in SLE patients. / My first step was to elucidate the prevalence and metabolic abnormalities in SLE patients with microalbuminuria. Twenty percent of patients were found to have microalbuminuria, which was associated with higher mean arterial pressure, total plasma antioxidant and homocysteine levels. / Next, we recruited 12 SLE patients and 15 controls and gave them oral methionine loading to achieve acute hyperhomocysteinemia. After oral methionine loading, von Willebrand factor (vWF) levels increased significantly in both groups. The increase in vWF was apparently more pronounced in SLE (20%) compared to controls (8%). Fibrinogen binding to platelets increased significantly only in SLE patients. / Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease of unknown cause which can affect any organs. Studies have reported an increased prevalence of cardiovascular disease (CVD) in these patients. We performed a series of studies to elucidate the interaction between microalbuminuria, dyslipidaemia, hyperhomocysteinemia, oxidative stress and immune dysregulation from the underlying disease in order to understand the accelerated atherosclerotic process in SLE. / We then evaluated the effects of long-term antioxidant vitamins. The plasma malondialdehyde level was significantly decreased after treatment in the vitamin group. Other oxidative stress markers and antioxidant levels and endothelial function remained unchanged in both groups. / We then proceeded to study the relative effect of antimalarial agents on fasting lipid fractions in patients with active SLE. Total cholesterol, very low-density lipoprotein cholesterol, and low density lipoprotein cholesterol levels were significantly lower in patients taking antimalarial agents, particularly for those patients taking concomitant prednisone. In the last study, we demonstrated that hydroxychloroquine had no significant effect on the serum lipid profile in these lupus patients with mild or inactive disease. / Tam Lai Shan. / Adviser: Edmund K. Li. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1550. / Thesis (M.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 178-214). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

Koon Chi Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (leaves 158-174). / Abstracts in English and Chinese. / Acknowledgment --- p.i / Abbreviations --- p.ii / Abstract --- p.v / Chinese Abstract --- p.viii / Table of Content --- p.x / Chapter Chapter one: --- Introduction --- p.1 / Chapter 1.1 --- Introduction --- p.1 / Chapter 1.2 --- Classification of Plant Polysaccharides --- p.2 / Chapter 1.2.1 --- Definition of Dietary Fiber --- p.3 / Chapter 1.2.2 --- Types of Soluble Dietary Fiber --- p.3 / Chapter 1.3 --- Physiological Effect of Fiber --- p.6 / Chapter 1.3.1 --- Reduction in Absorption by Viscous Polysaccharides --- p.7 / Chapter 1.3.2 --- Gastric Emptying --- p.7 / Chapter 1.3.3 --- Effect of Viscous Polysaccharides on Intraluminal Mixing --- p.8 / Chapter 1.3.4 --- Effect of Luminal Secretions on Viscosity --- p.9 / Chapter 1.4 --- Physicochemical Qualities and Hypocholesterolemic Effects --- p.9 / Chapter 1.5 --- Gastrointestinal Events and Hypocholesterolemic Effects --- p.11 / Chapter 1.5.1 --- Mouth --- p.11 / Chapter 1.5.2 --- Stomach --- p.12 / Chapter 1.5.3 --- Small intestine --- p.12 / Chapter 1.5.4 --- Large intestine --- p.13 / Chapter 1.6 --- Proposed Mechanisms for Hypocholesterolemic Effects --- p.13 / Chapter 1.6.1 --- Altered Bile Acid Absorption and Metabolism --- p.14 / Chapter 1.6.2 --- Modified Lipid Absorption and Metabolism --- p.15 / Chapter 1.6.3 --- Effects of SCFA on Lipid Metabolism --- p.15 / Chapter 1.6.4 --- Changed Hormone Concentrations --- p.16 / Chapter Chapter Two: --- Materials and Methods --- p.17 / Chapter 2.1 --- Materials --- p.17 / Chapter 2.1.1 --- Fungus --- p.17 / Chapter 2.1.2 --- Animals --- p.17 / Chapter 2.1.2.1 --- Golden Syrian Hamster --- p.17 / Chapter 2.1.2.2 --- Rabbit --- p.18 / Chapter 2.1.3 --- Characterization of Auricularia Polytricha --- p.18 / Chapter 2.1.4 --- Chromatographic materials --- p.22 / Chapter 2.1.5 --- "Determination of Plasma TC，HDL-C, LDL-C，TG，AST and ALT" --- p.24 / Chapter 2.1.6 --- HMG-CoA Reductase Activity Assay --- p.26 / Chapter 2.1.7 --- "Quantitative Determination of Liver Cholesterol, Acidic and Neutral Sterol" --- p.27 / Chapter 2.1.8 --- Animal Diets --- p.29 / Chapter 2.1.8.1 --- Hamster Diets --- p.29 / Chapter 2.1.8.2 --- Rabbit Diets --- p.29 / Chapter 2.2 --- Methods --- p.33 / Chapter 2.2.1. --- Extraction of Water-Soluble AP Polysaccharide (APP) --- p.33 / Chapter 2.2.2. --- Characterization of Auricularia Polytricha --- p.34 / Chapter 2.2.2.1 --- Determination of carbohydrate content of AP Polysaccharide --- p.34 / Chapter 2.2.2.2 --- Determination of uronic acid content of AP Polysaccharide --- p.34 / Chapter 2.2.2.3 --- Determination of protein content of AP Polysaccharide by BCA protein assay --- p.35 / Chapter 2.2.2.4 --- Determination of component sugar units of AP Polysaccharide --- p.35 / Chapter 2.2.2.5 --- Fractionation of AP Polysaccharide --- p.36 / Chapter 2.2.2.6 --- Determination of monosaccharides of AP Polysaccharide by HPLC --- p.37 / Chapter 2.2.3 --- "Determination of plasma TC, HDL-C, LDL-C,TG,AST and ALT" --- p.39 / Chapter 2.2.3.1 --- Plasma Total Cholesterol --- p.39 / Chapter 2.2.3.2 --- Plasma HDL-Cholesterol --- p.40 / Chapter 2.2.3.3 --- Plasma LDL-Cholesterol --- p.40 / Chapter 2.2.3.4 --- Plasma Triglyceride --- p.41 / Chapter 2.2.3.5 --- Plasma Aspartate Aminotransferase --- p.41 / Chapter 2.2.3.6 --- Plasma Alanine Aminotransferase --- p.42 / Chapter 2.2.4 --- HMG-CoA Reductase Activity Assay --- p.42 / Chapter 2.2.4.1 --- Preparation of Hepatic Microsome --- p.42 / Chapter 2.2.4.2 --- HMG-CoA Activity Assay --- p.43 / Chapter 2.2.5 --- Quantitative Determination of Liver Cholesterol --- p.44 / Chapter 2.2.5.1 --- Cholesterol Extraction and its Silylation --- p.44 / Chapter 2.2.5.2 --- GLC Analysis of TMS-Ether Derivative of Cholesterol --- p.45 / Chapter 2.2.6 --- Quantitative Determination of Neutral and Acidic Sterols --- p.45 / Chapter 2.2.6.1 --- Separation of Neutral and Acidic Sterols --- p.45 / Chapter 2.2.6.2 --- Conversion of Neutral Sterols to its TMS-Ether Derivative --- p.46 / Chapter 2.2.6.3 --- Conversion of Acidic Sterols to its TMS-Ether Derivatives --- p.46 / Chapter 2.2.6.4 --- GLC Analysis of Neutral and Acidic Sterols --- p.47 / Chapter 2.2.7 --- Study of Atherosclerosis of Rabbit --- p.48 / Chapter 2.2.7.1 --- Sudan III staining of the thoracic aorta --- p.48 / Chapter 2.2.7.2 --- Measurement of atheroma formation in the aorta --- p.49 / Chapter 2.2.8 --- Animal Experiments --- p.51 / Chapter 2.2.8.1 --- Protective Effect of APP in Hyperlipidemic Study (Exp. 1) --- p.51 / Chapter 2.2.8.2 --- Therapeutic Effect of APP in Hyperlipidemic Study (Exp. 2) --- p.52 / Chapter 2.2.8.3 --- Dose Response of APP in Hyperlipidemic Study (Exp. 3) --- p.52 / Chapter 2.2.8.4 --- Hypolipidemic Effect of Short Chain Fatty Acid (Exp. 4) --- p.53 / Chapter 2.2.8.5 --- Effect of APP and SCFA on HMG-CoA Reductase Activity (Exp5） --- p.53 / Chapter 2.2.8.6 --- Hypolipidemic and Anti-atherosclerotic Effect of APP (Exp. 6) ´Ø… --- p.54 / Chapter 2.3 --- Statistical analysis --- p.54 / Chapter Chapter Three: --- Fractionation and Characterization of Auricularia Polytricha Polysaccharide --- p.55 / Chapter 3.1 --- Introduction --- p.55 / Chapter 3.2 --- Fungal polysaccharides from Auricularia Polytricha --- p.55 / Chapter 3.3 --- Results --- p.57 / Chapter 3.3.1 --- Extraction and Fractionation of Auricularia Polytricha --- p.57 / Chapter 3.3.2 --- Determination of Carbohydrates Content --- p.58 / Chapter 3.3.3 --- Determination of Protein Content --- p.61 / Chapter 3.3.4 --- Determination of Uronic Acid Content --- p.61 / Chapter 3.3.5 --- Determination of component sugars of AP Polysaccharide --- p.65 / Chapter 3.3.6 --- Fractionation of AP Polysaccharide --- p.67 / Chapter 3.3.7 --- Determination of monosaccharide components of AP Polysaccharide by HPLC --- p.72 / Chapter 3.4 --- Discussion --- p.79 / Chapter Chapter Four: --- "Protective, Therapeutic and Dose Effect of Auricularia Polytricha Polysaccharide (APP) on Hyperlipidemia" --- p.83 / Chapter 4.1 --- Introduction --- p.83 / Chapter 4.2 --- Results (Exp. 1) --- p.86 / Chapter 4.2.1 --- Body Weight and Food Intake --- p.86 / Chapter 4.2.2 --- Effect of APP Supplementation on Hepatic Cholesterol --- p.86 / Chapter 4.2.3 --- "Effect of APP Supplementation on Plasma TC, HDL-C and TG" --- p.87 / Chapter 4.2.4 --- Effect of APP Supplementation on Fecal Output of Neutral Sterols --- p.94 / Chapter 4.2.5 --- Effect of APP Supplementation on Fecal Output of Acidic Sterols --- p.94 / Chapter 4.3 --- Discussion (Exp. 1) --- p.99 / Chapter 4.4 --- Results (Exp. 2) --- p.102 / Chapter 4.4.1 --- Body Weight and Food Intake --- p.102 / Chapter 4.4.2 --- Effect of APP Supplementation on Hepatic Cholesterol --- p.102 / Chapter 4.4.3 --- Effect of APP Supplementation on Plasma TC and TG --- p.103 / Chapter 4.4.4 --- Effect of APP Supplementation on Plasma HDL-C and LDL-C --- p.104 / Chapter 4.5 --- Discussion (Exp. 2) --- p.109 / Chapter 4.6 --- Results (Exp. 3) --- p.111 / Chapter 4.6.1 --- Body Weight and Food Intake --- p.111 / Chapter 4.6.2 --- Dose Response of APP Supplementation on Hepatic Cholesterol --- p.111 / Chapter 4.6.3 --- Dose Response of APP Supplementation on Plasma TG --- p.112 / Chapter 4.6.4 --- Dose Response of APP Supplementation on Plasma HDL-C and LDL-C --- p.112 / Chapter 4.6.5 --- Dose Response of APP Supplementation on ALT and AST Activity --- p.113 / Chapter 4.6.6 --- Dose Response of APP Supplementation on Fecal Output of Neutral and Acidic Sterols --- p.113 / Chapter 4.7 --- Discussion --- p.121 / Chapter Chapter Five: --- Hypolipidemic Effect of Short Chain Fatty Acids --- p.123 / Chapter 5.1 --- "Introduction (Exp. 4,5)" --- p.123 / Chapter 5.2 --- "Results (Exp. 4,5)" --- p.125 / Chapter 5.2.1 --- Body Weight and Food Intake --- p.125 / Chapter 5.2.2 --- Effect of SCFA Supplementation on Hepatic Cholesterol --- p.125 / Chapter 5.2.3 --- "Effect of SCFA Supplementation on Plasma TG, HDL-C and LDL-C" --- p.128 / Chapter 5.2.4 --- Effect of SCFA Supplementation on AST and ALT Activity --- p.128 / Chapter 5.2.5 --- Effect of SCFA supplementation on HMG-CoA Reductase Activity --- p.133 / Chapter 5.3 --- "Discussion (Exp. 4,5)" --- p.135 / Chapter Chapter Six: --- Hypolipidemic and Antiatherosclerotic Effect of APP --- p.137 / Chapter 6.1 --- Introduction (Exp. 6) --- p.137 / Chapter 6.2 --- Results (Exp. 6) --- p.139 / Chapter 6.2.1 --- Body Weight and Food Intake --- p.139 / Chapter 6.2.2 --- Effect of APP Supplementation on Hepatic Cholesterol --- p.139 / Chapter 6.2.3 --- "Effect of APP Supplementation on Plasma TG, HDL- and LDL-C" --- p.141 / Chapter 6.2.3 --- Effect of APP Supplementation on AST and ALT Activity --- p.142 / Chapter 6.2.5 --- Effect of APP supplementation on HMG-CoA Reductase Activity --- p.146 / Chapter 6.2.6 --- Effect of APP supplementation on the Formation of Atheroma --- p.146 / Chapter 6.3 --- Discussion (Exp. 6) --- p.151 / Chapter Chapter Seven: --- General Discussion and Future Perspectives --- p.153 / References --- p.158

Sit Ling. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 135-150). / Abstracts in English and Chinese. / Acknowledgment --- p.i / Abbreviations --- p.ii / Abstract --- p.v / Chinese Abstract --- p.vii / Table of Content --- p.ix / Chapter Chapter one: --- General Introduction --- p.1 / Chapter 1.1 --- Introduction --- p.1 / Chapter 1.2 --- Definition of Dietary Fiber --- p.1 / Chapter 1.3 --- Classification of Dietary Fiber --- p.2 / Chapter 1.4 --- Hypocholesterolemic Effects of Soluble Dietary Fibers --- p.3 / Chapter 1.5 --- Proposed Mechanisms for Hypocholesterolemic Effects --- p.4 / Chapter 1.5.1 --- Alter Eating Pattern --- p.4 / Chapter 1.5.2 --- Delay Gastric Emptying --- p.4 / Chapter 1.5.3 --- Modify Lipid Digestion and Absorption --- p.5 / Chapter 1.5.4 --- Effects of SCFA on Lipid Metabolism --- p.6 / Chapter 1.5.5 --- Enhance Bile Acid Excretion --- p.7 / Chapter 1.6 --- Auricularia polytricha --- p.8 / Chapter Chapter Two: --- Chemical Analysis of Auricularia polytrica --- p.11 / Chapter 2.1 --- Introduction --- p.11 / Chapter 2.2 --- Materials and Methods --- p.12 / Chapter 2.2.1 --- Extraction and Fractionation of Auricularia polytricha --- p.12 / Chapter 2.2.2 --- Determination of Carbohydrate Content --- p.12 / Chapter 2.2.3 --- Determination of Protein Content --- p.13 / Chapter 2.2.4 --- Determination of Uronic Acid Content --- p.13 / Chapter 2.2.5 --- Determination of Molecular Weight by Gel Filtration Chromatography --- p.14 / Chapter 2.2.6 --- Determination of Monosaccharide Components by HPLC --- p.15 / Chapter 2.3 --- Results --- p.18 / Chapter 2.3.1 --- Yield of Auricularia polytricha polysaccharides --- p.18 / Chapter 2.3.2 --- Carbohydrate Content of APPs --- p.18 / Chapter 2.3.3 --- Protein Content of APPs --- p.18 / Chapter 2.3.4 --- Uronic Acid Content of APPs --- p.19 / Chapter 2.3.5 --- Molecular Weight of APPs --- p.22 / Chapter 2.3.6 --- Monosaccharide Components of APPs --- p.27 / Chapter 2.4 --- Discussion --- p.33 / Chapter Chapter Three: --- Hypolipidemic Effects of APPs --- p.36 / Chapter 3.1 --- Introduction --- p.36 / Chapter 3.2 --- Materials and Methods --- p.38 / Chapter 3.2.1 --- Golden Syrian Hamster --- p.38 / Chapter 3.2.2 --- Animal Experiments --- p.40 / Chapter 3.2.2.1 --- Protective Effect and Dose Response of APPs (Exp. 1) --- p.40 / Chapter 3.2.2.2 --- Therapeutic Effect of APPs (High-cholesterol Diet) (Exp. 2) --- p.40 / Chapter 3.2.2.3 --- Therapeutic Effect of APPII (Normal Diet) (Exp. 3) --- p.41 / Chapter 3.2.2.4 --- Effect of APPs on HMG-CoA Reductase and AC AT Activity (Exp. 4) --- p.42 / Chapter 3.2.3 --- Determination of Plasma AST and ALT --- p.42 / Chapter 3.2.4 --- "Determination of Plasma TC, LDL-C, HDL-C and TG" --- p.43 / Chapter 3.2.5 --- Quantitative Determination of Hepatic and Heart Cholesterol --- p.43 / Chapter 3.2.6 --- Quantitative Determination of Perirenal Adipose Tissue Triglyceride --- p.44 / Chapter 3.2.7 --- Statistical analysis --- p.45 / Chapter 3.3 --- Results (Exp. 1) --- p.47 / Chapter 3.3.1 --- Food Intake and Growth --- p.47 / Chapter 3.3.2 --- Effect of APPs on Plasma AST and ALT --- p.47 / Chapter 3.3.3 --- "Effect of APPs on Plasma TC, LDL-C, HDL-C and TG" --- p.53 / Chapter 3.3.4 --- Effect of APPs on Hepatic and Heart Cholesterol --- p.59 / Chapter 3.4 --- Discussion (Exp. 1) --- p.64 / Chapter 3.5 --- Results (Exp. 2) --- p.67 / Chapter 3.5.1 --- Food Intake and Growth --- p.67 / Chapter 3.5.2 --- Effect of APPs on Plasma AST and ALT --- p.67 / Chapter 3.5.3 --- "Effect of APPs on Plasma TC, LDL-C, HDL-C and TG" --- p.67 / Chapter 3.5.4 --- Effect of APPs on Hepatic and Heart Cholesterol --- p.71 / Chapter 3.6 --- Discussion (Exp. 2) --- p.74 / Chapter 3.7 --- Results (Exp. 3) --- p.76 / Chapter 3.7.1 --- Food Intake and Growth --- p.76 / Chapter 3.3.2 --- Effect of APPII on Plasma AST and ALT --- p.76 / Chapter 3.7.3 --- "Effect of APPII on Plasma TC, LDL-C, HDL-C and TG" --- p.76 / Chapter 3.7.4 --- Effect of APPII on Hepatic and Heart Cholesterol --- p.80 / Chapter 3.8 --- Discussion (Exp. 3) --- p.83 / Chapter Chapter Four: --- Influences of APPs on Cholesterol Homeostasis --- p.84 / Chapter 4.1 --- Introduction --- p.84 / Chapter 4.2. --- Materials and Methods --- p.87 / Chapter 4.2.1 --- HMG-CoA Reductase Activity Assay --- p.87 / Chapter 4.2.1.1 --- Preparation of Hepatic Microsome --- p.87 / Chapter 4.2.1.2 --- HMG-CoA Reductase Activity Assay --- p.87 / Chapter 4.2.2 --- ACAT Activity Assay --- p.88 / Chapter 4.2.2.1 --- Preparation of Hepatic and Intestinal Microsome --- p.89 / Chapter 4.2.2.2 --- ACAT Activity Assay --- p.89 / Chapter 4.2.3 --- Quantitative Determination of Neutral and Acidic Sterols --- p.90 / Chapter 4.2.3.1 --- Extraction of Neutral and Acidic Sterols --- p.90 / Chapter 4.2.3.2 --- Conversion of Neutral Sterols to its TMS-Ether Derivative --- p.91 / Chapter 4.2.3.3 --- Conversion of Acidic Sterols to its TMS-Ether Derivatives --- p.91 / Chapter 4.2.3.4 --- GLC Analysis of Neutral and Acidic Sterols --- p.92 / Chapter 4.3 --- Statistic Analysis --- p.93 / Chapter 4.4 --- Results (Exp. 4) --- p.94 / Chapter 4.4.1 --- Effect of APPs on Hepatic HMG-CoA Reductase Activity --- p.94 / Chapter 4.4.2 --- Effect of APPs on Hepatic and Intestinal AC AT Activity --- p.94 / Chapter 4.4.3 --- Effect of APPs on Fecal Excretion (Exp. 1 & 4) --- p.98 / Chapter 4.5 --- Discussion (Exp. 4) --- p.105 / Chapter Chapter Five: --- Hypolipidemic and Antiatherosclerotic Effect of APPII in Rabbit --- p.110 / Chapter 5.1 --- Introduction --- p.110 / Chapter 5.2 --- Materials and Methods --- p.113 / Chapter 5.2.1 --- New Zealant White Rabbit --- p.113 / Chapter 5.2.2 --- Hypolipidemic and Anitatherosclerosis Effect of APPII (Exp. 5) --- p.113 / Chapter 5.2.3 --- Measurement of Atheroma Formation --- p.115 / Chapter 5.3 --- Results (Exp. 5) --- p.117 / Chapter 5.3.1 --- Food Intake and Growth --- p.117 / Chapter 5.3.2 --- Effect of APPII on Plasma AST and ALT --- p.117 / Chapter 5.3.3 --- "Effect of APPII on Plasma TC, LDL-C, HDL-C and TG" --- p.117 / Chapter 5.3.4 --- Effect of APPII on Hepatic and Heart Cholesterol --- p.125 / Chapter 5.3.5 --- Effect of APPII on Perirenal Adipose Tissue Triglycerige Composition --- p.125 / Chapter 5.3.6 --- Effect of APPII on the Formation of Atheroma --- p.125 / Chapter 5.4 --- Discussion (Exp. 5) --- p.130 / Chapter Chapter Six: --- Conclusion --- p.132 / References --- p.135

As the prevalence of atherosclerosis has risen to an alarming level throughout the world, this thesis investigated: (1) the effects of type 2 diabetes mellitus on the risk factors for atherosclerosis and the intima-media thickness (IMT) of the common carotid arteries (a surrogate marker for atherosclerosis), (2) the contribution of various risk factors to the IMT of the common carotid arteries and (3) the interrelationship between the risk factors. / Atherosclerosis is the process by which the inner lining of a large or medium artery is deposited with lipids, cellular waste and other substances. It reduces the vessel's elasticity, lumen size and blood flow. Atherosclerosis is the primary underlying mechanism leading to cardiovascular and cerebrovascular diseases, the second and third leading causes of death in Hong Kong. / Both traditional and emerging risk factors for atherosclerosis were studied: traditional risk factors include age, blood pressure, indices of glycaemia control (fasting glucose, insulin and haemoglobin-Alc), and fasting lipids, while the emerging risk factors include, abdominal fat volume (subcutaneous and visceral), inflammatory markers (interleukin-6 (IL-6), interleukin-8 (IL-8) and high sensitivity c-reactive protein (hsCRP)), adiponectin, stress hormones (24 hr urinary noradrenaline and adrenaline, and plasma cortisol), and occupational stress (measured by a effort-reward imbalance questionnaire). / Starting with 204 subjects recruited from three different studies, data from 84 normoglycaemic subjects, 23 patients with impaired glucose tolerance (IGT) and 77 patients with diabetes mellitus (DM) were included in the analysis. When the IMT of the common carotid arteries and various risk factors were compared between normoglycaemic, IGT and DM subjects: (1) the IMT of the common carotid arteries showed an increasing trend with the worsening of glycaemia control (normal<IGT<DM), (2) increased prevalence of hypertension, dyslipidaemia, and obesity were observed among DM patients, and (3) increased levels of inflammatory markers, reduced concentration of adiponectin (a anti-inflammatory substance), and increased plasma cortisol concentration were also found among DM subjects. As the studies were limited by sample size, only a few risk factors were found significantly related to the carotid IMT. Age was the only common risk factor which was found to be correlated to the IMT of both the normoglycaemic and the DM/IGT subjects. (Abstract shortened by UMI.) / Fok Siu Pong. / "June 2005." / Adviser: Lester A. H. Critchley. / Source: Dissertation Abstracts International, Volume: 67-01, Section: B, page: 0173. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 200-228). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

L’aterosclerosi carotídia és una de les principals causes del ictus isquèmic, el qual és una de les principals causes de mort i morbiditat als països desenvolupats. Avui dia es considera l’aterosclerosi una malaltia multifactorial en la que intervenen des d’un component genètic fins a diferents factors de risc clàssics com la hipertensió, l’edat, la diabetis, etc. Aquests factors de risc clàssics només són capaços d’explicar el 90% dels cassos, de forma que nous factors de risc, encara desconeguts, deuen estar implicats en el inici i progressió de l’arteriosclerosi. S’ha proposat que la infecció per virus o bactèries, com Cytomegalovirus o Herpes simplex virus, pot ser un d’aquests factors. Tanmateix, el microorganisme més estudiat ha estat Chlamydia pneumoniae, ja que es tracta d’una bactèria de vida intracel•lular obligada, capaç de causar estats d’infecció crònics. S’ha realitzat un estudi pilot amb l’objectiu de la determinació de marcadors d’hipòxia, inflamació i angiogènesi en plaques carotídies amb estenosi lleu o moderada (<50%). Posteriorment, s’ha analitzat la relació entre presència d’infecció per C. pneumoniae y aterosclerosi analitzant la presència d’infecció en plaques carotídies de baix a elevat grau, i en sèrum de pacients sotmesos a endarterectomia. Finalment, s’ha realitzat un estudi de genoma complet mitjançant microarrays en cèl•lules endotelials de caròtida humana per tal de determinar les vies de senyalització claus activades per la infecció d’aquestes cèl•lules amb C. pneumoniae i veure quins processos proaterogènics s’activen. S’ha comprovat l’activació de plaques carotídies arterioscleròtiques en estats inicials per la presència de marcadors d’hipòxia, inflamació, angiogènesi i respostes immunes. S’ha detectat presència d’ADN de C. pneumoniae per PCR en lesions carotídies inicials suggerint que C. pneumoniae pot jugar un paper clau en el inici i progressió de la lesió arterioscleròtica. Mitjançant un model in vitro d’infecció de cèl•lules endotelials de caròtida humana hem pogut establir vies metabòliques claus en la propagació d’inflamació, generació de respostes immunes i d’apoptosi. Per tant, suggerim la possible implicació de la infecció per C. pneumoniae en el inici i progressió de l’aterosclerosi carotídia. / ROLE OF CHLAMYDIA PNEUMONIAE IN THE GENERATION OF IMMUNE RESPONSES INVOLVED IN THE CEREBROVASCULAR DISEASE Carotid atherosclerosis is one of the main causes of ischemic brain stroke which is one of the most common causes of death and morbidity in developed countries. Nowadays atherosclerosis is considered a multi-factorial disease in which take part a genetic component and different classic risk factors such as hypertension, age, diabetes, etc. These classic risk factors are only able to explain the 90% of cases, so new risk factors, still unknown, should be involved in initial stages and development of atherosclerosis. Infectious agents, like Cytomegalovirus or Herpes simplex virus, have been related to the development of cardiovascular disease. However, Chlamydia pneumoniae is the most studied microorganism because it is bound intracellular Gram-negative bacterium able to cause chronic infection stages. A pilot study had been performed to identified hypoxia, inflammation and angiogenesis markers in atherosclerotic carotid plaques with low to moderate stenosis (<50%). We investigated the presence of C. pneumoniae infection in different vascular territories related with risk of ischemic stroke and we also identified any differences between early and advanced lesions. Furthermore, we studied the relationship between the presence of C. pneumoniae and over-expression of the HIF-1α in carotid lesions to confirm an association between hypoxic tissue environment and bacterial infection in our specimen. A whole genome microarrays study was performed in human carotid artery endothelial cells infected with C. pneumoniae in order to identified important pathways and proatherogenic processes activated by the infection. There was an activation of initial carotid atherosclerotic plaques due to the presence of hypoxia, inflammation, angiogenesis and immune responses markers. DNA of C. pneumoniae was detected by PCR in early lesions. Using an in vitro human carotid artery endothelial cells infection model we defined important metabolic pathways in inflammation progress, immune responses generation and apoptosis. Therefore, we suggest that C. pneumoniae might play an important role in activation and development of the initial stages of carotid atherosclerosis.

L'arteriosclerosis és un procés caracteritzat per l'engruximent i enduriment dela paret arterial, aquest procés es troba accelerat en pacients amb insuficiència renalcrònica (IRC). A més a més, aquests pacients pateixen una disminució de la síntesisde 1,25-dihidroxivitamina D3 (1,25(OH)2D3) que comporta altres complicacions comel hiperparatïroidisme secundari (HPT2). Per aquesta raó es comú l'ús de 1,25(OH)2D3en el tractament del HPT2. L'efecte de la 1,25(OH)2D3 en la calcificació de les cèl·lulesde múscul llis (CMLV) està força estudiat, però el seu efecte en la proliferació noés molt clar.Vàrem analitzar l'efecte de la 1,25(OH)2D3 en la proliferació de les CMLV perincorporació de BrdU i citometria de flux. Els nostres resultats mostren que la1,25(OH)2D3 indueix la proliferació de manera dosis depenent tant en estat quiescentcom proliferatiu. L'efecte de la 1,25(OH)2D3 en la proliferació es correlaciona ambun increment de l'expressió del factor de creixement de l'endoteli vascular (vascularendothelial growth factor, VEGF). A més a més, inhibint l'activitat d'aquest factors'observa que la proliferació induïda per 1,25(OH)2D3 es troba totalment bloquejada.A partir d'aquests resultats vàrem analitzar la zona promotora del VEGF i vàremdetectar la presència de tres zones amb una seqüència molt semblant als elementsde resposta de la vitamina D (VDRE) presents en els gens diana de la 1,25(OH)2D3.A partir de l'anàlisis per Immunoprecipitació de Cromatina (ChIP) detectem un VDREen el promotor del VEGF on el receptor de la vitamina D (VDR) s'uneix desprésde tractar les CMLV amb 1,25(OH)2D3.Després vàrem plantejar un model diferent per comparar l'efecte de la 1,25(OH)2D3i el 19-nor-1,25(OH)2D2 en el procés de proliferació i de calcificació in vitro, ex vivoi in vivo. Vàrem observar un increment de la proliferació en les CMLV, els anellsd'artèria aorta i en rates amb IRC tractades amb 1,25(OH)2D3, però no en els tractamentsamb 19-nor-1,25(OH)2D2. També vàrem determinar l'efecte que poden tenir aqueststractaments en la pressió arterial i ambdòs tractaments incrementen la tensió arterialsistòlica (TAS) de manera significativa, en canvi la 1,25(OH)2D3 no incrementa ladiastòlica (TAD) de la mateixa manera que el 19-nor-1,25(OH)2D2. La pressió del pols(PP) incrementa significativament en els animals tractats amb 1,25(OH)2D3.vL'arteriosclerosis és un procés caracteritzat per l'engruximent i enduriment dela paret arterial, aquest procés es troba accelerat en pacients amb insuficiència renalcrònica (IRC). A més a més, aquests pacients pateixen una disminució de la síntesisde 1,25-dihidroxivitamina D3 (1,25(OH)2D3) que comporta altres complicacions comel hiperparatïroidisme secundari (HPT2). Per aquesta raó es comú l'ús de 1,25(OH)2D3en el tractament del HPT2. L'efecte de la 1,25(OH)2D3 en la calcificació de les cèl·lulesde múscul llis (CMLV) està força estudiat, però el seu efecte en la proliferació noés molt clar.Vàrem analitzar l'efecte de la 1,25(OH)2D3 en la proliferació de les CMLV perincorporació de BrdU i citometria de flux. Els nostres resultats mostren que la1,25(OH)2D3 indueix la proliferació de manera dosis depenent tant en estat quiescentcom proliferatiu. L'efecte de la 1,25(OH)2D3 en la proliferació es correlaciona ambun increment de l'expressió del factor de creixement de l'endoteli vascular (vascularendothelial growth factor, VEGF). A més a més, inhibint l'activitat d'aquest factors'observa que la proliferació induïda per 1,25(OH)2D3 es troba totalment bloquejada.A partir d'aquests resultats vàrem analitzar la zona promotora del VEGF i vàremdetectar la presència de tres zones amb una seqüència molt semblant als elementsde resposta de la vitamina D (VDRE) presents en els gens diana de la 1,25(OH)2D3.A partir de l'anàlisis per Immunoprecipitació de Cromatina (ChIP) detectem un VDREen el promotor del VEGF on el receptor de la vitamina D (VDR) s'uneix desprésde tractar les CMLV amb 1,25(OH)2D3.Després vàrem plantejar un model diferent per comparar l'efecte de la 1,25(OH)2D3i el 19-nor-1,25(OH)2D2 en el procés de proliferació i de calcificació in vitro, ex vivoi in vivo. Vàrem observar un increment de la proliferació en les CMLV, els anellsd'artèria aorta i en rates amb IRC tractades amb 1,25(OH)2D3, però no en els tractamentsamb 19-nor-1,25(OH)2D2. També vàrem determinar l'efecte que poden tenir aqueststractaments en la pressió arterial i ambdòs tractaments incrementen la tensió arterialsistòlica (TAS) de manera significativa, en canvi la 1,25(OH)2D3 no incrementa ladiastòlica (TAD) de la mateixa manera que el 19-nor-1,25(OH)2D2. La pressió del pols(PP) incrementa significativament en els animals tractats amb 1,25(OH)2D3.Posteriorment, vàrem analitzar les diferències en la calcificació en les ratestractades amb els dos compostos i a l'analitzar el calci i el fosfat del sèrum, observemun increment significatiu de calci en els dos tractaments. Després vàrem estudiarlas àrees calcificades de l'artèria aorta on observem un increment clar en les ratestractades amb 1,25(OH)2D3 que no va ser observat en les rates tractades amb 19-nor-1,25(OH)2D2. També mostrem la ratio de la túnica mitja respecte el lumen ipodem observar un increment significatiu en les rates tractades amb 1,25(OH)2D3.Finalment vàrem analitzar el procés de calcificació in vitro en les CMLV onvàrem observar un clar increment del contingut de calci en aquestes cèl·lules desprésdel tractament amb 1,25(OH)2D3, cosa que no vàrem observar en les cèl·lules tractadesamb 19-nor-1,25(OH)2D2. També vàrem observar un major increment en les cèl·lulestractades amb 1,25(OH)2D3 de l'expressió de RANKL, una citoquina essencial en elprocés d'osteoclastogènesis secretada pels osteoblasts (en el nostre cas probablementper cèl·lules semblants a osteoblasts).Per tant, els nostres resultats suggereixen que la 1,25(OH)2D3 estimula laproliferació mitjançant el factor de creixement VEGF y la calcificació de les CMLV.En canvi, el 19-nor-1,25(OH)2D2 solament presenta un lleu efecte en la proliferació. / La arteriosclerosis es un proceso caracterizado por el engrosamiento yendurecimiento de la pared de las arterias. Este proceso se encuentra acelerado enpacientes con insuficiencia renal crónica (IRC). Además, estos pacientes sufren unadisminución de la síntesis de 1,25-dihidroxivitamina D3 (1,25(OH)2D3) que les conducea otras complicaciones como el hiperparatiroidismo secundario (HPT2). Por estarazón el uso de 1,25(OH)2D3 es común en el tratamiento del HPT2. El efecto de la1,25(OH)2D3 en la calcificación de las células de músculo liso (CMLV) está bastanteestudiado, pero su efecto en la proliferación no está muy claro.Analizamos el efecto de la 1,25(OH)2D3 en la proliferación de las CMLV porincorporación de BrdU y citometría de flujo. Nuestros resultados muestran que la1,25(OH)2D3 induce la proliferación de las CMLV de una manera dosis dependientetanto en estado quiescente como proliferativo. El efecto de la 1,25(OH)2D3 en laproliferación se correlaciona con un incremento de expresión del factor de crecimientodel endotelio vascular (vascular endothelial growth factor, VEGF). Además, al inhibirla actividad de este VEGF observamos que la proliferación inducida por la 1,25(OH)2D3se encuentra totalmente bloqueada.A partir de estos resultados analizamos la zona promotora de VEGF y observamosla presencia de 3 zonas con secuencias muy parecidas a los elementos de respuestade la vitamina D (VDRE) presentes en los genes diana de la 1,25(OH)2D3. A partirdel análisis por Inmunoprecipitación de Cromatina (ChIP) detectamos un VDRE enel promotor del VEGF donde el receptor de la vitamina D (VDR) se une tras eltratamiento con 1,25(OH)2D3.Luego planteamos un modelo distinto para comparar el efecto de la 1,25(OH)2D3y el 19-nor-1,25(OH)2D2 en el proceso de proliferación y de calcificación in vitro,ex vivo e in vivo en un modelo de ratas IRC. Observamos un incremento de laproliferación en las CMLV, los anillos de arteria aorta y en los animales tratados con1,25(OH)2D3 pero no en los tratamientos con 19-nor-1,25(OH)2D2. Tambiéndeterminamos el efecto de ambos tratamientos en la presión arterial y ambostratamientos incrementan la TAS de manera significativa, en cambio la 1,25(OH)2D3no aumenta la TAD de la misma manera que el 19-nor-1,25(OH)2D2. La presión delpulso incrementa significativamente en los animales tratados con 1,25(OH)2D3.Posteriormente, analizamos las diferencias en la calcificación en ratas tratadascon los dos compuestos y al analizar el calcio y fosfato del suero observamos unincremento significativo del calcio en los dos tratamientos. También determinamosla ratio media/lumen donde podemos observar un incremento significativo en lasratas tratadas con 1,25(OH)2D3. A continuación, estudiamos las áreas calcificadasde la arteria aorta y determinamos un claro incremento en las ratas tratadas con1,25(OH)2D3 que no es observado en las tratadas con 19-nor-1,25(OH)2D2.Finalmente, analizamos el proceso de calcificación in vitro en las CMLV yobservamos un incremento claro del contenido de calcio en estas células despuésdel tratamiento con 1,25(OH)2D3 que no fue observado en el tratamiento con 19-nor-1,25(OH)2D2. También observamos un incremento mayor en las células tratadascon 1,25(OH)2D3 de la expresión de RANKL, una citoquina esencial en el procesode osteoclastogénesis, secretada por los osteoblastos (en nuestro caso probablementepor células parecidas a osteoblatos).Por lo tanto, nuestros resultados sugieren que la 1,25(OH)2D3 estimula laproliferación mediante el factor de crecimiento VEGF y la calcificación de las CMLV.En cambio el 19-nor-1,25(OH)2D2v solamente presenta un leve efecto en la calcificación. / Atherosclerosis is a complex process characterized by an increase in the wallthickness due to accumulation of cells and extracellular matrix between theendothelium and the smooth muscle cell wall. This process is accelerated in patientswith chronic renal failure. In these patients, decreased sinthesis of 1,25-DihydroxyvitaminD3 (1,25(OH)2D3) leads to secondary complications, like hyperparathyroidism, beingtreatment with 1,25(OH)2D3 a common practice. The effect of 1,25(OH)2D3 on vascularsmooth muscle cells (VSMC) calcification has been widely studied, but the role of1,25(OH)2D3 on VSMC proliferation remains obscure.We have analyzed the effects of 1,25(OH)2D3 in the proliferation of VSMC. Wefound that 1,25(OH)2D3 induces a dose-dependent increase in VSMC proliferationin quiescent cells and in cells stimulated to grow. The effect of 1,25(OH)2D3 onVSMC proliferation is mediated by an increase of the expression of vascular endothelialgrowth factor (VEGF), since the inhibition of VEGF activity totally blunted the1,25(OH)2D3-induced VSMC proliferation. These results led us to study the promoterzone of VEGF gene. In this sequence we detected three putative sequences resemblingvitamin D response elements (VDRE). Using chromatin immunoprecipitation (ChIP)analysis we determined one VDRE in VEGF promoter that binds to the vitamin Dreceptor (VDR) after treatment with 1,25(OH)2D3.Then, we aimed to study the effect of 1,25(OH)2D3 and 19-nor-1,25-(OH)2D2in VSMC proliferation and calcification in vitro, ex vivo and in vivo in a model ofchronic renal failure (5/6 nephrectomy). We found an increase in proliferation invitro, ex vivo in aortic rings incubated with 1,25(OH)2D3 and in animals treated with1,25(OH)2D3 for 8 weeks. Furthermore, 19-nor-1,25-(OH)2D2 treatment did notincrease VSMC proliferation. We determined the effect of 1,25(OH)2D3 and 19-nor-1,25-(OH)2D2 in blood pressure. Both treatment increased SBP significantly. However19-nor-1,25-(OH)2D2 induced a significant increase in DBP which was not seen inthe 1,25(OH)2D3 treated animals. The pulse pressure increased significantly with1,25(OH)2D3 treatment. Then, we analized calcium and phosphate serum levels inrats and we observed a significant elevation of serum calcium in both treatments.This elevation was not different between 1,25(OH)2D3 and 19-nor-1,25-(OH)2D2. Theratio media/lumen area increased significantly in the 1,25(OH)2D3-treated group.Finally, we studied the calcified areas and we noticed a clear increase of calcificationin rats treated with 1,25(OH)2D3 compared with control and 19-nor-1,25-(OH)2D21,25(OH)2D3 stimulated VSMC proliferation and calcification in vivo. In contrast, 19-nor-1,25-(OH)2D2 had a slight effect in proliferation process with no effect oncalcification, despite the increases in plasma calcium observed in both groups.Finally, we evaluated the calcification proces in VSMC in vitro. Firstly, wedetermined calcium content in VSMC treated with 1,25(OH)2D3 or 19-nor-1,25-(OH)2D2 and we observed an increase of VSMC calcification only in cells treatedwit 1,25(OH)2D3. Moreover, we analized different osteoblastic markers and wedetected that RANKL expression incresased 5 fold in 1,25(OH)2D3 treatment.Therefore, this results suggest that 1,25(OH)2D3 stimulate vascular smooth musclecells through VEGF mediated pathway. 1,25(OH)2D3 stimulate calcification processtoo. Analog of vitamin D, 19-nor-1,25-(OH)2D2 only present slight efect in VSMCcalcification.

Coronary artery disease (CAD) is the most prevalent disorder and the leading cause of death worldwide. There are a number of CAD medications, which are effective and safe in most patients, but have been associated with adverse reactions such as angioedema induced by angiotensin I-converting enzyme inhibitors (AE-ACEi). In this study, we identified aminopeptidase P (APP) activity as an endophenotype for AE-ACEi, which is a heritable quantitative trait (heritability =0.336 +/- 0.251 SD) and is significantly reduced in a majority of our cases. Although initial mutation screening did not reveal any coding variants in XPNPEP2, which encodes membrane-bound APP, subsequent linkage analysis of APP activity in eight families provided a maximum LOD score (3.75) for this locus. Sequencing of additional cases identified a splice variant (314_431del) and a non-coding polymorphism (rs3788853) in this locus, which cosegregate with low plasma APP activity. The latter accounts for the linkage signal and is associated with AE-ACEi (P = 0.036). In addition, we identified other potential loci for APP activity and demonstrated that certain ACEi (Captopril and Enalapril) non-specifically inhibit APP activity. Furthermore, we detected polymorphisms associated with reduced APP and ACE activities among females with estrogen-dependent inherited angioedema. / We also conducted a genetic investigation of depression among CAD patients to identify common susceptibility loci which might explain the correlation between these diseases. Our candidate gene association study identified a polymorphism (rs216873) in the von Willebrand factor gene that was significantly associated (P = 7.4 x 10-5) with elevated depressive symptoms in our CAD cohort. These results suggest that risk factors for atherosclerosis also underlie susceptibility to depression among CAD patients. / This dissertation contributes to the field of genetics and pharmacogenomics of CAD. A better understanding of the toxic effects of CAD drugs will assist in the development of safer and more effective treatments. In addition, our results may facilitate clinical assays to identify individuals who are susceptible to angioedema prior to ACEi or estrogen therapy. Finally, our genetic investigation of depression in CAD patients reveals a novel drug target (VWF) for treatment of depression in cardiac cases.

This study investigates the clinical and major risk factor profiles in Whites, Indians and Blacks with atherosclerotic peripheral vascular disease at the Vascular Service in Durban; and compares them to that for coronary artery disease in the same race groups. The clinical profile for chronic peripheral vascular disease was established in a retrospective study of 2175 patients seen at the Vascular Service during 1981-1986. Atherosclerosis was confirmed in 1974 patients (92,3%) on the basis of clinical, doppler, angiographic and histological evidence. The disease predominantly affected the aorta and distal peripheral vessels. Extracranial cerebrovascular disease occurred less commonly in Blacks than in Whites and Indians. Occlusive disease was the most common pathological type in all race groups. Aneurysmal disease occurred mainly in the aorta with peripheral aneurysms being most common in Blacks. The disease manifested in Blacks at an . earlier age and more aggressively than in Whites and Indians. The risk factor profile for atherosclerotic peripheral vascular disease was established in a prospective study of 302 male patients consisting of 100 Whites, 97 Indians and 105 Blacks on the basis of historical, clinical and haematological data. The sample was randomly selected, and not strictly representative of the clinical pattern in the retrospective study. All patients were confirmed to have atherosclerosis on the basis of the previously mentioned criteria. Smoking was the single most common risk factor in all race groups. Hypertension occurred more commonly in Whites and Indians than in Blacks, while diabetes was commonest in Indians. Insulin resistance did not occur in Blacks, but was possibly present in Whites and Indians. Total cholesterol, LDL cholesterol and triglycerides were raised in Whites and Indians, but not in Blacks. HDL cholesterol was reduced in all 3 race groups. These findings suggest that contrary to the established view, atherosclerotic peripheral vascular disease is an established entity in Blacks seen at the Vascular Service in Durban without a concomitant increase in coronary and extracranial cerebrovascular disease. In Whites and Indians atherosclerosis occurred in all of the vascular beds. This could support the contention that in a socially developing society atherosclerosis affects the aorta and distal peripheral vessels before the coronary vascular bed. Since this occurs in the presence of normal levels of total cholesterol, LDL cholesterol and triglycerides, it does not support the contention that hypercholesterolaemic states are essential for atherosclerotic lesions to develop. On this basis it is postulated that with social transition there is a differential atherosclerotic involvement of the vascular beds due to a differential vascular susceptibility. Smoking is an important socio-environmental risk factor, while at the biochemical level a reduced HDL cholesterol and not a raised total cholesterol, LDL cholesterol or triglyceride could trigger the 'lipid pathway' in atherogenesis. It is further postulated that the differential vascular susceptibility does not exist in a fully developed society once lipid aberrations include a raised total cholesterol, LDL cholesterol and triglycerides. Insulin resistance/hyperinsulinaemia may play a role in the evolution of the disease within the coronary vascular bed. / Thesis (M.D.)-University of Natal, Durban, 1996.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.